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ALERT: U.S. Boxed Warning

The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section and/or refer to product labeling for additional detail.

Medication Safety Issues

Sound-alike/look-alike issues:

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

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

Pronunciation

(WAR far in)

U.S. Brand Names

• Coumadin®
• Jantoven™

Index Terms

• Warfarin Sodium

Generic Available

Yes: Tablet

Canadian Brand Names

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

Pharmacologic Category

• Anticoagulant, Coumarin Derivative

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/Investigational

Prevention of recurrent transient ischemic attacks

Restrictions

An FDA-approved medication guide must be distributed when dispensing an outpatient prescription (new or refill) where this medication is to be used without direct supervision of a healthcare provider. Medication guides are available at http://www.fda.gov/cder/Offices/ODS/medication_guides.htm.

Pregnancy Risk Factor

X

Pregnancy Considerations

Oral anticoagulants cross the placenta and produce fetal abnormalities. May also cause fatal fetal hemorrhage. Warfarin should not be used during pregnancy because of significant risks. Adjusted-dose heparin can be given safely throughout pregnancy in patients with venous thromboembolism.

Lactation

Does not enter breast milk, only metabolites are excreted (AAP rates “compatible”)

Breast-Feeding Considerations

Warfarin does not pass into breast milk and can be given to nursing mothers (AAP rates “compatible”). However, limited data suggests prolonged PT may occur in some infants. Women who are breast-feeding should be carefully monitored to avoid excessive anticoagulation. Evaluation of coagulation tests and vitamin K status of breast-feeding infant is considered prudent.

Contraindications

Hypersensitivity to warfarin or any component of the formulation; hemorrhagic tendencies (eg, patients bleeding from the GI, respiratory, or GU tract; aneurysm; cerebrovascular hemorrhage; following 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 surgery resulting in large, open surfaces; blood dyscrasias; severe uncontrolled or malignant hypertension; pericarditis or pericardial effusion; subacute bacterial endocarditis; history of warfarin-induced necrosis; an unreliable, noncompliant patient; 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/Precautions

Boxed warnings:

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

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.

• “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.

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 of ovulation.

• 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.

• 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 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: 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 long-term use), paralysis, paresthesia, weakness

Respiratory: Dyspnea, tracheobronchial calcification

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

Metabolism/Transport Effects

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

Drug Interactions

Acetaminophen: May enhance the anticoagulant effect of Coumarin Derivatives. Most likely with daily acetaminophen doses >1.3 g for >1 week. Risk C: Monitor therapy

Allopurinol: May enhance the anticoagulant effect of Coumarin Derivatives. Risk D: Consider therapy modification

Aminoglutethimide: May increase the metabolism of Coumarin Derivatives. Risk D: Consider therapy modification

Amiodarone: May enhance the anticoagulant effect of Coumarin Derivatives. Risk D: Consider therapy modification

Androgens: May enhance the anticoagulant effect of Coumarin Derivatives. Risk D: Consider therapy modification

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

Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of Coumarin Derivatives. Risk D: Consider therapy modification

Antineoplastic Agents: May enhance the anticoagulant effect of Coumarin Derivatives. Antineoplastic Agents may diminish the anticoagulant effect of Coumarin Derivatives. 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 (Oral); 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 Coumarin Derivatives. 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 Coumarin Derivatives. Risk C: Monitor therapy

Barbiturates: May increase the metabolism of Coumarin Derivatives. Risk D: Consider therapy modification

Bile Acid Sequestrants: May decrease the absorption of Coumarin Derivatives. Risk C: Monitor therapy

Bosentan: May increase the metabolism of Coumarin Derivatives. Risk C: Monitor therapy

Capecitabine: May decrease the metabolism of Coumarin Derivatives. Risk D: Consider therapy modification

Carbamazepine: May decrease the serum concentration of Coumarin Derivatives. Risk D: Consider therapy modification

Cephalosporins: May enhance the anticoagulant effect of Coumarin Derivatives. Exceptions: Cefaclor; Cefadroxil; Cefdinir; Cefepime; Cefixime; Cefonicid; Cefotaxime; Cefpodoxime; Cefprozil; Ceftazidime; Ceftibuten; Ceftizoxime; Cefuroxime; Cephalexin; Cephradine [Off Market]. Risk C: Monitor therapy

Cimetidine: May enhance the anticoagulant effect of Coumarin Derivatives. 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 Coumarin Derivatives. Risk C: Monitor therapy

Contraceptive (Progestins): May diminish the anticoagulant effect of Coumarin Derivatives. In contrast, enhanced anticoagulant effects have also been noted with some products. Risk D: Consider therapy modification

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

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

CYP2C9 Inhibitors (Moderate): May decrease the metabolism of CYP2C9 Substrates (High risk with Highly Effective Inhibitors). Risk C: Monitor therapy

CYP2C9 Inhibitors (Strong): May decrease the metabolism of CYP2C9 Substrates (High risk with Highly Effective Inhibitors). Risk D: Consider therapy modification

CYP2C9 Substrates (High risk with Highly Effective Inhibitors): CYP2C9 Inhibitors (Moderate) may decrease the metabolism of CYP2C9 Substrates (High risk with Highly Effective Inhibitors). Risk C: Monitor therapy

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

Dicloxacillin: May diminish the anticoagulant effect of Coumarin Derivatives. Risk C: Monitor therapy

Disulfiram: May increase the serum concentration of Coumarin Derivatives. Risk C: Monitor therapy

Drotrecogin Alfa: Coumarin Derivatives may enhance the adverse/toxic effect of Drotrecogin Alfa. Bleeding may occur. Risk D: Consider therapy modification

Efavirenz: May increase the serum concentration of Coumarin Derivatives. Risk C: Monitor therapy

Etoposide: May enhance the anticoagulant effect of Coumarin Derivatives. 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

Fenugreek: May enhance the anticoagulant effect of Coumarin Derivatives. Risk D: Consider therapy modification

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

Fluconazole: May decrease the metabolism of Coumarin Derivatives. Risk D: Consider therapy modification

Fluorouracil: May enhance the anticoagulant effect of Coumarin Derivatives. 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

Gefitinib: May enhance the anticoagulant effect of Coumarin Derivatives. Risk C: Monitor therapy

Ginkgo Biloba: May enhance the anticoagulant effect of Coumarin Derivatives. 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 Coumarin Derivatives. Risk C: Monitor therapy

Glutethimide: May increase the metabolism of Coumarin Derivatives. Risk D: Consider therapy modification

Griseofulvin: May increase the metabolism of Coumarin Derivatives. 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 Coumarin Derivatives. Exceptions: Atorvastatin. Risk C: Monitor therapy

Ifosfamide: May enhance the anticoagulant effect of Coumarin Derivatives. Risk C: Monitor therapy

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

Leflunomide: May enhance the anticoagulant effect of Coumarin Derivatives. Risk C: Monitor therapy

Macrolide Antibiotics: May decrease the metabolism of Coumarin Derivatives. Exceptions: Dirithromycin [Off Market]; Spiramycin. Risk C: Monitor therapy

Mercaptopurine: May diminish the anticoagulant effect of Coumarin Derivatives. Risk C: Monitor therapy

Metronidazole: May decrease the metabolism of Coumarin Derivatives. Risk D: Consider therapy modification

Nafcillin: May diminish the anticoagulant effect of Coumarin Derivatives. Risk D: Consider therapy modification

NSAID (COX-2 Inhibitor): May enhance the anticoagulant effect of Coumarin Derivatives. Risk C: Monitor therapy

NSAID (Nonselective): May enhance the anticoagulant effect of Coumarin Derivatives. Risk D: Consider therapy modification

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

Oral Contraceptive (Estrogens): May diminish the anticoagulant effect of Coumarin Derivatives. In contrast, enhanced anticoagulant effects have also been noted with some products. Risk D: Consider therapy modification

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

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

Phenytoin: May enhance the anticoagulant effect of Coumarin Derivatives. Coumarin Derivatives may increase the serum concentration of Phenytoin. Risk D: Consider therapy modification

Phytonadione: May diminish the anticoagulant effect of Coumarin Derivatives. Risk D: Consider therapy modification

Propafenone: May increase the serum concentration of Coumarin Derivatives. Risk C: Monitor therapy

Propoxyphene: May decrease the metabolism of Coumarin Derivatives. 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

Proton Pump Inhibitors: May increase the serum concentration of Warfarin. Exceptions: Esomeprazole; Lansoprazole; Pantoprazole; Rabeprazole. Risk C: Monitor therapy

Quinidine: May enhance the anticoagulant effect of Coumarin Derivatives. Note that the prothrombin time might be unchanged in the face of increased bleeding. Risk C: Monitor therapy

Quinolone Antibiotics: May enhance the anticoagulant effect of Coumarin Derivatives. Risk C: Monitor therapy

Rifamycin Derivatives: May increase the metabolism of Coumarin Derivatives. Risk C: Monitor therapy

Salicylates: May enhance the anticoagulant effect of Coumarin Derivatives. Risk D: Consider therapy modification

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

Sitaxsentan: 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. Risk C: Monitor therapy

St Johns Wort: May increase the metabolism of Coumarin Derivatives. Risk D: Consider therapy modification

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

Sulfonamide Derivatives: May enhance the anticoagulant effect of Coumarin Derivatives. Risk D: Consider therapy modification

Tamoxifen: May increase the serum concentration of Coumarin Derivatives. Risk X: Avoid combination

Tetracycline Derivatives: May enhance the anticoagulant effect of Coumarin Derivatives. Risk C: Monitor therapy

Thyroid Products: May enhance the anticoagulant effect of Coumarin Derivatives. Risk D: Consider therapy modification

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

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

Tricyclic Antidepressants: May enhance the anticoagulant effect of Coumarin Derivatives. Risk C: Monitor therapy

Vitamin A: May enhance the anticoagulant effect of Coumarin Derivatives. Risk C: Monitor therapy

Vitamin E: May enhance the anticoagulant effect of Coumarin Derivatives. Risk C: Monitor therapy

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

Vorinostat: May enhance the anticoagulant effect of Coumarin Derivatives. Risk C: Monitor therapy

Zafirlukast: May decrease the metabolism of Coumarin Derivatives. Risk C: Monitor therapy

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

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid 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.

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.

Herb/Nutraceutical: Cranberry, fenugreek, ginkgo biloba, glucosamine, may enhance bleeding or increase warfarin's effect. Ginseng (American), coenzyme Q₁₀, and St John'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, horse chestnut seed, horseradish, licorice, omega-3-acids, prickly ash, red clover, reishi, SAMe (s-adenosylmethionine), sweet clover, turmeric, and white willow (all have additional antiplatelet activity).

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, cefazolin, ceftriaxone, dopamine, epinephrine, heparin, lidocaine, metaraminol, morphine, nitroglycerin, oxytocin, potassium chloride, ranitidine. Incompatible: Aminophylline, bretylium, ceftazidime, cimetidine, ciprofloxacin, dobutamine, esmolol, gentamicin, labetalol, metronidazole, promazine, Ringer's injection. Variable (consult detailed reference): Ammonium chloride, vancomycin.

Compatibility in syringe: Incompatible: 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 re-activated 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: New 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. A genotyping test is available, and may provide important guidance on initiation of anticoagulant therapy.

Oral:

Infants and Children (unlabeled use): Initial loading dose (if baseline INR is 1.0-1.3): 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.

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. 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). 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.

Adult INR ranges based upon indication: See table.

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

It is imperative that you inform prescriber of all prescriptions, OTC medications, or herbal products you are taking. Do not take any new medication during therapy unless approved by prescriber. Take exactly as directed; if dose is missed, take as soon as possible. Do not double dose. Follow diet and activity as recommended by prescriber; check with prescriber before changing diet. Avoid 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 (use soft toothbrush, waxed dental floss, electric razor, and avoid scissors or sharp knives and potentially harmful activities). May cause nausea, vomiting, disturbed taste (small frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help). Report any unusual bleeding or bruising (eg, bleeding gums, nosebleed, blood in urine, dark stool, bloody emesis, heavier than usual menses, or menstrual irregularities); 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. Pregnancy precautions: Do not get pregnant while taking this medication. Consult prescriber for appropriate barrier contraceptive measures.

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 now 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

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.

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/min) (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.

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.

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 and continued until platelets return. 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.

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; consultation with prescribing physician is advisable prior to surgery to determine temporary dose reduction or withdrawal of medication.

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 (eg, dietary vitamin K or C deficiency, hypertension, open wounds, TB, PUD, diabetes, thyroid or renal disease, recent surgery). Assess potential for interactions with other pharmacological agents and herbal products patient may be taking (especially those medications that may affect coagulation or platelet aggregation). Assess results of laboratory tests closely. Patient should be monitored frequently for therapeutic effectiveness and adverse reactions (eg, bleeding from any site, rash, urticaria, gastrointestinal upset, abdominal pain, diarrhea, hypersensitivity reaction). Teach patient possible side effects/appropriate interventions (eg, safety precautions) and adverse symptoms to report. Pregnancy risk factor X: Determine that patient is not pregnant before beginning treatment. Teach patients of childbearing age appropriate use of contraceptives.

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

Coumadin®, Jantoven™: 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7.5 mg, 10 mg

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

Tablets (Coumadin)

1 mg (30): $35.99

2 mg (30): $35.99

2.5 mg (30): $35.99

3 mg (30): $36.99

4 mg (30): $36.99

5 mg (30): $36.99

6 mg (30): $44.89

7.5 mg (30): $45.96

10 mg (30): $49.99

Tablets (Jantoven)

2 mg (30): $19.99

4 mg (30): $20.99

5 mg (30): $22.80

6 mg (30): $27.99

Tablets (Warfarin Sodium)

1 mg (30): $13.99

2 mg (30): $14.88

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): $23.21

10 mg (30): $24.24

References

Albers GW, Amarenco P, Easton JD, et al, “Antithrombotic and Thrombolytic Therapy for Ischemic Stroke: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy,” Chest, 2004, 126(3 Suppl):483-512.

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, Poller L, et al, “The Pharmacology and Management of the Vitamin K Antagonists: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy, ” Chest, 2004, 126(3 Suppl):204-33.

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. Available at: http://www.circulationaha.org/cgi/content/full/110/5/588. Last accessed October 26, 2004.

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

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. Available at http://stroke.ahajournals.org/cgi/content/short/STROKEAHA.107.183689.

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.

“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.

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.

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.

Harrington RA, Becker RC, Ezekowitz M, et al, “Antithrombotic Therapy for Coronary Artery Disease: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy,” Chest, 2004, 126(3 Suppl):514-38.

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.

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.

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, Chan A, Massicotte P, et al, “Antithrombotic Therapy in Children: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy,” Chest, 2004, 126(3 Suppl):645-87.

“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.

Salem DN, Stein PD, Al-Ahmad A, et al, “Antithrombotic Therapy in Valvular Heart Disease - Native and Prosthetic: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy,” Chest, 2004, 126(3 Suppl):457-82.

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.

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.

International Brand Names

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

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Last full review/revision August 2008