Warfarin - Drug Information

Warfarin: Drug information
http://www.uptodate.com/contents/warfarin-drug-information...
Official reprint from UpToDate www.uptodate.com 2012 UpToDate

Copyright 1978-2012 Lexicomp, Inc. All rights reserved. (For additional information see "Warfarin: Patient drug information" and see "Warfarin: Pediatric drug information")
Special Alerts
Warfarin (Jantoven): Recall Due to Mislabeled Bottle (Update) February 2011 Upsher-Smith Laboratories has initiated a voluntary recall of Jantoven warfarin sodium tablets. The precautionary recall was prompted after a single bottle labeled with 3 mg tablets (tan colored tablets) was found to actually contain the 10 mg strength tablets (white colored tablets). The risk of administering a 10 mg strength tablet in place of the intended 3 mg strength tablet could potentially result in life-threatening hemorrhage. As an additional precautionary measure, Upsher-Smith Laboratories has expanded its previously announced recall to include additional products and lots produced on the same line during a similar period of time. For the most recent information, including the products recalled, please refer to http://www.upsher-smith.com.
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.
Brand Names: U.S.
Coumadin; Jantoven Apo-Warfarin; Coumadin; Mylan-Warfarin;
Brand Names: Canada

Novo-Warfarin; Taro-Warfarin
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.
Pharmacologic Category
Antagonist
Anticoagulant, Coumarin Derivative; Vitamin K
Dosing: Adult
Note: Labeling identifies genetic factors which may increase patient sensitivity to warfarin. Specifically, genetic variations in the proteins CYP2C9 and VKORC1, responsible for warfarins 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.
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Prevention/treatment of thrombosis/embolism: I.V. (administer as a slow bolus injection): 2-5 mg/day Oral: Initial dosing must be individualized. Consider the patient (hepatic function, cardiac function, age, nutritional status, concurrent therapy, risk of bleeding) 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).
Range1 of Expected Therapeutic Maintenance Dose Based on CYP2C92 and VKORC13 Genotypes VKORC1 *1/*1 GG AG AA 5-7 mg 5-7 mg 3-4 mg *1/*2 5-7 mg 3-4 mg 3-4 mg CYP2C9 *1/*3 3-4 mg 3-4 mg *2/*2 3-4 mg 3-4 mg *2/*3 3-4 mg *3/*3 0.5-2 mg
0.5-2 mg 0.5-2 mg
0.5-2 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg
Note: Must also take into account other patient related factors when determining initial dose (eg, age, body weight, concomitant medications, comorbidities).
1
Ranges derived from multiple published clinical studies. Patients with CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3 alleles may take up to 4 weeks to achieve maximum INR with a given dose regimen. VKORC1 -1639G>A (rs 9923231) variant is used in this table; other VKORC1 variants may also be important determinants of dose.
Dosing: Pediatric
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(For additional information see "Warfarin: Pediatric drug information") Prevention/treatment of thrombosis: Oral: Infants and Children (unlabeled use): Initial loading dose (if baseline INR is 1-1.3): 0.2 mg/kg (maximum: 10 mg/dose); 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.
Dosing: Geriatric
Oral: Initial dose 5 mg. Usual maintenance dose: 2-5 mg/day. The elderly tend to require lower dosages to produce a therapeutic level of anticoagulation (due to changes in the pattern of warfarin metabolism).
Dosing: Renal Impairment
No adjustment required, however, patients with renal failure have an increased risk of bleeding complications. Monitor closely.
Dosing: Hepatic Impairment
Monitor effect at usual doses. The response to oral anticoagulants may be markedly enhanced in obstructive jaundice, hepatitis, and cirrhosis. INR should be closely monitored.
Dosage Forms: U.S.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. Injection, powder for reconstitution, as sodium: Coumadin: 5 mg Tablet, oral, as sodium: 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7.5 mg, 10 mg Coumadin: 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7.5 mg [scored] Coumadin: 10 mg [scored; dye free] Jantoven: 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7.5 mg [scored] Jantoven: 10 mg [scored; dye free]
Generic Equivalent Available: U.S. Administration
Yes: Tablet
Oral: Administer with or without food. Take at the same time each day. I.V.: Administer as a slow bolus injection over 1-2 minutes; avoid all I.M. injections
Compatibility
Stable in D5LR, D51/2NS, D5NS, D5W, D10W, variable stability (consult detailed reference) in LR, NS. Y-site administration: Compatible: Amikacin, ascorbic acid injection, bivalirudin, cefazolin, dopamine, epinephrine, heparin, lidocaine, morphine, nitroglycerin, oxytocin, potassium chloride, ranitidine. Incompatible: Aminophylline, ceftazidime, cimetidine, ciprofloxacin, dobutamine, esmolol, gentamicin, labetalol. Variable (consult detailed reference): Ammonium chloride, ceftriaxone, metronidazole, vancomycin. Compatibility in syringe: Incompatible: Ceftriaxone, heparin.
Use
Prophylaxis and treatment of thromboembolic disorders (eg, venous, pulmonary)
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and embolic complications arising from atrial fibrillation or cardiac valve replacement; adjunct to reduce risk of systemic embolism (eg, recurrent MI, stroke) after myocardial infarction
Use - Unlabeled/Investigational
attacks
Prevention of recurrent transient ischemic
Medication Safety Issues

Sound-alike/look-alike issues: Coumadin may be confused with Avandia, Cardura, Compazine, Kemadrin Jantoven may be confused with Janumet, Januvia High alert medication: The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs which have a heightened risk of causing significant patient harm when used in error. 2009 National Patient Safety Goals: The Joint Commission on Accreditation of Healthcare Organizations requires healthcare organizations that provide anticoagulant therapy to have a process in place to reduce the risk of anticoagulant-associated patient harm. Patients receiving anticoagulants should receive individualized care through a defined process that includes standardized ordering, dispensing, administration, monitoring and education. This does not apply to routine short-term use of anticoagulants for prevention of venous thromboembolism when the expectation is that the patients laboratory values will remain within or close to normal values (NPSG.03.05.01).
Adverse Reactions Significant
Bleeding is the major adverse effect of warfarin. Hemorrhage may occur at virtually any site. Risk is dependent on multiple variables, including the intensity of anticoagulation and patient susceptibility. Cardiovascular: Angina, chest pain, edema, hemorrhagic shock, hypotension, pallor, syncope, vasculitis Central nervous system: Coma, dizziness, fatigue, fever, headache, lethargy, malaise, pain, stroke Dermatologic: Alopecia, bullous eruptions, dermatitis, rash, pruritus, urticaria Gastrointestinal: Abdominal cramps, abdominal pain, anorexia, diarrhea, flatulence, gastrointestinal bleeding, mouth ulcers, nausea, taste disturbance, vomiting Genitourinary: Hematuria, priapism Hematologic: Agranulocytosis, anemia, leukopenia, retroperitoneal hematoma, unrecognized bleeding sites (eg, colon cancer) may be uncovered by anticoagulation Hepatic: Cholestatic jaundice, hepatic injury, hepatitis, transaminases increased Neuromuscular & skeletal: Joint pain, muscle pain, osteoporosis (potential association with
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long-term use), paralysis, paresthesia, weakness Respiratory: Dyspnea, tracheobronchial calcification Miscellaneous: Anaphylactic reaction, cold intolerance, hypersensitivity/allergic reactions, skin necrosis, gangrene, purple toes syndrome
Contraindications
Hypersensitivity to warfarin or any component of 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. Special handling: Hazardous agent: Use appropriate precautions for handling and disposal. Concerns related to adverse effects: Anaphylaxis/hypersensitivity: May cause hypersensitivity reactions, anaphylaxis; use with caution in patients with anaphylactic disorders. including
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
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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 insufficiencies (vitamin K deficiency). in patients with prolonged dietary
Heparin-induced thrombocytopenia: Use with caution in patients with heparininduced 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.
Metabolism/Transport Effects Drug Interactions

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Substrate of CYP1A2 (minor), 2C9 (major), 2C19 (minor), 3A4 (minor); Inhibits CYP2C9 (moderate), 2C19 (weak)
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(For additional information: Launch Lexi-Interact Drug Interactions Program ) 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; AzaCITIDine; Bleomycin; Capecitabine; CARBOplatin; Carmustine; Chlorambucil; CISplatin; Cladribine; Cytarabine; Cytarabine (Liposomal); Dacarbazine; DACTINomycin; DAUNOrubicin Citrate (Liposomal); DAUNOrubicin Hydrochloride; Denileukin Diftitox; DOCEtaxel; DOXOrubicin (Liposomal); Epirubicin; Estramustine; Etoposide Phosphate; Exemestane; Fludarabine; Goserelin; Hydroxyurea; IDArubicin; Irinotecan; Letrozole; Leuprolide; Lomustine; Mechlorethamine; Megestrol; MitoMYcin; MitoXANtrone; Nilutamide; PACLitaxel; Pegaspargase; Pentostatin; Polyestradiol; Porfimer; RiTUXimab; Streptozocin; Tamoxifen; Temozolomide; Teniposide; Thioguanine; Thiotepa; Topotecan; Toremifene; Tretinoin (Systemic); Valrubicin; VinBLAStine; Vinorelbine. Risk C: Monitor therapy Antiplatelet Agents: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy Antithyroid Agents: May diminish the anticoagulant effect of Vitamin K Antagonists. Risk D: Consider therapy modification Aprepitant: May decrease the serum concentration of Warfarin. Risk C: Monitor therapy Atazanavir: May increase the serum concentration of Warfarin. Risk C: Monitor therapy AzaTHIOprine: May diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy Barbiturates: May increase the metabolism of Vitamin K Antagonists. Risk D: 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:
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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 (Highly Effective): May increase the metabolism of CYP2C9 Substrates (High risk). Risk C: Monitor therapy
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CYP2C9 Inhibitors (Moderate): May decrease the metabolism of CYP2C9 Substrates (High risk). Risk C: Monitor therapy CYP2C9 Inhibitors (Strong): May decrease the metabolism of CYP2C9 Substrates (High risk). 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: Vitamin K Antagonists may enhance the adverse/toxic effect of Drotrecogin Alfa. 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
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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.
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Green Tea may diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy Griseofulvin: May decrease the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May 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 (Systemic); Spiramycin. Risk C: Monitor therapy Mercaptopurine: May diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy Methylphenidate: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy MetroNIDAZOLE: May increase the serum concentration of Vitamin K Antagonists. Management: Consider alternatives to concomitant therapy with these agents. 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
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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 (High risk). 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 Propoxyphene: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
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Prostacyclin Analogues: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the antiplatelet effects of these agents may lead to an increased risk 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
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Sulfonamide Derivatives: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk D: Consider therapy modification Tamoxifen: May increase the serum concentration of Vitamin K Antagonists. Risk X: 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: 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.
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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 Johns 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).
Pregnancy Risk Factor Pregnancy Implications
X (show table)
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). Use is contraindicated during pregnancy (or in women of reproductive potential), 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.
Lactation
pending)
Does not enter breast milk (AAP rates compatible; AAP 2001 update
Breast-Feeding Considerations
Breast-feeding women may be treated with warfarin. Based on limited data, warfarin does not pass into breast milk; however, prolonged PT may occur in some infants (product labeling). Women who are breast-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). Warfarin was not detected in breast milk in 2 reports of warfarin exposure during breast-feeding in 9 infants. Evaluation of coagulation tests and vitamin K status of breast-feeding infant is considered prudent (product labeling).
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.
Pricing: U.S. (www.drugstore.com)
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Tablets (Coumadin) 1 mg (30): $46.99 2 mg (30): $50.99 2.5 mg (30): $52.99 3 mg (30): $55.99 4 mg (30): $54.99 5 mg (30): $53.99 6 mg (30): $56.99 7.5 mg (30): $58.99 10 mg (30): $62.99 Tablets (Jantoven) 2 mg (30): $17.99 4 mg (30): $17.99 5 mg (30): $17.99 Tablets (Warfarin Sodium) 1 mg (30): $13.99 2 mg (30): $14.99 2.5 mg (30): $14.99 3 mg (30): $15.99 4 mg (30): $14.99 5 mg (30): $13.99 7.5 mg (30): $23.99 10 mg (30): $24.99
Monitoring Parameters Reference Range
Prothrombin time, hematocrit, INR; consider genotyping of CYP2C9 and VKORC1 prior to initiation of therapy, if available
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).
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Adult Target INR Ranges Based Upon Indication Targeted INR Targeted INR Range
Indication
Cardiac Acute myocardial infarction (high risk)1,2,3 Atrial fibrillation or atrial flutter Valvular Bileaflet or Medtronic Hall tilting disk mechanical aortic valve in normal sinus rhythm and normal LA size Bileaflet or tilting disk mechanical mitral valve Caged ball or caged disk mechanical valve 2.5 2.5 2-3 2-3
2.5
2-3
3 3
2.5-3.5 2.5-3.5 2.5-3.5
Mechanical prosthetic valve with systemic embolism despite adequate anticoagulation4
3 or 3.5
or 3-4
Mechanical valve and risk factors for thromboembolism (eg, AF, MI5, LA enlargement, hypercoagulable state, low EF) or history of atherosclerotic vascular disease6 Bioprosthetic mitral valve7 Bioprosthetic mitral or aortic valve with prior history of systemic embolism7 Bioprosthetic mitral or aortic valve with evidence of LA thrombus at surgery8 Bioprosthetic mitral or aortic valve with risk factors for thromboembolism (eg, AF, hypercoagulable state or low EF)
9
2.5-3.5
2.5
2-3
2.5
2-3
2.5
2-3
2.5
2-3
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Indication
Targeted INR
Targeted INR Range 3.5-4.5 3-4
Prosthetic mitral valve thrombosis (resolved)3 Prosthetic aortic valve thrombosis (resolved)3 Rheumatic mitral valve disease and normal sinus rhythm (LA diameter >5.5 cm), AF, previous systemic embolism, or LA thrombus Thromboembolism Treatment Venous thromboembolism10,11 Thromboprophylaxis Chronic thromboembolic pulmonary hypertension (CTPH) Idiopathic pulmonary artery hypertension (IPAH)12 Lupus inhibitor (no other risk factors) Lupus inhibitor and recurrent thromboembolism Major trauma patients with impaired mobility undergoing rehabilitation Spinal cord injury (acute) undergoing rehabilitation Total hip or knee replacement (elective) or hip fracture surgery13 Other Indications Cerebral venous sinus thrombosis14 Ischemic stroke due to AF
1
4 3.5
2.5
2-3
2.5
2-3
2.5
2-3
2 2.5 3
1.5-2.5 2-3 2.5-3.5
2.5
2-3
2.5
2-3
2.5
2-3
2.5 2.5
2-3 2-3
High-risk includes large anterior MI, significant heart failure,
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Indication
Targeted INR
Targeted INR Range
intracardiac thrombus, atrial fibrillation, history of thromboembolism.

2
Maintain anticoagulation for 3 months. Combine with aspirin 81 mg/day. Combine with aspirin 81 mg/day, if not previously receiving, and/or if previous target INR was 2.5, then new target INR should be 3 (2.5-3.5). If previous target INR was 3, then new target INR should be 3.5 (3-4). MI refers to anterior-apical ST-segment elevation myocardial infarction. Combine with aspirin 81 mg/day unless patient is at high risk of bleeding (eg, history of GI bleed, age >80 years). Maintain anticoagulation for 3 months after valve insertion then switch to aspirin 81 mg/day if no other indications for warfarin exist or clinically reassess need for warfarin in patients with prior history of systemic embolism. Maintain anticoagulation with warfarin until thrombus resolution. If patient has history of atherosclerotic vascular disease, combine with aspirin 81 mg/day unless patient is at high risk of bleeding (eg, history of GI bleed, age >80 years). Treat for 3 months in patients with VTE due to transient reversible risk factor. Treat for a minimum of 3 months in patients with unprovoked VTE and evaluate for long term therapy. Other risk groups (eg, cancer) may require >3 months of therapy. In patients with unprovoked VTE who prefer less frequent INR monitoring, low-intensity therapy (INR range: 1.5-1.9) with less frequent monitoring is recommended over stopping treatment. Recommendation from the ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension (McLaughlin, 2009) Continue for at least 10 days and up to 35 days after surgery.
10
11
12
13
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Indication
Targeted INR
Targeted INR Range
14
Continue for up to 12 months.
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.
International Brand Names
Aldocumar (ES); Befarin (TH); Circuvit (AR); Cofarin (TW); Coumadan (AR); Coumadin (AE, AU, BF, BH, BJ, CI, CN, CY, DE, EC, EG, ET, GH, GM, GN, IL, IQ, IR, IT, JO, KE, KP, KW, LB, LR, LY, MA, ML, MR, MU, MW, MX, NE, NG, NZ, OM, PE, PH, PK, PY, QA, SA, SC, SD, SL, SN, SY, TN, TR, TZ, UG, VE, YE, ZM, ZW); Coumadine (FR); Dagonal (UY); Fargem (TH); Lawarin (CZ); Lennon-Warfarin (ZA); Mafarin (TW); Maforan (TH); Marevan (AU, BE, BR, DK, EE, FI, GB, IE, LU, NO, NZ, SG); Marfarin (HN); Marivarin (HR); Orfarin (MY, TH, TW); Panwarfin (GR); Simarc-2 (ID); Tedicumar (ES); Tufam (TH); UniWarfin (IN); Varfine (PT); Waran (SE); Warfar (CO, KP); Warfil 5 (DO); Warfin (PL); Warik (PH); Zydarin (TH); Zyfarin (PH)
Mechanism of Action
Hepatic synthesis of coagulation factors II, VII, IX, and X, 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
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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) Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Albers GW, Amarenco P, Easton JD, et al, Antithrombotic and Thrombolytic Therapy for Ischemic
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