Product Name
:
WARFINE
Chemical Name
:
Warfarin Sodium
Therapeutic Category
:
Cardiovascular drugs
Pharmacologic Category
:
Anticoagulant, Coumarin Derivative - Vitamin K Antagonist
Pharmaceutical Form
:
Tablets
Composition
:
Warfarin Sodium 2mg / 5mg
Dosing
 
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 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.
Prevention/treatment of thrombosis/embolism:
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
CYP2C9

Note: Must also take into account other patient related factors when determining initial dose (eg, age, body weight, concomitant medications, comorbidities).

1Ranges derived from multiple published clinical studies.

2Patients with CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3 alleles may take up to 4 weeks to achieve maximum INR with a given dose regimen.

3VKORC1 -1639G>A (rs 9923231) variant is used in this table; other VKORC1 variants may also be important determinants of dose.


*1/*1
*1/*2
*1/*3
*2/*2
*2/*3
*3/*3
GG
5-7 mg
5-7 mg
3-4 mg
3-4 mg
3-4 mg
0.5-2 mg
AG
5-7 mg
3-4 mg
3-4 mg
3-4 mg
0.5-2 mg
0.5-2 mg
AA
3-4 mg
3-4 mg
0.5-2 mg
0.5-2 mg
0.5-2 mg
0.5-2 mg

Dosing: Pediatric
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.
Use
 
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
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
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 Drug
 
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.
• “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.
Metabolism/Transport Effects
Substrate of CYP1A2 (minor), 2C9 (major), 2C19 (minor), 3A4 (minor); Inhibits CYP2C9 (moderate), 2C19 (weak).
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; 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: 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
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
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 (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 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
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
Pregnancy
 
X
Pregnancy Implications
Warfarin crosses the placenta; concentrations in the fetal plasma are similar to maternal values. Teratogenic effects have been reported following first trimester exposure and may include coumarin embryopathy (nasal hypoplasia and/or stippled epiphyses; limb hypoplasia may also be present). Adverse 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
 
Does not enter breast milk (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; 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).
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).
Adult Target INR Ranges Based Upon Indication
Indication
Targeted INR
Targeted INR Range

1High-risk includes large anterior MI, significant heart failure, intracardiac thrombus, atrial fibrillation, history of thromboembolism.

2Maintain anticoagulation for 3 months.
3Combine with aspirin 81 mg/day.

4Combine with aspirin 81 mg/day, if not previously receiving, and/or 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).

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

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

7Maintain 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.

8Maintain anticoagulation with warfarin until thrombus resolution.

9If 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).

10Treat 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.

11In 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.

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

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

14Continue for up to 12 months.
Cardiac
Acute myocardial infarction (high risk)1,2,3
2.5
2-3
Atrial fibrillation or atrial flutter
2.5
2-3
Valvular

Bileaflet or Medtronic Hall tilting disk mechanical aortic valve in normal sinus rhythm and normal LA size

2.5
2-3
Bileaflet or tilting disk mechanical mitral valve
3
2.5-3.5
Caged ball or caged disk mechanical valve
3
2.5-3.5

Mechanical prosthetic valve with systemic embolism despite adequate anticoagulation4

3 or 3.5
2.5-3.5
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

3
2.5-3.5
Bioprosthetic mitral valve7
2.5
2-3

Bioprosthetic mitral or aortic valve with prior history of systemic embolism7

2.5
2-3

Bioprosthetic mitral or aortic valve with evidence of LA thrombus at surgery8

2.5
2-3

Bioprosthetic mitral or aortic valve with risk factors for thromboembolism (eg, AF, hypercoagulable state or low EF)9

2.5
2-3
Prosthetic mitral valve thrombosis (resolved)3
4
3.5-4.5
Prosthetic aortic valve thrombosis (resolved)3
3.5
3-4

Rheumatic mitral valve disease and normal sinus rhythm (LA diameter >5.5 cm), AF, previous systemic embolism, or LA thrombus

2.5
2-3
Thromboembolism Treatment
Venous thromboembolism10,11
2.5
2-3
Thromboprophylaxis
Chronic thromboembolic pulmonary hypertension (CTPH)
2.5
2-3
Idiopathic pulmonary artery hypertension (IPAH)12
2
1.5-2.5
Lupus inhibitor (no other risk factors)
2.5
2-3
Lupus inhibitor and recurrent thromboembolism
3
2.5-3.5

Major trauma patients with impaired mobility undergoing rehabilitation

2.5
2-3
Spinal cord injury (acute) undergoing rehabilitation
2.5
2-3

Total hip or knee replacement (elective) or hip fracture surgery13

2.5
2-3
Other Indications
Cerebral venous sinus thrombosis14
2.5
2-3
Ischemic stroke due to AF
2.5
2-3

Warfarin levels are not used for monitoring degree of anticoagulation. They may be useful if a patient with unexplained coagulopathy is using the drug surreptitiously or if it is unclear whether clinical resistance is due to true drug resistance or lack of drug intake.
Normal prothrombin time (PT): 10.9-12.9 seconds. Healthy premature newborns have prolonged coagulation test screening results (eg, PT, aPTT, TT) which return to normal adult values at approximately 6 months of age. Healthy prematures, however, do not develop spontaneous hemorrhage or thrombotic complications because of a balance between procoagulants and inhibitors.
Mechanism of Action
 
Hepatic synthesis of coagulation factors II, 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)