warfarin sodium
Coumadin

Available forms
Available by prescription only
Injection: 5 mg/vial
Tablets: 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7.5 mg, 10 mg

Indications and dosages
 Pulmonary emboli, deep vein thrombosis, MI, rheumatic heart disease with heart valve damage, atrial arrhythmias. Adults: Initially, 2 to 5 mg P.O. or I.V.; then daily. PT and INR are used to establish optimal dose. Usual maintenance dosage, 2 to 10 mg P.O. daily.

Pharmacodynamics
Anticoagulant action: Warfarin inhibits vitamin K-dependent activation of clotting factors II, VII, IX, and X, which are formed in the liver; it has no direct effect on established thrombi and can’t reverse ischemic tissue damage. However, warfarin may prevent additional clot formation, extension of formed clots, and secondary complications of thrombosis.

Pharmacokinetics
Absorption: Rapidly and completely absorbed from GI tract.
Distribution: Highly bound to plasma protein, especially albumin; it crosses the placental barrier but doesn’t appear to accumulate in breast milk.
Metabolism: Warfarin is hydroxylated by liver into inactive metabolites.
Excretion: Metabolites are reabsorbed from bile and excreted in urine. Half-life of parent drug is 1 to 3 days, but is highly variable. Because therapeutic effect is relatively more dependent on clotting factor depletion (factor X has half-life of 40 hours).

Contraindications and precautions
Contraindicated in pregnant women and in patients with bleeding or hemorrhagic tendencies, GI ulcerations, severe hepatic or renal disease, severe uncontrolled hypertension, subacute bacterial endocarditis, aneurysm, ascorbic acid deficiency, and a history of warfarin-induced necrosis, threatened abortion, eclampsia, preeclampsia, regional or lumbar block anesthesia, polycythemia vera, and vitamin K deficiency. Also contraindicated in patients in whom diagnostic tests or therapeutic procedures may cause uncontrolled bleeding; unsupervised patients with senility, alcoholism, psychosis, or lack of cooperation; and patients who had recent eye, brain, or spinal cord surgery.
  Use cautiously in breast-feeding patients and in patients with diverticulitis, colitis, hypertension, hepatic or renal disease, drainage tubes in any orifice, infectious disease or disturbance of intestinal flora, trauma, surgery resulting in large exposed surface, indwelling catheters, known or suspected deficiency in protein C or S, heart failure, severe diabetes, vasculitis, polycythemia vera, concurrent use of NSAIDs, or risk of hemorrhage.

Interactions
Drug-drug. Acetaminophen: May increase bleeding with use of acetaminophen longer than 2 weeks and doses above 2 g daily. Monitor patient closely.
Allopurinol, amiodarone, anabolic steroids, azithromycin, capecitabine, celecoxib, cephalosporins, chloramphenicol, cimetidine, ciprofloxacin, clofibrate, co-trimoxazole, danazol, diazoxide, diflunisal, disulfiram, erythromycin, fenofibrate, fenoprofen calcium, fluoroquinolones, fluoxetine, flutamide, fluvoxamine, glucagon, heparin, ibuprofen, influenza virus vaccine, isoniazid, itraconazole, ketoprofen, lovastatin, meclofenamate, methimazole, metronidazole, miconazole, neomycin (oral), norfloxacin, ofloxacin, omeprazole, pentoxifylline, propafenone, propoxyphene, propylthiouracil, quinidine, quinine, rofecoxib, salicylates, sertraline, simvastatin, streptokinase, sulfinpyrazone, sulfonamides, sulindac, tamoxifen, tetracyclines, thiazides, thyroid drugs, tramadol, tricyclic antidepressants, urokinase, vitamin E, zafirlukast, zileuton: Increases PT. Monitor patient closely for bleeding. Reduce warfarin dosage as necessary.
Aminoglutethimide, atorvastatin, carbamazepine, corticosteroids, ethchlorvynol, glutethimide, griseofulvin, hormonal contraceptives, mercaptopurine, methaqualone, nafcillin, rifampin, spironolactone, trazodone, sucralfate, vitamin K: Decreases anticoagulant effect. Avoid use together.
Anticonvulsants: Increases serum levels of phenytoin and phenobarbital. Monitor patient closely.
Barbiturates: May inhibit anticoagulant effect for several weeks after barbiturate withdrawal, and fatal hemorrhage can occur after cessation of barbiturate effect. Monitor patient closely. If barbiturates are withdrawn, reduce anticoagulant dose.
Chloral hydrate: May increase or decrease anticoagulant effect. Avoid use together.
Cholestyramine: Decreases anticoagulant effect. Administer 6 hours after warfarin.
Ethacrynic acid, indomethacin, mefenamic acid, phenylbutazone, sulfinpyrazone: Increases anticoagulant effect and risk of severe GI irritation (may be ulcerogenic). Avoid use together.
Drug-herb. Angelica root, anise, arnica flower, asafetida, bromelain, celery, chamomile, clove, Dan-shen, devil’s claw, dong quai, fenugreek, feverfew, garlic, ginger, ginkgo biloba, horse chestnut, licorice, meadowsweet, motherwort, onion, papain, parsley, passion flower, quassia, reishi mushroom, rue, sweet clover, turmeric: Increases risk of bleeding. Discourage use together.
Angelica sinensis: May significantly prolong PT. Discourage use together.
Ginseng, St. John’s wort, ubiquinone: May decrease anticoagulant effect. Discourage use together.
Green tea: Decreases anticoagulant effect from vitamin K content of green tea. Tell patient to minimize variable consumption of green tea and other foods or nutritional supplements containing vitamin K.
Drug-food. Foods or enteral products that contain vitamin K: May impair warfarin effects. Advise patient to maintain a consistent daily intake of leafy green vegetables.
Drug-lifestyle. Alcohol use: May enhance anticoagulation. Discourage alcohol use.

Adverse reactions
CNS: fever.
GI: anorexia, nausea, vomiting, cramps, diarrhea, mouth ulcerations, sore mouth.
GU: hematuria.
Hematologic: hemorrhage with excessive dosage).
Hepatic: hepatitis, jaundice.
Skin: dermatitis, urticaria, necrosis, gangrene, alopecia, rash, "purple toe" syndrome.
Other: enhanced uric acid excretion.

Effects on lab test results
• May increase ALT and AST levels.
• May increase INR, PT, and PTT.

Overdose and treatment
Signs and symptoms of overdose vary with severity and may include internal or external bleeding or skin necrosis of fat-rich areas, but most common sign is hematuria. Excessive prolongation of PT and INR or minor bleeding mandates withdrawal of therapy; withholding one or two doses may be adequate in some cases.
 Treatment to control bleeding may include oral or I.V. phytonadione (vitamin K₁) and, in severe hemorrhage, fresh frozen plasma or whole blood. Use of phytonadione may interfere with subsequent oral anticoagulant therapy.

Special considerations
• I.V. warfarin provides an alternative for patients who can’t tolerate or receive oral medication.
• PT and INR are used to determine optimal dose.
 ALERT Use of a large loading dose may increase the risk of hemorrhage or other complications and doesn’t offer faster protection against thrombi formation.
• Monitor patient for signs of bleeding.
• In patients with known or suspected protein C deficiency, concurrent therapy with heparin for 4 to 7 days may reduce the risk of necrosis.
• Warfarin causes false-negative serum theophylline levels.
• After reconstitution, warfarin injection is stable for 4 hours at controlled room temperature.
• Store drug in light-resistant containers at 59° to 86° F (15° to 30° C).
Pregnant patients
• Drug use is contraindicated during pregnancy.
Breast-feeding patients
• Although drug doesn’t appear to accumulate in breast milk, use cautiously in breast-feeding women.
Pediatric patients
• Infants, especially neonates, may be more susceptible to anticoagulants because of vitamin K deficiency. Safety and efficacy haven’t been established in children younger than age 18.
Geriatric patients
• Elderly patients are more susceptible to effects of anticoagulants and have an increased risk of hemorrhage possibly because of altered hemostatic mechanisms or age-related deterioration of hepatic and renal functions.

Patient education
• Tell patient to promptly report any unusual bruising or bleeding.
• Warn patient to avoid taking OTC products containing aspirin, other salicylates, or drugs that may interact with the anticoagulant, causing an increase or decrease in action of drug, and to seek medical approval before stopping or starting medication.
• Advise patient not to substantially alter daily intake of foods that contain vitamin K, such as asparagus, broccoli, cabbage, lettuce, turnip greens, spinach, watercress, fish, pork, beef liver, green tea, or tomatoes. Widely varying daily intake may alter anticoagulant effect of warfarin.
• Instruct patient to inform all health care providers (including dentists) about use of warfarin.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use