Hemorrhage is the most serious risk of therapy. Patient must be instructed to report bleeding, accidents, or falls. Patient must also report any new or discontinued medications, herbal or alternative products used, significant changes in smoking or dietary habits. Necrosis or gangrene of the skin and other tissues can occur (rarely) due to early hypercoagulability. "Purple toes syndrome," due to cholesterol microembolization, may rarely occur (often after several weeks of therapy). Women may be at risk of developing ovarian hemorrhage at the time of ovulation. The elderly may be more sensitive to anticoagulant therapy.

Additional adverse effects are often related to idiosyncratic reactions, and the frequency cannot be accurately estimated.

Cardiovascular: Vasculitis, edema, hemorrhagic shock

Central nervous system: Fever, lethargy, malaise, asthenia, pain, headache, dizziness, stroke

Dermatologic: Rash, dermatitis, bullous eruptions, urticaria, pruritus, alopecia

Gastrointestinal: Anorexia, nausea, vomiting, stomach cramps, abdominal pain, diarrhea, flatulence, gastrointestinal bleeding, taste disturbance, mouth ulcers

Genitourinary: Priapism, hematuria

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

Hepatic: Hepatic injury, jaundice, transaminases increased

Neuromuscular & skeletal: Paresthesia, osteoporosis

Respiratory: Hemoptysis, epistaxis, pulmonary hemorrhage, tracheobronchial calcification

Miscellaneous: Hypersensitivity/allergic reactions

Skin necrosis/gangrene, due to paradoxical local thrombosis, is a known but rare risk of warfarin therapy. Its 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 toes syndrome," caused by cholesterol microembolization, also occurs rarely. 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 symptom of vascular compromise.

Management of elevated INR: See table.

Management of Elevated INR

See tables.

Decreased Anticoagulant Effects

Increased Bleeding Tendency

Enhanced Anticoagulant Effects

Decrease Vitamin K	Displace Anticoagulant	Inhibit Metabolism	Other
Oral antibiotics: Can / INR. Check INR 3 days after a patient begins antibiotics to see the INR value and adjust the warfarin dose accordingly	Chloral hydrate Clofibrate Diazoxide Ethacrynic acid Miconazole (including intravaginal use) Nalidixic acid Salicylates Sulfonamides Sulfonylureas	Allopurinol Amiodarone Azole antifungals Capecitabine Chloramphenicol Chlorpropamide Cimetidine Ciprofloxacin Co-trimoxazole Disulfiram Ethanol (acute ingestion)1 Flutamide Isoniazid Metronidazole Norfloxacin Ofloxacin Omeprazole Phenytoin Propafenone Propoxyphene Quinidine "Statins"2 Sulfinpyrazone Sulfonamides Tamoxifen Tolbutamide Zafirlukast Zileuton	Acetaminophen Anabolic steroids Capecitabine Celecoxib Clarithromycin Clofibrate Danazol Erythromycin Fenofibrate Gemfibrozil Glucagon Influenza vaccine Propranolol Propylthiouracil Ranitidine Rofecoxib SSRIs Sulindac Tetracycline Thyroid drugs Vitamin E (400 int. units)
1The hypoprothrombinemic effect of oral anticoagulants has been reported to be both increased and decreased during chronic and excessive alcohol ingestion. Data are insufficient to predict the direction of this interaction in alcoholic patients.
2Particularly lovastatin and fluvastatin; others (atorvastatin, pravastatin) rarely associated with increased PT.

CYP2C8/9 inducers: May decrease the levels/effects of warfarin. Example inducers include carbamazepine, phenobarbital, phenytoin, rifampin, rifapentine, and secobarbital.

CYP2C8/9 inhibitors: May increase the levels/effects of warfarin. Example inhibitors include delavirdine, fluconazole, gemfibrozil, ketoconazole, nicardipine, NSAIDs, pioglitazone, and sulfonamides.

CYP2C8/9 substrates: Warfarin may increase the levels/effects of CYP2C8/9 substrates. Example substrates include amiodarone, fluoxetine, glimepiride, glipizide, nateglinide, phenytoin, pioglitazone, rosiglitazone, and sertraline.

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

Food: The anticoagulant effects of warfarin may be decreased if taken with foods rich in vitamin K. Vitamin E may increase warfarin effect. Cranberry juice may increase warfarin effect.

Herb/Nutraceutical: St John's wort may decrease warfarin levels. Alfalfa contains large amounts of vitamin K as do many enteral products. Coenzyme Q10 may decrease response to warfarin. Avoid cat's claw, dong quai, bromelains, evening primrose, feverfew, red clover, horse chestnut, garlic, green tea, ginseng, ginkgo (all have additional antiplatelet activity).

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

Compatibility in syringe: Incompatible: Heparin

Onset of action: Anticoagulation: Oral: 36-72 hours

Peak effect: Full therapeutic effect: 5-7 days; INR may increase in 36-72 hours

Duration: 2-5 days

Absorption: Oral: Rapid

Metabolism: Hepatic

Half-life elimination: 20-60 hours; Mean: 40 hours; highly variable among individuals

Oral:

Infants and Children: 0.05-0.34 mg/kg/day; infants <12 months of age may require doses at or near the high end of this range; consistent anticoagulation may be difficult to maintain in children <5 years of age

Adults: Initial dosing must be individualized. Consider the patient (hepatic function, cardiac function, age, nutritional status, concurrent therapy, risk of bleeding) in addition to prior dose response (if available) and the clinical situation. Start 5-10 mg daily for 2 days. Adjust dose according to INR results; usual maintenance dose ranges from 2-10 mg daily (individual patients may require loading and maintenance doses outside these general guidelines).

Note: Lower starting doses may be required for patients with hepatic impairment, poor nutrition, CHF, elderly, or a high risk of bleeding. Higher initial doses may be reasonable in selected patients (ie, receiving enzyme-inducing agents and with low risk of bleeding).

I.V. (administer as a slow bolus injection): 2-5 mg/day

Dosing adjustment/comments in hepatic disease: Monitor effect at usual doses; the response to oral anticoagulants may be markedly enhanced in obstructive jaundice (due to reduced vitamin K absorption) and also in hepatitis and cirrhosis (due to decreased production of vitamin K-dependent clotting factors); prothrombin index should be closely monitored

Oral: Do not take with 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

Therapeutic: 2-5 mcg/mL (SI: 6.5-16.2 mol/L)

Prothrombin time should be 1¹/2 to 2 times the control or INR should be increased 2 to 3 times based upon indication

Normal prothrombin time: 10-13 seconds

INR ranges based upon indication: See table.

INR Ranges Based Upon Indication

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

The World Health Organization (WHO), in cooperation with other regulatory-advisory bodies, has developed system of standardizing the reporting of PT values through the determination of the International Normalized Ratio (INR). The INR involves the standardization of the PT by the generation of two pieces of information: the PT ratio and the International Sensitivity Index (ISI)

Therapeutic ranges are now available or being developed to assist practicing physicians in their treatment of patients with a wide variety of thrombotic disorders

Management of oral anticoagulation prior to surgery: Patients with low risk of thromboembolism (eg, patients without venous thromboembolism for >3 months or patients who have experienced atrial fibrillation who do not have a history of stroke): Stop warfarin therapy approximately 4 days before surgery, allow the INR to return to a near normal level, briefly administer postoperative prophylaxis (if the intervention itself creates a higher risk of thrombosis) using low-dose heparin and simultaneously begin warfarin therapy after surgery.

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

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

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

Heparin-induced Thrombocytopenia (HIT) or Heparin-induced Thrombotic Thrombocytopenia Syndrome (HITTS): When a patient develops HIT/HITTS, do not start warfarin. Rather, a direct thrombin inhibitor should be initiated and continued until platelets return. Warfarin anticoagulation should be postponed in the patient with HIT until substantial recovery of the platelet count has occurred.

Factor VII half-life: 4-6 hours

Factor X half-life: 27-48 hours

Factor II half-life: 42-72 hours

Overlapping heparin and warfarin therapy by at least 5 days is necessary in treatment of DVT/PE even if the INR is therapeutic earlier. Although an elevation in INR (factor VII depletion) may be seen early (first 24-48 hours) in warfarin therapy, it does not represent adequate anticoagulation. Factors II and X must be depleted which takes considerably longer.

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

Heparin-induced Thrombocytopenia (HIT) or Heparin-induced Thrombotic Thrombocytopenia Syndrome (HITTS): When a patient develops HIT/HITTS, do not start warfarin. Rather, a direct thrombin inhibitor should be initiated and continued until platelets return. Warfarin anticoagulation should be postponed in the patient with HIT until substantial recovery of the platelet count has occurred.

ST-Elevation Myocardial Infarction: The 2004 ACC/AHA guidelines for the management of patients with acute myocardial infarction suggest considering warfarin as a secondary prevention alternative to clopidogrel in aspirin allergic patients. If used alone, an INR of 2.5-3.5 is recommended.

Injection, powder for reconstitution, as sodium (Coumadin®): 5 mg

Tablet, as sodium (Coumadin®, Jantoven™): 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7.5 mg, 10 mg

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