Yes: Tablet

Anticoagulant, Coumarin Derivative

Prophylaxis and treatment of venous thrombosis, pulmonary embolism and thromboembolic disorders; atrial fibrillation with risk of embolism and as an adjunct in the prophylaxis of systemic embolism after myocardial infarction

D

Clinical effects on the fetus: Oral anticoagulants cross the placenta and produce fetal abnormalities. Warfarin should not be used during pregnancy because of significant risks. Adjusted-dose heparin can be given safely throughout pregnancy in patients with venous thromboembolism.

Breast-feeding/lactation: Warfarin does not pass into breast milk and can be given to nursing mothers

Hypersensitivity to warfarin or any component of the product; pregnancy; hemorrhagic tendencies; hemophilia; thrombocytopenia purpura; leukemia; recent or potential surgery of the eye or CNS; major regional lumbar block anesthesia or surgery resulting in large, open surfaces; patients bleeding from the GI, respiratory, or GU tract; threatened abortion; aneurysm; ascorbic acid deficiency; history of bleeding diathesis; prostatectomy; continuous tube drainage of the small intestine; polyarthritis; diverticulitis; emaciation; malnutrition; cerebrovascular hemorrhage; eclampsia/pre-eclampsia; blood dyscrasias; severe uncontrolled or malignant hypertension; severe hepatic disease; pericarditis or pericardial effusion; subacute bacterial endocarditis; visceral carcinoma; following spinal puncture and other diagnostic or therapeutic procedures with potential for significant bleeding; history of warfarin-induced necrosis; an unreliable, noncompliant patient; alcoholism; patient who has a history of falls or is a significant fall risk

Cautious use in severe renal disease, although has been used. Hemorrhage is the most serious risk. Have patient report any signs or symptoms of bleeding or any falls or accidents immediately. Patient must also report any new or discontinued medications, herbal or alternative products used, significant changes in smoking or eating habits. Necrosis or gangrene of the skin and other tissues can rarely occur 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. Use with caution in traumas, infection (antibiotics and fever may alter affects), renal insufficiency, prolonged dietary insufficiencies (vitamin K deficiency), moderate-severe hypertension, polycythemia vera, vasculitis, open wound, active TB, history of PUD, anaphylactic disorders, indwelling catheters, severe diabetes, and menstruating and postpartum women. Use with caution in protein C deficiency. The elderly may be more sensitive. Use care in selection of patients appropriate for this treatment. Ensure patient cooperation especially from the alcoholic, illicit drug user, demented, or psychotic patient.

As with all anticoagulants, 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.

"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, rash, 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.

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: Increased transaminases, hepatic injury, jaundice,

Neuromuscular & skeletal: Paresthesia, osteoporosis

Respiratory: Hemoptysis, epistaxis, pulmonary hemorrhage, tracheobronchial calcification

Miscellaneous: Hypersensitivity/allergic reactions

Symptoms of overdose include internal or external hemorrhage and hematuria. Avoid emesis and lavage to avoid possible trauma and incidental bleeding. When an overdose occurs, the drug should be immediately discontinued and vitamin K₁ (phytonadione) may be administered, up to 25 mg I.V. for adults. When hemorrhage occurs, fresh frozen plasma transfusions can help control bleeding by replacing clotting factors. In urgent bleeding, prothrombin complex concentrates may be needed.

Management of elevated INR:

INR >3 and less than or equal to 6: If no bleeding or need for rapid reversal (ie, no need for surgery), omit next few warfarin doses and restart at lower dose when INR less than or equal to 3.0

INR >6 and <10.0: If no bleeding but in need of rapid reversal for surgery, stop warfarin and give phytonadione 0.5-1 mg I.V.; repeat 0.5 mg phytonadione I.V. if INR >3 after 24 hours; restart warfarin at a lower dose; oral vitamin K (1-2.5mg) can be given in place of parenteral phytonadione when a more gradual reversal is acceptable

INR >10.0 and <20.0: If no bleeding, stop warfarin and give phytonadione 3-5 mg I.V.; check INR every 6-12 hours; repeat phytonadione if needed; reassess need and dose of warfarin

INR >20.0: If serious bleeding or warfarin overdose, stop warfarin; give phytonadione 10 mg I.V.; check INR every 6 hours, if needed, repeat phytonadione every 12 hours and give plasma transfusion or factor concentrate; consider giving heparin if warfarin still indicated

Symptoms of overdose include internal or external hemorrhage and hematuria. Avoid emesis and lavage to avoid possible trauma and incidental bleeding. When an overdose occurs, the drug should be immediately discontinued and vitamin K₁ (phytonadione) may be administered, up to 25 mg I.V. for adults. When hemorrhage occurs, fresh frozen plasma transfusions can help control bleeding by replacing clotting factors. In urgent bleeding, prothrombin complex concentrates may be needed.

CYP1A2 enzyme substrate (minor), CYP2C8, 2C9, 2C18, 2C19, and 3A3/4 enzyme substrate; CYP2C9 enzyme inhibitor

Induction of enzymes: Barbiturates, carbamazepine, glutethimide, griseofulvin, nafcillin, phenytoin, rifampin

Increased procoagulant factors: Estrogens, oral contraceptives, vitamin K (including nutritional supplements)

Decreased drug absorption: Aluminum hydroxide, cholestyramine*, colestipol*

Other: Ethchlorvynol, griseofulvin, spironolactone**, sucralfate

*Cholestyramine and colestipol may increase the anticoagulant effect by binding vitamin K in the gut; yet, the decreased drug absorption appears to be of more concern.

**Diuretic-induced hemoconcentration with subsequent concentration of clotting factors has been reported to decrease the effects of oral anticoagulants.

Increased bleeding tendency: (Use of these agents with oral anticoagulants may increase the chances of hemorrhage.)

Inhibit platelet aggregation: Cephalosporins, dipyridamole, indomethacin, oxyphenbutazone, penicillin (parenteral), phenylbutazone, salicylates, sulfinpyrazone

Inhibit procoagulant factors: Antimetabolites, quinidine, quinine, salicylates

Ulcerogenic drugs: Adrenal corticosteroids, indomethacin, oxyphenbutazone, phenylbutazone, potassium products, salicylates

Enhanced anticoagulant effects:

Decrease Vitamin K: Oral antibiotics can increase or decrease INR. Check INR 3 days after patient begins antibiotics to see the INR value and adjust the warfarin dose accordingly.

Displace anticoagulant: Chloral hydrate, clofibrate, diazoxide, ethacrynic acid, miconazole, nalidixic acid, phenylbutazone, salicylates, sulfonamides, sulfonylureas, triclofos

Inhibit Metabolism: Alcohol (acute ingestion)*, Allopurinol, amiodarone, chloramphenicol, chlorpropamide, cimetidine, co-trimoxazole, disulfiram, metronidazole, phenylbutazone, phenytoin, propoxyphene, sulfinpyrazone, sulfonamides, tolbutamide

Other: Acetaminophen, anabolic steroids, clofibrate, danazol, erythromycin, gemfibrozil, glucagon, influenza vaccine, ketoconazole, propranolol, ranitidine, sulindac, thyroid drugs, capecitabine, celecoxib, rofecoxib

*The 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.

Protect from light; injection is stable for 4 hours at room temperature after reconstitution with 2.7 mL of sterile water

Interferes with hepatic synthesis of vitamin K-dependent coagulation factors (II, VII, IX, X)

Onset of anticoagulation effect: Oral: Within 36-72 hours

Peak effect: Within 5-7 days

Absorption: Oral: Rapid

Metabolism: In the liver

Half-life: 42 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: 5-15 mg/day for 2-5 days, then adjust dose according to results of prothrombin time; usual maintenance dose ranges from 2-10 mg/day

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

Alcohol: Chronic use of alcohol inhibits warfarin metabolism; avoid or limit use

Food:

Vitamin K: 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, watercress. It is recommended that the diet contain a CONSISTENT vitamin K content of 70-140 mcg/day. Check with physician before changing diet.

Vitamin E: May increase warfarin effect; do not change dietary habits or vitamin supplements once stabilized on warfarin therapy

Prothrombin time, hematocrit, INR

Therapeutic: 2-5 mg/mL (SI: 6.5-16.2 mmol/L)

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

Normal prothrombin time: 10-13 seconds

INR ranges based upon indication:

Atrial fibrillation: 2.0-3.0

Venous thromboembolism (DVT, PE): 2.0-3.0

TIA and stroke: 2.0-3.0

Bioprosthetic heart valve: 2.0-3.0

Acute myocardial infarction with risk factors*: 2.5-3.5

Mechanical heart valve (bileaflet, tilting disk): 2.5-3.5

Mechanical heart valve (caged ball, caged disk): 3.0-4.0

*Anterior Q-wave infarction, severe left-ventricular dysfunction, mural thrombus on 2D echo, atrial fibrillation, history of systemic or pulmonary embolism, congestive heart failure

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

Warfarin PTT

Warfarin is used for anticoagulation in a broad spectrum of cardiovascular diseases, including atrial fibrillation, venous thromboses, refractory myocardial ischemia, and in patients with prosthetic heart valves. It is important that patients be closely monitored and that the INR be maintained in the range considered optimal for the therapeutic objective.

Warfarin is teratogenic and therefore, should not be used in pregnancy. The advent of low molecular weight heparins have provided an important alternative to warfarin therapy, particularly in pregnant women with prosthetic heart valves. Administration of low molecular weight heparins in predetermined doses at home has obviated the need for hospitalization with intravenous heparin therapy for these patients.

It is important that INR be closely monitored for several reasons. These include the problem of dietary changes, changing warfarin efficacy. Furthermore, warfarin interacts with a very wide spectrum of prescription and over-the-counter medications. Any change in a patient's medication profile should be carefully monitored and potential effects on increasing or attenuating warfarin effectiveness should be addressed. It is important to advise patients on warfarin to seek prompt medical evaluation if they develop very severe headache or backache or should they experience significant trauma to rule out the possibility of significant concealed bleeding.

None reported

May cause leukopenia; use caution with clozapine and carbamazepine; barbiturates and carbamazepine may decrease the anticoagulant effect of warfarin; chloral hydrate, alcohol, disulfiram, and SSRIs may enhance the anticoagulant effect

No information available to require special precautions

Signs of warfarin overdose may first appear as bleeding from gingival tissue; consultation with prescribing physician is advisable prior to surgery to determine temporary dose reduction or withdrawal of medication

Take exactly as directed; if dose is missed, take as soon as possible. Do not double doses. Do not take any medication your prescriber is not aware of and follow diet and activity as recommended by prescriber. You may have a tendency to bleed easily while taking this drug; brush teeth with soft brush, floss with waxed floss, use electric razor, and avoid scissors or sharp knives and potentially harmful activities. You may experience nausea or vomiting (small frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help). May discolor urine or stool. Report skin rash or irritation, unusual fever, persistent nausea or GI upset, unusual bleeding or bruising (bleeding gums, nosebleed, blood in urine, dark stool, bloody emesis), pain in joints or back, swelling or pain at injection site.

Should not be given in close proximity to other drugs because absorption may be decreased. Administer warfarin at least 1-2 hours prior to, or 6 hours after, cholestyramine or sucralfate, because cholestyramine or sucralfate may bind warfarin and decrease its total absorption; avoid all I.M. injections.

Powder for injection, as sodium, lyophilized: 2 mg, 5 mg

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

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