Warfarin Sodium

Trade Names:
Coumadin
- Tablets 1 mg
- Tablets 2 mg
- Tablets 2.5 mg
- Tablets 3 mg
- Tablets 4 mg
- Tablets 5 mg
- Tablets 6 mg
- Tablets 7.5 mg
- Tablets 10 mg
- Powder for Injection, lyophilized 2 mg/mL

Trade Names:
Jantoven
- Tablets 1 mg
- Tablets 2 mg
- Tablets 2.5 mg
- Tablets 3 mg
- Tablets 4 mg
- Tablets 5 mg
- Tablets 6 mg
- Tablets 7.5 mg
- Tablets 10 mg

Pharmacology

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Interferes with hepatic synthesis of vitamin K–dependent clotting factors, resulting in in-vivo depletion of clotting factors II, VII, IX, and X, and proteins C and S.

Pharmacokinetics

Absorption

It is completely absorbed. T _max is 4 h.

Distribution

Vd is about 0.14 L/kg. It is about 99% bound to plasma protein.

Metabolism

The elimination of warfarin is almost entirely by metabolism. It is metabolized by CYP-450 to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolites (warfarin alcohols).

Elimination

Metabolites are principally excreted into urine and to a lesser extent into the bile. The t _½ after a single dose is about 1 wk; however, the effective t _½ ranges from 20 to 60 h. The Cl of R-warfarin is 50% that of S-warfarin. The t _½ of R-warfarin is about 37 to 89 h and S-warfarin about is 21 to 43 h. About 92% of orally administered doses are recovered in urine.

Special Populations

No dosage adjustment is needed.

Hepatic function impairment can potentiate the response to warfarin through impaired synthesis of clotting factors and decreased metabolism of warfarin.

Patients 60 yr of age and older appear to exhibit greater than expected PT/INR response to warfarin. As a patient's age increases, a lower dose is usually required to produce a therapeutic level of anticoagulation.

Asian patients may require lower initiation and maintenance doses.

About 55% of the variability in warfarin dose can be explained by polymorphisms in the vitamin K epoxide reductase (VKORC1) and CYP2C9 genotypes.

Indications and Usage

Prophylaxis and treatment of pulmonary embolism, and venous thrombosis and its extension; prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation and cardiac valve replacement; reduction of risk of death, recurrent MI, and thromboembolic events such as stroke or systemic embolism after MI.

Contraindications

Pregnancy; hemorrhagic tendencies or blood dyscrasias; recent or contemplated surgery of the CNS, eye, or traumatic surgery resulting in large open surfaces; bleeding tendencies associated with active ulceration or overt bleeding of GI, GU, or respiratory tracts; cerebrovascular hemorrhage; cerebral or dissecting aorta aneurysms; pericarditis and pericardial effusions; bacterial endocarditis; threatened abortion, eclampsia, and preeclampsia; spinal puncture and other diagnostic or therapeutic procedures with potential for uncontrolled bleeding; major regional, lumbar block anesthesia; malignant hypertension; inadequate laboratory facilities; unsupervised patients with senility; hypersensitivity to any component of the product.

Dosage and Administration

PO 2 to 5 mg/day initially; adjust daily dose according to PT or INR determinations. Usual maintenance dose is 2 to 10 mg/day. Lower dosages are recommended in patients with genetic variations in CYP2C9 and VKORC1 enzymes as well as in elderly and/or debilitated patients.

IV Provides an alternative administration route for patients who cannot receive oral drugs. The IV dosages would be the same as those that would be used orally. Administer as a slow bolus injection over 1 to 2 min in a peripheral vein.

General Advice

• Do not give large loading dose.
• Do not switch brands.
• Administer at same time each day.
• Tablets can be broken in half for more flexible dosing.
• For IV use, give a slow bolus injection over 1 to 2 min in a peripheral vein.
• Reconstitute IV vial with 2.7 mL of sterile water for injection.
• After reconstitution, solution is stable for 4 h at room temperature.
• Check solution for particle matter or discoloration immediately before use. If either is present, do not use.
• Discard unused solution.

Storage/Stability

Store at 59° to 86°F. Protect from light. After reconstitution, store IV solution at 59° to 86°F and use within 4 h. Do not refrigerate.

Drug Interactions

Decreased anticoagulant effect of warfarin.

Increased anticoagulant effect of warfarin.

Serum hydantoin concentration may be elevated, increasing risk of toxicity.

Laboratory Test Interactions

Oral anticoagulants may cause red-orange discoloration of alkaline urine, interfering with some laboratory tests.

Adverse Reactions

Cardiovascular

Angina syndrome; hypotension; syncope; vasculitis.

CNS

Asthenia; dizziness; fatigue; headache; lethargy; loss of consciousness; malaise; paresthesia (including feeling cold and chills).

Dermatologic

Alopecia; dermatitis (including bullous eruptions); necrosis of skin; pallor; pruritus; rash; urticaria.

EENT

Tracheal calcification.

GI

Abdominal pain (including cramping); bloating; diarrhea; flatulence; nausea; taste perversion; vomiting.

Genitourinary

Priapism.

Hematologic-Lymphatic

Anemia; bleeding; hemorrhagic complication (including difficulty breathing or swallowing; dizziness; headache; hypotension; pain in the abdomen, chest, joint, or muscle; paralysis; paresthesia; shortness of breath; unexplained shock; unexplained swelling; weakness).

Hepatic

Cholestatic hepatic injury; elevated liver enzymes; hepatitis; jaundice.

Respiratory

Tracheobronchial calcification.

Miscellaneous

Allergic/hypersensitivity reactions (including anaphylactic reactions); chest pain; cold intolerance; coma; edema; fever; purple toe syndrome; systemic cholesterol microembolism; pain.

Precautions

Pregnancy

Category X .

Lactation

Undetermined.

Children

Safety and efficacy not established in children younger than 18 yr of age.

Elderly

May be more sensitive to effects.

Hypersensitivity

Reactions range from mild to life-threatening. Symptoms may be dermatologic (eg, erythema, eczematous rash, exfoliative dermatitis, exudative erythema multiforme, alopecia), hematologic (eg, eosinophilia, leukopenia, thrombocytopenia), renal (eg, nephropathy, nephritis, oliguria), GI (eg, enanthema, severe stomatitis), or hepatic (eg, mixed hepatocellular damage, cholestasis, jaundice). If signs or symptoms occur, discontinue therapy.

Hepatic Function

Use cautiously.

Special Risk Patients

There is increased risk associated with using warfarin in patients with trauma, infection, renal function impairment, dietary insufficiency, uncontrolled hypertension, polycythemia vera, vasculitis, indwelling catheters. Evaluate benefits of therapy vs risks.

Adrenal hemorrhage

Discontinue therapy if patient develops signs and symptoms of adrenal insufficiency.

Protein C deficiency

Hereditary, familial, or clinical protein C deficiency has been associated with necrosis following warfarin therapy. If warfarin is the suspected cause of necrosis, discontinue administration.

Purple toe syndrome

Systemic cholesterol microembolization from release of atheromatous plaque emboli. Discontinue therapy.

Surgical/Dental procedures

Adjust dose to maintain PT or INR at low end of therapeutic range for patients who must be anticoagulated during dental or surgical procedures.

Overdosage

Symptoms

Hematuria, excessive menstrual bleeding, melena, oozing from superficial injuries, petechiae.

Patient Information

• Caution patient that this medication must not be taken during pregnancy or when pregnancy is possible. Advise patient to use reliable form of birth control while taking this drug.
• Advise patient not to change dose unless advised by health care provider.
• Inform patients that if a dose is missed to take the dose as soon as possible on the same day and not to take the missed dose by doubling the dose to make up for a missed dose.
• Advise patient not to drastically change diet or consume alcohol.
• Advise patient not to change brands of medicine.
• Advise patient to limit intake of vitamin K–rich foods, including avocados, bananas, broccoli, dried fruits, grapefruit, lima beans, nuts, oranges, peaches, potatoes, sunflower seeds, spinach, and tomatoes.
• Instruct patient to report any GI upset, pink or red discoloration of urine, red or tar-black stools or diarrhea, rash, yellowish tint of skin or eyes, or unusual bleeding (eg, heavier than normal menstrual flow), or bruising.
• Caution patient not to take aspirin or other salicylates without consulting health care provider.
• Instruct patient in safety practices: use a soft toothbrush, electric razor, and night lights, and avoid activities that could result in bruising or bleeding.
• Remind patient to wear medical identification (eg, card, bracelet).

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