Warfarin Sodium

Pronunciation: (WAR-far-in SOE-dee-um)
Class: Anticoagulant

Trade Names

Coumadin
- Tablets, oral 1 mg
- Tablets, oral 2 mg
- Tablets, oral 2.5 mg
- Tablets, oral 3 mg
- Tablets, oral 4 mg
- Tablets, oral 5 mg
- Tablets, oral 6 mg
- Tablets, oral 7.5 mg
- Tablets, oral 10 mg
- Injection, lyophilized powder for solution 2 mg/mL

Jantoven
- Tablets, oral 1 mg
- Tablets, oral 2 mg
- Tablets, oral 2.5 mg
- Tablets, oral 3 mg
- Tablets, oral 4 mg
- Tablets, oral 5 mg
- Tablets, oral 6 mg
- Tablets, oral 7.5 mg
- Tablets, oral 10 mg

Apo-Warfarin (Canada)
Gen-Warfarin (Canada)
Taro-Warfarin (Canada)

Pharmacology

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

Completely absorbed after oral administration. T _max is 4 h.

Distribution

Vd is approximately 0.14 L/kg. Approximately 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 the urine and, to a lesser extent, into the bile. The half-life after a single dose is approximately 1 wk; however, the effective half-life ranges from 20 to 60 h. The Cl of R-warfarin is 50% that of S-warfarin. The half-life of R-warfarin is approximately 37 to 89 h and S-warfarin is approximately 21 to 43 h. Approximately 92% of orally administered doses are recovered in the urine.

Onset

Within 24 h.

Peak

72 to 96 h.

Duration

2 to 5 days.

Special Populations

Renal Function Impairment

Renal Cl is a minor determinant of anticoagulant response to warfarin.

Hepatic Function Impairment

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

Elderly

Patients 60 y and older appear to exhibit greater than expected PT/INR response to warfarin. Cl may be unchanged or reduced with increasing age.

Race

Asian patients may require lower initiation and maintenance doses.

Pharmacogenetics

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

Unlabeled Uses

Primary venous thromboembolism prophylaxis in cancer patients; venous thromboembolism prophylaxis in cancer patients with a central venous catheter.

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, alcoholism, psychosis, or other lack of patient cooperation; malignant hypertension; hypersensitivity to any component of the product.

Dosage and Administration

Adults

IV/PO 2 to 5 mg/day initially; adjust daily dose according to PT or INR determinations. Usual maintenance dosage 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. For more information on the range of expected therapeutic warfarin doses based on CYP2C9 and VKORC1 genotypes, refer to the manufacturer's prescribing information.

Duration of therapy

The following duration of therapy recommendations are based on the 8th American College of Chest Physicians (ACCP) Conference on Antithrombotic and Thrombolytic Therapy.

Bioprosthetic valves in the aortic position

3 mo after valve insertion.

Myocardial infarction (high risk)

3 mo after the MI.

Venous thromboembolism First episode, transient (reversible) risk factor

3 mo.

First episode, unprovoked

At least 3 mo; evaluate risk-benefit of long-term therapy.

Two or more episodes of documented deep venous thrombosis or pulmonary embolism

Indefinite; periodically reassess the risk-benefit of anticoagulation.

INR goals

The following INR goals are based on the 8th ACCP Conference on Antithrombotic and Thrombolytic Therapy recommendations.

Atrial fibrillation or flutter; bileaflet valve or Medtronic Hall tilting disc valve in aortic position; bioprosthetic valve in the mitral position or in any position in patients with a history of systemic embolism, evidence of left atrial thrombus at surgery, or additional risk factors for thromboembolism; lupus inhibitor and no additional risk factors for thromboembolism; mitral valve prolapse with atrial fibrillation, documented systemic embolism, or recurrent transient ischemic attack; rheumatic mitral valve disease complicated by atrial fibrillation, previous systemic embolism, and/or left atrial thrombus; venous thromboembolism (including DVT and PE)

2.5 (range, 2 to 3).

Caged ball or caged disk valve; lupus inhibitor and additional risk factors for thromboembolism or recurrent thromboembolic events despite therapeutic INR; mechanical heart valves in aortic or mitral position and additional risk factors for thromboembolism; tilting disk valve or bileaflet valve in the mitral position

3 (range, 2.5 to 3.5).

Mechanical heart valve with systemic embolism despite a therapeutic INR

3 (range, 2.5 to 3.5) or 3.5 (range, 3 to 4), depending on original INR goal.

Myocardial infarction (high risk [eg, large anterior MI, significant heart failure, intracardiac thrombus visible on echocardiography, history of a thrombolic event])

2 to 3.

Elderly

PO/IV Lower initiation and maintenance doses are recommended.

Hepatic Function Impairment

PO/IV May require dosage adjustments.

General Advice

Routine use of loading doses is not recommended.
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; not recommended for IM administration.
Reconstitute IV vial with 2.7 mL of sterile water for injection.

Storage/Stability

Store between 59° and 86°F. Protect from light. After reconstitution, store IV solution between 59° and 86°F and use within 4 h. Do not refrigerate. Discard any unused IV solution.

Drug Interactions

Acetaminophen, aminoglycosides oral, aminosalicylic acid, amiodarone, anabolic steroids (eg, danazol, oxandrolone, oxymetholone, stanozolol), androgens, anticoagulants (eg, argatroban, bivalirudin, dicumarol, lepirudin), antiplatelet agents (eg, clopidogrel, prasugrel), azole antifungal agents (eg, fluconazole, itraconazole, miconazole, voriconazole), beta-blockers (eg, atenolol, propranolol), bromelains, capecitabine, carboplatin, cefamandole, cefazolin, cefoperazone, cefotetan, cefoxitin, ceftriaxone, chenodiol, chitosan, chloramphenicol, chlorpropamide, cimetidine, ciprofloxacin, cisapride, cranberry, cyclophosphamide, danshen, dextran, dextrothyroxine, diazoxide, diflunisal, disulfiram, dronedarone, dong quai, doxycycline, etoposide, felbamate, fenofibrate, fish oil, fluorouracil, flutamide, garlic, gefitinib, gemcitabine, gemfibrozil, ginkgo biloba, ginseng, glucagon, halothane, heparin, herbal teas, HMG-CoA reductase inhibitors (eg, fluvastatin, lovastatin, simvastatin), ifosfamide, imatinib, influenza virus vaccine, isoniazid, leflunomide, levamisole, levofloxacin, loop diuretics (ie, ethacrynic acid, furosemide), macrolide and related antibiotics (eg, azithromycin, clarithromycin, erythromycin, telithromycin), maitake, mefloquine, methimazole, methylsalicylate ointment, metronidazole, methyldopa, methylphenidate, mifepristone, mineral oil, moxifloxacin, nalidixic acid, neomycin, norfloxacin, NSAIDs (eg, naproxen), ofloxacin, olsalazine, orlistat, paclitaxel, penicillins (high-dose IV), pentoxifylline, phenylbutazone, prasugrel, propafenone, propoxyphene, propylthiouracil, proton pump inhibitors (eg, esomeprazole, lansoprazole, omeprazole), quinidine, quinine, ropinirole, salicylates, selective COX-2 inhibitors (eg, celecoxib, rofecoxib, valdecoxib), SSRIs (ie, fluoxetine, fluvoxamine, paroxetine, sertraline), sulfinpyrazone, sulfonamides (eg, sulfamethizole, sulfisoxazole), tamoxifen, tetracyclines, thrombolytics (eg, streptokinase, tissue plasminogen activator, urokinase), thyroid hormones, ticlopidine, tolbutamide, tolterodine, tramadol, trastuzumab, valproate, vitamin E, zafirlukast, zileuton

Increased anticoagulant effect of warfarin. Careful monitoring and appropriate dosage adjustments will usually permit combination therapy. Critical times during therapy will usually permit combination therapy. Critical times during therapy occur when an interacting drug is added to or discontinued from a patient stabilized on anticoagulants.

Alcohol, atorvastatin, chloral hydrate, cholestyramine, corticosteroids, cyclophosphamide, methimazole, moricizine, propylthiouracil, ranitidine

Increased and decreased PT/INR responses have been reported. May increase or decrease the anticoagulant effect of warfarin; the mechanism is unknown. Careful monitoring and appropriate dosage adjustments will usually permit combination therapy. Critical times during therapy will usually permit combination therapy. Critical times during therapy occur when an interacting drug is added to or discontinued from a patient stabilized on anticoagulants.

Aminoglutethimide, aprepitant, ascorbic acid (high-dose), barbiturates (eg, butabarbital, secobarbital), bosentan, carbamazepine, chlordiazepoxide, clozapine, contraceptives (oral), cyclosporine, dicloxacillin, estrogens, ethchlorvynol, glutethimide, griseofulvin, haloperidol, isotretinoin, menthol, meprobamate, mesalamine, mitotane, nafcillin, nevirapine, paraldehyde, primidone, protease inhibitors (eg, indinavir, ritonavir), raloxifene, ribavirin, rifabutin, rifampin, smoking, spironolactone, St. John's wort, sucralfate, terbinafine, thiazide diuretics (eg, chlorthalidone), thiopurines (eg, azathioprine), trazodone, ubiquinone, and vitamin K

Decreased anticoagulant effect of warfarin. Careful monitoring and appropriate dosage adjustments will usually permit combination therapy. Critical times during therapy will usually permit combination therapy. Critical times during therapy occur when an interacting drug is added to or discontinued from a patient stabilized on anticoagulants.

Herbal supplements

Caution should be exercised when herbal products are taken concurrently with warfarin. Advise patients to consult their health care provider regarding the use of herbal products, and to report any unexplained signs of bleeding.

Hydantoins (eg, phenytoin)

Serum hydantoin concentration may be elevated, increasing risk of toxicity. Increased and decreased PT/INR may occur. Monitor patients for signs and symptoms of altered response to hydantoins or warfarin when either drug is started or stopped.

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 and other tissues; pallor; pruritus; rash; urticaria.

GI

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

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.

Hypersensitivity

Allergic/hypersensitivity reactions (including anaphylactic reactions).

Respiratory

Tracheal or tracheobronchial calcification.

Miscellaneous

Chest pain; cold intolerance; coma; edema; fever; pain; priapism; purple toe syndrome; systemic cholesterol microembolism.

Precautions

Warnings

Bleeding risk

Major or fatal bleeding can occur. Bleeding is more likely to occur during the starting period and with a higher dose. Risk factors include INR greater than 4, age 65 y and older, highly variable INRs, history of GI bleeding, hypertension, cerebrovascular disease, serious heart disease, anemia, malignancy, trauma, renal impairment, concomitant drugs (see Interactions), and long duration of warfarin therapy. Perform regular monitoring of INR in all patients. Instruct patients about prevention measures to minimize risk of bleeding.

Monitor

Regularly monitor INR in all patients. Individualize treatment based on PT or INR.

Pregnancy

Category X . May cause hemorrhage to the fetus and/or birth malformations.

Lactation

Undetermined. The American Academy of Pediatrics classifies warfarin as compatible with breast-feeding.

Children

Safety and efficacy not established in patients younger than 18 y.

Elderly

May be more sensitive to effects; use with caution.

Hepatic Function

Use cautiously.

Special Risk Patients

There is increased risk associated with using warfarin in patients with surgery or trauma, infection or disturbances of intestinal flora (sprue, antibiotic therapy), severe to moderate hepatic or renal impairment, severe diabetes, dietary insufficiency, severe to moderate hypertension, polycythemia vera, vasculitis or indwelling catheters. Evaluate benefits of therapy versus risks.

Atheroemboli/Microemboli

Therapy may enhance the release of atheromatous plaque emboli, thereby increasing the risk of complications from systemic cholesterol microembolization, including purple toes syndrome. Discontinue therapy when such phenomena are observed.

Hemorrhage/Necrosis

Most serious risks associated with warfarin therapy.

Heparin-induced thrombocytopenia

Use warfarin with caution in patients with heparin-induced thrombocytopenia and deep vein thrombosis; cases of venous limb ischemia, necrosis, and gangrene have occurred.

IM injections

Confine IM injections of concomitant medications to the upper extremities.

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.

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

Blood in the stools, excessive bruising, excessive menstrual bleeding, hematuria, melena, oozing from superficial injuries, petechiae.

Patient Information

Advise patients to read the Medication Guide before starting therapy and with each refill.
Caution patient that this medication must not be taken during pregnancy or when pregnancy is possible. Advise patient to use a reliable form of birth control while taking this drug.
Advise patients not to change their 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 patients not to drastically change their diet or consume alcohol.
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, unusual bleeding (eg, heavier than normal menstrual flow), or bruising.
Caution patient not to take aspirin or other salicylates without consulting their 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).
Advise patients that regular INR testing and visits to their health care provider are needed to monitor therapy.
Advise patients to avoid any activity or sport that may result in traumatic injury.
Instruct patients to contact their health care provider to report any illness, such as diarrhea, infection, or fever.