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Warfarin Sodium

Pronunciation

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 5 mg (2 mg/mL when reconstituted)

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.

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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

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 INR response to warfarin.

Race

Asian patients may require lower initiation and maintenance doses.

Pharmacogenetics

Vitamin K epoxide reductase (VKORC1) and CYP2C9 gene variants generally explain the largest proportion of known variability in warfarin dose requirements.

Indications and Usage

Prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism; 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, except in pregnant women with mechanical heart valves who are at high risk of thromboembolism; hemorrhagic tendencies or blood dyscrasias; recent or contemplated surgery of the CNS or eye, or traumatic surgery resulting in large open surfaces; bleeding tendencies associated with active ulceration or overt bleeding of GI, GU, or respiratory tracts; CNS hemorrhage; cerebral aneurysms; dissecting aorta; 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 or lumbar block anesthesia; malignant hypertension; unsupervised patients with conditions associated with a potential high level of noncompliance; 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 INR determinations. Usual maintenance dosage is 2 to 10 mg/day. Lower dosages are recommended in elderly and/or debilitated patients. Dosage requirements are variable in patients with genetic variations in CYP2C9 and VKORC1 enzymes. 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 9th American College of Chest Physicians (ACCP) Conference on Antithrombotic and Thrombolytic Therapy.

Atrial fibrillation

Indefinite.

Bioprosthetic valves in the mitral position

3 mo after valve insertion.

Anterior myocardial infarction with left ventricular thrombus or high risk of left ventricular thrombus

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. For patients at high risk of bleeding who have a second unprovoked venous thromboembolism, 3 mo of therapy is recommended.

INR goals

The following INR goals are based on the 9th ACCP Conference on Antithrombotic and Thrombolytic Therapy recommendations.

Atrial fibrillation or flutter; anterior myocardial infarction and left ventricular thrombus or at high risk of left ventricular thrombus

2 to 3.

Mechanical heart valve in aortic and mitral position

3 (range, 2.5 to 3.5).

Mechanical valve in aortic position; bioprosthetic valve in the mitral position; rheumatic mitral valve disease and normal sinus rhythm with left atrial diameter more than 55 mm; rheumatic mitral valve disease complicated by atrial fibrillation, previous systemic embolism, and/or left atrial thrombus; venous thromboembolism (including deep vein thrombosis and pulmonary embolism)

2.5 (range, 2 to 3).

Elderly

PO/IV Lower initiation and maintenance doses are recommended.

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 to yield 2 mg/mL.

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, acyclovir, alprazolam, aminoglycosides oral (eg, neomycin, paromomycin), aminosalicylic acid, amiodarone, amlodipine, anabolic steroids (eg, danazol, oxandrolone, oxymetholone), androgens (eg, oxymetholone), anticoagulants (eg, argatroban, bivalirudin, dicumarol, lepirudin), antiplatelet agents (eg, clopidogrel, prasugrel), atovaquone, azole antifungal agents (eg, fluconazole, itraconazole, ketoconazole, miconazole, posaconazole, voriconazole), beta-blockers (eg, atenolol, propranolol), bicalutamide, bromelains, caffeine, capecitabine, carboplatin, cefamandole, cefazolin, cefoperazone, cefotetan, cefoxitin, ceftriaxone, chenodiol, chitosan, chloramphenicol, chlorpropamide, cilostazol, ciprofloxacin, cisapride, cisplatin, conivaptan, cranberry, cyclophosphamide, cyclosporine, dabigatran, danshen, desirudin, dextran, dextrothyroxine, diazoxide, diflunisal, diltiazem, dipyridamole, disulfiram, dronedarone, dong quai, doxycycline, etoposide, felbamate, fenofibrate, fish oil, fluorouracil, flutamide, garlic, gefitinib, gemcitabine, gemfibrozil, ginkgo biloba, ginseng, glucagon, heparin, herbal teas, histamine H 2 antagonists (eg, cimetidine, famotidine, ranitidine), 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, methoxsalen, methylsalicylate ointment, methyldopa, methylphenidate, metronidazole, mexiletine, mifepristone, mineral oil, moxifloxacin, nalidixic acid, nefazodone, neomycin, niacin, nilotinib, norfloxacin, NSAIDs (eg, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac, tolmetin), ofloxacin, olsalazine, orlistat, paclitaxel, penicillins (high-dose IV), pentoxifylline, prasugrel, propafenone, propoxyphene, propylthiouracil, proton pump inhibitors (eg, esomeprazole, lansoprazole, omeprazole), quinidine, quinine, ranolazine, rivaroxaban, ropinirole, salicylates (eg, aspirin), selective cyclooxygenase 2 inhibitors (eg, celecoxib, rofecoxib, valdecoxib), SNRIs (eg, desvenlafaxine, duloxetine, milnacipran, venlafaxine), SSRIs (ie, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, vilazodone), sulfinpyrazone, sulfonamides (eg, sulfamethizole, sulfisoxazole), tamoxifen, tetracyclines, thrombolytics (eg, drotrecogin, streptokinase, ticlopidine, tigecycline, tissue plasminogen activator, urokinase), thyroid hormones, ticlopidine, tolbutamide, tolterodine, tramadol, trastuzumab, valproate, vemurafenib, verapamil, 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 starting, stopping, or changing the dose of an interacting drug in a patient stabilized on anticoagulants.

Alcohol, atorvastatin, chloral hydrate, cholestyramine, corticosteroids, cyclophosphamide, etravirine, methimazole, moricizine, propylthiouracil, ranitidine, terbinafine, thiazolidinediones (eg, pioglitazone, rosiglitazone)

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, colesevelam, contraceptives (oral), cyclosporine, dicloxacillin, efavirenz, estrogens, glutethimide, griseofulvin, haloperidol, isotretinoin, menthol, meprobamate, mesalamine, mitotane, modafinil, montelukast, nafcillin, nevirapine, paraldehyde, primidone, protease inhibitors (eg, atazanavir, darunavir/ritonavir, fosamprenavir, indinavir, nelfinavir, ritonavir), raloxifene, ribavirin, rifabutin, rifampin, rifaximin, rufinamide, smoking, spironolactone, St. John's wort, sucralfate, terbinafine, thiazide diuretics (eg, chlorthalidone), thiopurines (eg, azathioprine), trazodone, ubiquinone, 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 concentrations 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

Dermatologic

Alopecia; dermatitis (including bullous eruptions); pruritus; rash.

GI

Abdominal pain; bloating; diarrhea; flatulence; nausea; taste perversion; vomiting.

Hematologic-Lymphatic

Minor bleeding (11%); major bleeding (3%).

Hepatic

Cholestatic hepatitis; elevated liver enzymes; hepatitis; jaundice.

Hypersensitivity

Allergic/hypersensitivity reactions (including anaphylactic reactions, urticaria).

Respiratory

Tracheal or tracheobronchial calcification.

Miscellaneous

Chills; vasculitis.

Precautions

Warnings

Bleeding risk

Major or fatal bleeding can occur. Bleeding is more likely to occur within the first month. Risk factors include INR greater than 4, age 65 y and older, highly variable INRs, history of GI bleeding, hypertension, cerebrovascular disease, anemia, malignancy, trauma, renal impairment, certain genetic factors, 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 the risk of bleeding.


Monitor

Determine INR daily after the initial dose until the INR results stabilize in the therapeutic range. Maintain dosing within the therapeutic range by performing periodic INRs. Base the frequency of INR monitoring on the clinical situation; generally acceptable intervals are 1 to 4 wk. Perform additional INR tests when other warfarin products are interchanged, as well as when other medications are initiated, discontinued, or taken regularly.


Pregnancy

Category D for women with mechanical valves; Category X for other pregnant populations. Warfarin exposure during pregnancy causes a pattern of major congenital malformations (warfarin embryopathy), fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality.

Lactation

Undetermined. The American Academy of Pediatrics classifies warfarin as compatible with breast-feeding. Monitor breast-feeding infants for bruising or bleeding.

Children

Adequate and well-controlled studies with warfarin have not been conducted in any pediatric population, and the optimum dosing, safety, and efficacy in pediatric patients are not known.

Elderly

May be more sensitive to effects; use with caution.

Hepatic Function

Use cautiously.

Special Risk Patients

The risks of warfarin therapy may be increased in the following: severe to moderate hepatic impairment, infectious diseases or disturbances of intestinal flora (sprue, antibiotic therapy), use of an indwelling catheter, severe to moderate hypertension, polycythemia vera, vasculitis, diabetes mellitus.

Atheroemboli/Microemboli

Therapy may enhance the release of atheromatous plaque emboli. Can present with a variety of signs and symptoms and commonly involves the kidney, pancreas, spleen, and liver. Purple toe syndrome may result from microemboli to the feet. Discontinue therapy when such phenomena are observed.

Eye surgery

In cataract surgery, warfarin use was associated with a significant increase in minor complications of sharp needle and local anesthesia block, but not sight-threatening operative hemorrhagic complications. Because warfarin cessation or reduction may lead to serious thromboembolic complications, base the decision to discontinue warfarin for relatively less invasive and complex eye surgery on the risks weighed against the benefits.

Heparin-induced thrombocytopenia

Do not use warfarin as initial therapy in patients with heparin-induced thrombocytopenia or heparin-induced thrombocytopenia with thrombosis syndrome. Cases of limb ischemia, necrosis, and gangrene have occurred in patients with heparin-induced thrombocytopenia or heparin-induced thrombocytopenia with thrombosis syndrome. Warfarin treatment may be considered after the platelet count has normalized.

Protein C deficiency

Hereditary or acquired deficiencies of protein C or S have been associated with necrosis following warfarin therapy. If warfarin is the suspected cause of necrosis, discontinue administration.

Surgical/Dental procedures

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

Tissue necrosis

Necrosis and/or gangrene of skin and other tissues is an uncommon but serious risk (less than 0.1%). Necrosis may be associated with local thrombosis and usually appears within a few days of treatment initiation.

Overdosage

Symptoms

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

Patient Information

  • Advise patients to read the Medication Guide before starting therapy and with each refill.
  • Advise patients to tell their health care provider if they fall often because this may increase their risk for complications.
  • Advise patients to contact their health care provider immediately if they think they are pregnant, to discuss pregnancy planning, or if they are considering breast-feeding. Advise patients 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 to eat a normal, balanced diet to maintain a consistent intake of vitamin K and to avoid drastic changes in dietary habits, such as eating large amounts of leafy, green vegetables.
  • Instruct patients to report any GI upset, pink or red discoloration of urine, red or tar-black stools or diarrhea, rash, yellowish tint of the skin or eyes, unusual bleeding (eg, heavier than normal menstrual flow), or bruising.
  • Caution patients not to take or discontinue any other medication, including aspirin or other salicylates, other nonprescription medications, and herbal products, without consulting their health care provider.
  • Remind patients 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.
  • If therapy with warfarin is discontinued, caution patients that the anticoagulant effect may persist for approximately 2 to 5 days.

Copyright © 2009 Wolters Kluwer Health.

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