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warfarin sodium 10 mg tablet

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Uses

Warfarin is used for prophylaxis and/or treatment of venous thrombosis and its extension, prophylaxis and treatment of pulmonary embolism, prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement, and as an adjunct in the treatment of coronary occlusion. The drug also is used to reduce the risk of death, reinfarction, and thromboembolic events such as stroke or systemic embolization following myocardial infarction (MI).

The most widely accepted indications for anticoagulant therapy include the treatment of venous thrombosis and pulmonary embolism and prevention of these conditions in high-risk patients, such as those with a history of thromboembolism, those undergoing certain types of major surgery, or those who require prolonged immobilization. Because the effects of warfarin are delayed and early full-dose anticoagulant therapy reduces the risk of extension or recurrence of venous thrombosis, a rapid-acting parenteral anticoagulant such as heparin (referring throughout this monograph to unfractionated heparin), a low molecular weight heparin, or fondaparinux is used for the initial treatment of venous thromboembolism. Warfarin generally is used for follow-up anticoagulant therapy after the effects of the initial parenteral anticoagulant have been established and when long-term anticoagulant therapy is indicated. Therapy with warfarin and the parenteral anticoagulant should be overlapped for a short period of time until the therapeutic effects of warfarin are achieved.(See Dosage and Administration: Dosage.)

Deep-Vein Thrombosis and Pulmonary Embolism

Treatment and Secondary Prevention

In the treatment of acute proximal deep-vein thrombosis (DVT) or pulmonary embolism (PE) (i.e., venous thromboembolism) in adults, the American College of Chest Physicians (ACCP) recommends that warfarin therapy be initiated concomitantly with a parenteral anticoagulant (heparin, a low molecular weight heparin, or fondaparinux). Warfarin should be initiated on the same day that the parenteral anticoagulant is started, and such therapy should be overlapped for at least 5 days and until a stable international normalized ratio (INR) of at least 2 has been maintained for 24 hours or longer. Anticoagulant therapy generally is not recommended for the treatment of isolated distal DVT unless symptoms are severe and there is a risk for thrombus extension. ACCP recommends a moderate intensity (target INR of 2.5, range 2-3) of warfarin anticoagulation in most patients for the treatment of DVT and PE. While use of either a lower intensity of anticoagulation (INR <2) or a higher intensity of anticoagulation (INR of 3-5) has been evaluated for these indications, both low-intensity and high-intensity anticoagulation appear to be less optimal than moderate-intensity warfarin; low-intensity warfarin is no safer than moderate-intensity warfarin, and high-intensity warfarin is associated with an increased incidence of bleeding complications.

In patients with venous thromboembolism, ACCP recommends that anticoagulant therapy be continued beyond the acute treatment period for at least 3 months, and possibly longer depending on the individual clinical situation (e.g., location of thrombi, presence or absence of precipitating factors, presence of cancer, patient's risk of bleeding). Warfarin generally is the preferred anticoagulant for long-term treatment of venous thromboembolism in patients without cancer; however, in patients with cancer, ACCP suggests the use of a low molecular weight heparin over warfarin because of certain factors in such patients that may affect warfarin therapy (e.g., possible reduced response to warfarin, drug interactions, need for invasive procedures that require reversal of anticoagulation). While several randomized, controlled studies of patients receiving warfarin indicate that recurrence of venous thromboembolism is less frequent with longer periods of anticoagulation (exceeding 6 months) compared with shorter periods (3-6 months), particularly in patients with idiopathic (i.e., unprovoked) venous thromboembolism, prolonged therapy with warfarin (in addition to increased intensity of anticoagulation) is associated with an increased risk of bleeding complications. Therefore, the shortest period of anticoagulant therapy deemed to be effective should be used, keeping in mind the high morbidity and mortality of undertreated venous thromboembolism. ACCP states that 3 months of anticoagulant treatment usually is sufficient in patients experiencing a proximal DVT or PE provoked by surgery or other transient risk factor. For those with an unprovoked thromboembolic event, anticoagulant therapy should be continued for at least 3 months; after this time, the risks versus benefits of extended therapy (defined by ACCP as treatment beyond 3 months without a scheduled stop date) should be evaluated in individual patients. In general, extended anticoagulant therapy is suggested in patients with unprovoked (idiopathic) DVT or PE who are at low risk of bleeding. Extended therapy is recommended by ACCP in cancer patients with acute venous thromboembolism because of the high risk of recurrence in these patients. Patients with acute upper-extremity DVT involving the axillary or more proximal veins also should receive anticoagulant therapy for at least 3 months. If the upper-extremity DVT is associated with a central venous catheter, anticoagulation should be continued as long as the catheter remains in place; if the catheter is removed, ACCP states that 3 months of anticoagulation is sufficient. For additional information on treatment of venous thromboembolism, consult the most recent ACCP Evidence-based Clinical Practice Guidelines on Antithrombotic Therapy and Prevention of Thrombosis available at http://www.chestnet.org.

Although warfarin therapy can be problematic in children for several reasons (e.g., dietary differences, compliance issues, monitoring difficulty, lack of a commercially available liquid preparation), the drug has been used in selected pediatric patients with venous thromboembolism. Experience with warfarin in the pediatric population is mostly based on use of the drug in children older than 3 months of age; there is little efficacy or safety information in neonates. Heparin or a low molecular weight heparin generally is recommended for both the initial and ongoing treatment of venous thromboembolism in children. However, ACCP recommends that children with recurrent idiopathic venous thromboembolism receive indefinite treatment with warfarin. Unlike in adults, most episodes of venous thromboembolism in children are secondary to an identifiable risk factor such as the presence of a central venous access device (e.g., central venous catheter or umbilical venous catheter). In children with central venous catheter-related thromboembolism, ACCP recommends that the catheter be removed if no longer functioning or required; at least 3-5 days of therapeutic anticoagulation is suggested prior to its removal. If the central venous access device is required, ACCP suggests that anticoagulants be given until the catheter is removed. After the initial 3 months of therapy, use of prophylactic dosages of warfarin (target INR 1.5-1.9) or a low molecular weight heparin is suggested until the catheter is removed; however, if recurrent thromboembolism occurs, therapeutic-dose anticoagulation may be required.

Prophylaxis

Orthopedic Surgery

ACCP recommends routine thromboprophylaxis (with a pharmacologic and/or mechanical method [e.g., intermittent pneumatic compression]) in all patients undergoing major orthopedic surgery, including total hip-replacement, total knee-replacement, and hip-fracture surgery, because of the high risk for postoperative venous thromboembolism; thromboprophylaxis should be continued for at least 10-14 days, and possibly for up to 35 days after surgery. Several antithrombotic agents (e.g., low molecular weight heparins, fondaparinux, low-dose heparin, warfarin, aspirin) are recommended by ACCP for pharmacologic thromboprophylaxis in patients undergoing major orthopedic surgery. Although ACCP suggests that a low molecular weight heparin generally is preferred because of its relative efficacy and safety and extensive clinical experience, alternative agents such as warfarin may be a reasonable choice in situations in which a low molecular weight heparin is not available or cannot be used (e.g., in patients with heparin-induced thrombocytopenia or in those who refuse or are uncooperative with subcutaneous injections). ACCP states that when selecting an appropriate thromboprophylaxis regimen, factors such as relative efficacy and bleeding risk as well as logistics and compliance issues should be considered. For additional information on the prevention of venous thromboembolism in patients undergoing major orthopedic surgery, consult the most recent ACCP Evidence-based Clinical Practice Guidelines on Antithrombotic Therapy and Prevention of Thrombosis available at http://www.chestnet.org.

Thromboprophylaxis in Pediatric Patients

Warfarin also has been used for primary thromboprophylaxis in children with ventricular assist devices or with an arteriovenous fistula undergoing hemodialysis and in children with certain medical conditions associated with a high risk of thrombosis (e.g., moderate or giant coronary aneurysms following Kawasaki disease, primary pulmonary hypertension).

Embolism Associated with Atrial Fibrillation

Warfarin is used for the prevention of stroke and systemic embolism in patients with atrial fibrillation. In several randomized, controlled studies in patients with chronic atrial fibrillation unrelated to rheumatic fever (i.e., nonvalvular atrial fibrillation), the incidence of thromboembolic events (e.g., transient ischemic attack [TIA], ischemic stroke) in patients anticoagulated with warfarin was substantially reduced compared with that in patients receiving placebo. ACCP, the American College of Cardiology (ACC), the American Heart Association (AHA), the American Stroke Association (ASA), and other experts currently recommend that antithrombotic therapy be administered to all patients with nonvalvular atrial fibrillation (i.e., atrial fibrillation in the absence of rheumatic mitral stenosis, a prosthetic heart valve, or mitral valve repair) who are considered to be at increased risk of stroke, unless such therapy is contraindicated.

Recommendations regarding choice of antithrombotic therapy in patients with atrial fibrillation are based on the patient's risk for stroke and bleeding. In general, oral anticoagulant therapy (traditionally warfarin) is recommended in patients with atrial fibrillation who have a moderate to high risk for stroke and acceptably low risk of bleeding, while aspirin or no antithrombotic therapy may be considered in patients at low risk of stroke. Although many risk stratification methods have been used, patients considered to be at increased risk of stroke generally include those with prior ischemic stroke or TIA, advanced age (e.g., 75 years or older), history of hypertension, diabetes mellitus, or congestive heart failure. In addition, population-based studies suggest that female sex is an important risk factor for stroke in patients with atrial fibrillation, particularly in patients 75 years of age or older, and AHA and the American Stroke Association (ASA) recommend the use of risk stratification tools that account for age- and sex-specific differences in stroke risk. One such tool is the CHA2DS2-VASc score, an extension of the CHADS2 system (which considers the risk factors congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, and prior stroke/TIA) that adds extra points for female sex (1 point); previous MI, peripheral arterial disease, or aortic plaque (1 point); and age 65-74 years (1 point) or 75 years or older (2 points). In a large drug registry study in Sweden, women had a greater reduction in stroke (60%) than men (40%) with warfarin therapy while the risk of major hemorrhage was similar between groups.

Although warfarin traditionally has been used for oral anticoagulation in patients with atrial fibrillation at increased risk of stroke, some experts suggest that non-vitamin K antagonist oral anticoagulants such as apixaban, dabigatran, or rivaroxaban may provide certain advantages over warfarin (e.g., rapid onset of action, predictable anticoagulant effect, no requirement for coagulation monitoring, less potential for drug-drug and drug-food interactions) and may be considered as alternative therapy in selected patients. Warfarin generally should remain the treatment of choice in patients with severe renal impairment pending clinical outcomes data with the non-vitamin K antagonist oral anticoagulants in such patients. AHA and ASA state that while clinical trials of non-vitamin K antagonist oral anticoagulants were not designed to determine differences in efficacy compared with warfarin in men versus women, apixaban, dabigatran, or rivaroxaban may be a useful alternative to warfarin for the prevention of stroke and systemic thromboembolism in women with paroxysmal or permanent atrial fibrillation and prespecified risk factors (according to CHA2DS2-VASc) who do not have a prosthetic heart valve or hemodynamically important valve disease, severe renal failure (creatinine clearance less than 15 mL/minute), lower body weight (less than 50 kg), or advanced liver disease (impaired baseline clotting function). When selecting an appropriate anticoagulant for patients with atrial fibrillation, experts recommend that the risks versus benefits of such therapy be considered for individual patients based on the absolute and relative risks of stroke and bleeding; patient compliance, preference, tolerance, and comorbidities; cost; availability of agents to reverse anticoagulant effects in case of bleeding complications; and other clinical factors such as renal function, availability of facilities to monitor INR, and degree of current INR control in patients already receiving warfarin.

Pooled analysis of data from a number of comparative studies evaluating therapy with warfarin and aspirin in patients with chronic atrial fibrillation demonstrate that warfarin therapy is more effective than aspirin (e.g., 75-325 mg daily) in reducing thromboembolic complications. In addition, warfarin therapy appears to have a therapeutic advantage over aspirin in preventing nonfatal stroke. However, the anticipated greater benefits of warfarin compared with aspirin must be weighed against the greater risk of bleeding and inconvenience of monitoring oral anticoagulation. Because the net clinical benefit with warfarin relative to aspirin appears to be greatest in patients with a high (and possibly also intermediate) risk of stroke, ACCP and other experts generally recommend the use of oral anticoagulation (e.g., warfarin targeted to an INR of 2-3) over aspirin in such patients. For patients at low risk of stroke, the expected benefits of warfarin may not outweigh the risks of bleeding, and thus, aspirin is preferred. AHA and ASA state that oral anticoagulation is not recommended in women 65 years of age or younger with atrial fibrillation and no other risk factors (CHADS2 = 0 or CHA2DS2-VASc = 1); instead, antiplatelet therapy is a reasonable option in selected low-risk women.

Dual antiplatelet therapy with clopidogrel and aspirin was evaluated as a potential alternative to oral anticoagulation in a randomized controlled study in patients with atrial fibrillation at high risk of stroke. The study was terminated early because of clear evidence of superiority of warfarin over antiplatelet therapy for the primary outcome of stroke, systemic embolism, MI, or vascular death. Results of another study comparing dual antiplatelet therapy (clopidogrel and aspirin) with aspirin monotherapy in patients with atrial fibrillation who had an increased risk of stroke but were unable to take warfarin showed that the combination of clopidogrel and aspirin was more effective than aspirin in reducing the risk of nonfatal stroke; however, dual antiplatelet therapy was associated with an increased risk of bleeding. Based on these findings, ACCP and other experts recommend the use of clopidogrel and aspirin rather than aspirin alone as an alternative to oral anticoagulation in patients with atrial fibrillation at increased risk of stroke who cannot take or choose not to take oral anticoagulants for reasons other than concerns about major bleeding (e.g., those with difficulty maintaining stable INRs, compliance issues, dietary restrictions, or cost limitations). Because the risk of bleeding with combination aspirin and clopidogrel therapy is similar to the risk of bleeding with warfarin, such combination therapy is not recommended in patients with a hemorrhagic contraindication to warfarin.

Antiplatelet agents may be used in addition to warfarin in certain patients with atrial fibrillation who have coexisting conditions that warrant the use of antiplatelet therapy (e.g., patients with recent placement of an intracoronary stent or those experiencing an acute coronary syndrome).

While randomized clinical trials evaluating warfarin anticoagulation in patients with atrial fibrillation and prosthetic heart valves or rheumatic mitral valve disease have not been conducted, long-term warfarin therapy also is strongly recommended in such patients based on results of studies in patients who have atrial fibrillation without these coexisting conditions. The intensity of anticoagulation in patients with prosthetic heart valves should be based on the particular type of prosthesis but should not be less than that required to maintain an INR of 2.5; patients with prosthetic mechanical heart valves should have a target INR of at least 2.5.(See Uses: Thromboembolism Associated with Prosthetic Heart Valves.)

In patients with atrial fibrillation who have ischemic stroke or systemic embolism during warfarin anticoagulation at an INR of 2-3, ACC, AHA, and the European Society of Cardiology (ESC) suggest that it may be reasonable to increase the intensity of anticoagulation to a maximum target INR of 3-3.5; however, other experts state that data are lacking regarding the efficacy of increasing anticoagulation in providing future protection against thromboembolic events, and higher INRs are associated with an increased risk of bleeding.

The risk of thromboembolism in patients with atrial flutter is not as well established as it is in those with atrial fibrillation. In addition, many patients with atrial flutter have alternating periods of atrial fibrillation. Experts state that antithrombotic therapy in patients with atrial flutter generally should be managed in the same manner as in patients with atrial fibrillation.

Cardioversion of Atrial Fibrillation

Use of warfarin is recommended to decrease the risk of embolization in patients undergoing pharmacologic or electrical cardioversion of atrial fibrillation.

Because the risk of thromboembolism appears to be greatest when atrial fibrillation has been present for more than 48 hours, recommendations for the use of anticoagulant therapy in such patients vary based on the duration of the arrhythmia. ACCP and other experts recommend that patients with atrial fibrillation of unknown or greater than 48 hours' duration who are to undergo elective cardioversion receive therapeutic anticoagulation (e.g., usually with warfarin) for at least 3 weeks prior to cardioversion; alternatively, a transesophageal echocardiography (TEE)-guided approach may be used. In patients who have atrial fibrillation of short duration (e.g., 48 hours or less), cardioversion usually is performed without prolonged warfarin anticoagulation or TEE prior to the procedure. After successful cardioversion to sinus rhythm, all patients should receive therapeutic anticoagulation for at least 4 weeks.

Experts suggest that patients with atrial flutter undergoing cardioversion be managed according to the same approach as that used in patients with atrial fibrillation.

Embolism Associated with Valvular Heart Disease

Warfarin and/or aspirin is used to prevent thromboembolism associated with various types of valvular heart disease; the choice of antithrombotic therapy depends on balancing the risk of thromboembolism with the risk of hemorrhagic complications from antithrombotic therapy.

Analysis of data from trials evaluating thromboembolism in patients with nonvalvular atrial fibrillation indicate that oral anticoagulants are most effective in patients at highest risk for embolic events. Among the common types of valvular heart disease, rheumatic mitral valve disease is associated with the greatest risk of systemic thromboembolism, and the risk is further increased in patients with concurrent atrial fibrillation, left atrial thrombus, or a history of systemic embolism. Therefore, ACCP recommends warfarin anticoagulation (INR of 2-3) in such patients.

Patients with rheumatic mitral valve disease and in normal sinus rhythm who have a left atrial diameter exceeding 5.5 cm also may be considered for oral anticoagulation with warfarin (target INR 2.5, range 2-3) because of their high likelihood of developing atrial fibrillation. Antithrombotic therapy usually is not required in patients with rheumatic mitral valve disease who are in normal sinus rhythm and have a left atrial diameter of less than 5.5 cm.

In selected patients with mitral valve prolapse who have atrial fibrillation (i.e., those 65 years of age or older or those with a mitral valve regurgitation murmur, hypertension, or a history of heart failure), prophylaxis with warfarin is recommended by ACC and AHA. Warfarin (INR of 2-3) also is recommended by ACC and AHA for prevention of thromboembolic events in patients with mitral valve prolapse and a history of stroke who have concomitant mitral valve regurgitation, atrial fibrillation, or left atrial thrombus.

Warfarin has been used in a limited number of patients undergoing percutaneous balloon mitral valvotomy to prevent left atrial embolism. In patients who are being considered for percutaneous balloon mitral valvotomy who have TEE-confirmed left atrial thrombus, ACCP recommends postponing the procedure and administering warfarin (target INR 3, range 2.5-3.5) until confirmed thrombus resolution occurs. The procedure should not be performed if thrombus resolution does not occur with warfarin therapy.

Antithrombotic therapy generally should not be initiated in patients with infective endocarditis involving a native valve because of the risk of serious hemorrhage, including intracerebral hemorrhage, and lack of documented efficacy in such patients. In patients with a prosthetic valve who are already receiving warfarin therapy, ACCP suggests temporary discontinuance of the drug if infective endocarditis develops, and reinitiation of therapy once invasive procedures no longer are required and the patient is stabilized without signs of neurologic complications.

Thromboembolism Associated with Prosthetic Heart Valves

Warfarin is used to reduce the incidence of thromboembolism (e.g., stroke) in patients with prosthetic mechanical or biological heart valves. The risk of systemic embolism is higher with mechanical than with bioprosthetic heart valves, higher with first-generation mechanical (e.g., caged ball, caged disk) valves than with newer mechanical (e.g., bileaflet, Medtronic Hall tilting disk) heart valves, higher with more than one prosthetic valve, and higher with prosthetic mitral than with aortic valves; risk also is higher in the first few days and months after valve insertion (before full endothelialization) and increases in the presence of atrial fibrillation.

All patients with mechanical heart valves require long-term warfarin therapy because of the high risk of thromboembolism with these valves, which appears to average 1-2% annually even with the use of warfarin. During the early postoperative period following insertion of a mechanical heart valve, ACCP suggests bridging anticoagulation with heparin or a low molecular weight heparin until the patient is stable on warfarin therapy.(See Initial Dosage under Dosage and Administration: Dosage.) Warfarin therapy also is suggested by ACCP in patients with bioprosthetic heart valves in the mitral position, at least for the first 3 months after valve insertion; after the first 3 months, patients may be switched to aspirin therapy provided they are in normal sinus rhythm. In patients with aortic bioprosthetic valves who are in sinus rhythm and have no other indications for warfarin therapy, aspirin generally is suggested for initial (e.g., first 3 months after valve insertion) and long-term antithrombotic therapy. However, long-term warfarin therapy (INR 2.5, range 2-3) may be indicated in some patients with bioprosthetic heart valves who have additional risk factors for thromboembolism (e.g., atrial fibrillation, prior thromboembolism, left ventricular dysfunction, hypercoagulable states).

In general, a target INR of 2.5 (range 2-3) is suggested with warfarin therapy in patients with a mechanical heart valve in the aortic position, while a higher intensity of anticoagulation (target INR of 3; range 2.5-3.5) is recommended in those with a mechanical heart valve in the mitral position. A higher intensity of warfarin anticoagulation also may be considered in patients with mechanical heart valves in both the aortic and mitral positions.(See Initial Dosage under Dosage and Administration: Dosage.)

Because warfarin therapy alone does not completely prevent thrombosis in patients with prosthetic heart valves, aspirin or dipyridamole has been used in conjunction with warfarin to reduce the incidence of thrombosis in these patients. The combination of warfarin and aspirin appears to be more effective than warfarin alone but may increase the risk of bleeding. In 2 studies comparing treatment with warfarin alone or in combination with 500-mg or 1-g daily doses of aspirin, patients receiving 1 g of aspirin daily had an increased risk of GI bleeding. In another study comparing treatment with warfarin alone or in combination with aspirin (500 mg daily) or dipyridamole (400 mg daily), the combination regimen with aspirin was associated with an increased risk of bleeding complications compared to the other regimens. In a randomized, placebo-controlled study in patients with prosthetic heart valves who were at high risk for systemic embolism, addition of delayed-release, enteric-coated aspirin (100 mg daily) to warfarin therapy (adjusted to maintain an INR of 3-4.5) resulted in a substantial reduction in major systemic embolism or death, particularly from vascular causes, compared with warfarin therapy alone. Although the risk of hemorrhagic complications with combined aspirin-warfarin therapy was considerably higher than that with warfarin alone (55% increase, principally in minor bleeding), combined therapy was associated with a 61% reduction in relative risk (compared with warfarin alone) for the combined end point of major systemic embolism, nonfatal intracranial hemorrhage, death from hemorrhage, and death from vascular causes. Based on the current evidence, ACCP recommends the addition of an antiplatelet agent such as low-dose aspirin (e.g., 50-100 mg daily) to warfarin therapy in all patients with mechanical heart valves who are at low risk of bleeding. In addition, combination therapy with aspirin and warfarin also is recommended by ACC/AHA in patients with bioprosthetic valves who have additional risk factors for thrombosis (e.g., atrial fibrillation, previous thromboembolism, left ventricular dysfunction, hypercoagulable condition).

ST-Segment Elevation Myocardial Infarction

Treatment

Current treatment of acute ST-segment elevation MI (STEMI) includes the use of thrombolytic therapy for lysis of coronary artery thrombi, and adjunctive therapy with anticoagulants (e.g., heparin, low molecular weight heparin, fondaparinux, warfarin) and/or platelet-aggregation inhibitors (e.g., aspirin, clopidogrel) has been used during and after successful coronary artery reperfusion for the prevention of early reocclusion and death.

Current evidence suggests that treatment with full-dose heparin followed by short-term therapy with an oral anticoagulant (e.g., warfarin) may reduce the risk of early recurrence or extension of infarction in selected patients with acute STEMI.

ACC and AHA recommend continuation of full-dose IV heparin, low molecular weight heparin, or fondaparinux for at least 48 hours, followed by conversion to warfarin therapy (dosage adjusted to maintain an INR of 2-3) and low-dose aspirin at hospital discharge in patients at high risk for systemic emboli.

Secondary Prevention

Warfarin is used for secondary prevention to reduce the risk of death, recurrent MI, and thromboembolic events such as stroke or systemic embolization after an acute STEMI. In general, antiplatelet therapy is preferred to the use of anticoagulants for secondary prevention and risk reduction in patients with atherosclerosis, including those with acute STEMI; however, warfarin in conjunction with low-dose aspirin is recommended in patients who have other compelling indications for anticoagulation therapy (e.g., atrial fibrillation, prosthetic heart valve, left ventricular thrombus or high risk for such thrombi, concomitant venous thromboembolic disease). Anticoagulant therapy with warfarin has been shown to reduce the risk of left ventricular thrombus formation and systemic embolization in patients with Q-wave (transmural) anterior STEMI.

Results of a few prospective studies and analysis of pooled data from other controlled trials suggest that long-term therapy (1-2 years or longer) with a coumarin derivative (e.g., warfarin) may be useful in selected patients for secondary prevention of death and/or nonfatal recurrent STEMI. In a randomized, placebo-controlled study in patients with acute STEMI, therapy with warfarin, initiated 2-4 weeks postinfarction and continued for an average of 37 months, was associated with reductions in the risk of death (24% reduction), nonfatal or fatal reinfarction (34% reduction), and total cerebrovascular events (55% reduction). In another placebo-controlled study in patients randomized to treatment with a coumarin anticoagulant (nicoumalone or phenprocoumon, not currently available in the US) within 6 weeks (usually within 2 weeks) after hospital discharge following acute STEMI, anticoagulant therapy was associated with statistically significant reductions in the risks of reinfarction (53% reduction) and cerebrovascular events (40% reduction); a reduction in the risk of death from any cause (10%) also occurred but was not statistically significant. In an open-label, randomized, comparative study in hospitalized patients with recent acute STEMI, long-term (approximately 4 years) therapy with warfarin alone or in combination with aspirin was more effective than aspirin therapy alone in reducing the incidence of the composite end point of death, nonfatal reinfarction, or thromboembolic stroke. The benefit of warfarin (dosage adjusted to achieve an INR of 2-2.5) in combination with aspirin (75 mg daily) or warfarin alone (dosage adjusted to achieve an INR of 2.8-4.2) compared with aspirin alone (160 mg daily) was restricted to reduction of nonfatal reinfarction and thromboembolic stroke; overall mortality was similar among the treatment groups.

The manufacturers and other experts currently recommend the use of warfarin (target INR 2-3) in conjunction with low-dose aspirin (not exceeding 100 mg daily) for at least 3 months following an acute STEMI in high-risk patients (e.g., those with a large anterior STEMI, substantial heart failure, intracardiac thrombus visible on transthoracic echocardiography, atrial fibrillation, history of previous thromboembolic event). For patients with an anterior STEMI and left ventricular thrombus (or at high risk for such thrombi) who undergo coronary artery stent placement, some experts suggest the use of warfarin in combination with low-dose aspirin and clopidogrel; the recommended duration of such triple antithrombotic therapy is dependent on whether the patient has a bare-metal or drug-eluting stent.

Other Cardiovascular Disease

ACC and AHA recommend the use of anticoagulation in patients with heart failure who have persistent or paroxysmal atrial fibrillation or a prior thromboembolic event.(See Uses: Embolism Associated with Atrial Fibrillation.) However, routine use of aspirin or warfarin for prevention of thromboembolic events is not recommended by ACC and AHA in patients who have heart failure without an ischemic etiology (e.g., idiopathic, hypertensive) or in those who do not have atrial fibrillation or previous thromboembolism.

Cerebral Embolism

Antiplatelet agents are considered preferable to oral anticoagulation for secondary prevention of noncardioembolic stroke in patients with a history of ischemic stroke or TIA. However, oral anticoagulation with warfarin or one of the non-vitamin K antagonist oral anticoagulants (e.g., apixaban, dabigatran, rivaroxaban) is recommended for secondary prevention in patients with TIAs or ischemic stroke and concurrent atrial fibrillation, provided no contraindications to therapy exist.(See Uses: Embolism Associated with Atrial Fibrillation.) Warfarin anticoagulation (target INR 2-3) also is recommended for the prevention of recurrent stroke in patients at high risk for recurring cerebral embolism from other cardiac sources (e.g., prosthetic mechanical heart valves, recent MI, left ventricular thrombus, dilated cardiomyopathies, marantic endocarditis, extensive wall-motion abnormalities).

For arterial ischemic stroke associated with dissection or a cardioembolic cause in children, ACCP suggests the use of warfarin as an option for long-term anticoagulation.

In patients with cryptogenic stroke and a patent foramen ovale or atrial septal aneurysm, ACCP recommends aspirin therapy for secondary prophylaxis of such events; however, if recurrent events occur despite aspirin therapy or another condition requiring anticoagulation (e.g., DVT) exists in such patients, warfarin (target INR 2.5; range 2-3) is suggested over aspirin.

ACCP, AHA, and ASA state that oral anticoagulation with warfarin usually is recommended following initial therapy with heparin or a low molecular weight heparin in patients with acute cerebral venous sinus thrombosis. Following low molecular weight heparin therapy during pregnancy in women with cerebral venous sinus thrombosis, AHA and ASA recommend postpartum anticoagulation with warfarin (target INR of 2-3) as an alternative to low molecular weight heparin for at least 6 weeks (for a total minimum duration of 6 months of anticoagulant therapy). ACCP recommends initial therapy with heparin or a low molecular weight heparin followed by conversion to warfarin or continued therapy with a low molecular weight heparin for at least 3 months in children with cerebral venous sinus thrombosis without substantial intracranial hemorrhage. If symptoms persist or there is continued occlusion of the cerebral venous sinuses, another 3 months of anticoagulant therapy is suggested. For additional information on the use of anticoagulants in pediatric patients with cerebral venous sinus thrombosis, consult the most recent ACCP Evidence-based Clinical Practice Guidelines on Antithrombotic Therapy and Prevention of Thrombosis available at http://www.chestnet.org.

Arterial Occlusive Disease

Warfarin has been used in certain patients with peripheral arterial occlusive disease. However, ACCP generally recommends the use of antiplatelet agents (aspirin or clopidogrel) rather than anticoagulants for the primary or secondary prevention of cardiovascular events in patients with peripheral arterial disease.

Extended anticoagulant therapy (e.g., with warfarin) is recommended by ACCP in all patients with chronic thromboembolic pulmonary hypertension.

Heparin-Induced Thrombocytopenia

While warfarin should not be used for initial treatment of heparin-induced thrombocytopenia (HIT), the manufacturers and other clinicians state that therapy with the drug may be considered after platelet counts have normalized. Cases of venous limb ischemia, necrosis, and gangrene, sometimes resulting in amputation or death, have occurred in patients with HIT when heparin was discontinued and warfarin was initiated or continued. ACCP recommends against initiating warfarin in patients with strongly suspected or confirmed HIT until substantial platelet recovery occurs (e.g., platelet count of at least 150,000/mm); for patients already receiving warfarin at the time of diagnosis of HIT, use of vitamin K is suggested.

ACCP states that HIT should be treated initially with a nonheparin anticoagulant (e.g., lepirudin, argatroban). Conversion to warfarin therapy should be initiated with low dosages (maximum 5 mg daily) and only after substantial recovery from acute HIT has occurred. To avoid prothrombotic effects and ensure continuous anticoagulation, ACCP recommends that therapy with the nonheparin anticoagulant and warfarin be administered concurrently for at least 5 days and until the desired INR has been achieved.(See Initial Dosage under Dosage and Administration: Dosage)

Dosage and Administration

Administration

Oral Administration

Warfarin sodium is administered orally in a single, daily dose. Patients should adhere strictly to the prescribed dosage and schedule of warfarin. Patients should take warfarin tablets at the same time each day, with food or on an empty stomach. If a dose of warfarin is missed, or if an excess dose of warfarin is taken, patients should contact their clinician. The missed dose should be taken as soon as possible on the same day. However, a double dose of warfarin should not be taken the next day to make up for the missed dose.

IV Administration

The drug also is administered by IV injection when warfarin therapy is indicated and oral administration is not feasible. The manufacturer of commercially available warfarin sodium for injection states that this preparation is not recommended for IM administration.

Warfarin sodium sterile, lyophilized powder for injection is reconstituted by adding 2.7 mL of sterile water for injection to a vial labeled as containing 5 mg of warfarin sodium. The resultant solution contains 2 mg of warfarin sodium per mL. The appropriate dose of warfarin sodium should be injected slowly (over 1-2 minutes) into a peripheral vein.

Dosage

Warfarin is commercially available as oral tablets and as an injection. The drug is available as the sodium salt; dosage is expressed in terms of warfarin sodium.

Nonproprietary (generic) preparations of warfarin sodium are available, and the manufacturers warn that patients should be carefully instructed about what they are receiving so that overdosage from inadvertent simultaneous use of equivalent preparations is avoided.

Warfarin sodium dosage requirements vary greatly among individual patients, and dosage must be carefully individualized based on clinical and laboratory findings (i.e., determination of PT ratios/INRs) in order to obtain optimum therapeutic effects while minimizing the risk of hemorrhage. Pharmacogenomic factors (e.g., genetic variations in enzymes that metabolize warfarin or modulate its effect on clotting factor synthesis) also may be considered in determining the dosage of warfarin.(See Dosage: Factors Influencing Anticoagulant Response, under Dosage and Administration.) Dosage of warfarin sodium does not vary with the route of administration.

Laboratory Monitoring and Dosage Adjustment

The prothrombin time (PT) is the most commonly used laboratory method for monitoring therapy with warfarin. Clotting times and bleeding times are not effective methods for monitoring therapy with the drugs. The PT is sensitive to plasma concentrations of functional blood coagulation factors II, V, VII, and X and, to a minor extent, fibrinogen; the test is not sensitive to decreased concentrations of functional factor IX. The PT does not measure antithrombogenic effects but may provide an indication of the risk of hemorrhage. Although results of the test are frequently reported as a percentage of the normal prothrombin activity, it is more satisfactory to report actual PT values in seconds of the sample being tested compared with that of a control sample (PT ratio). PT values depend on the procedures and reagents used for each test and are relevant only in the laboratory in which they are determined. Clinicians must understand the test procedures employed and methods of reporting results in order to monitor therapy.

Variability in PT values obtained from the same plasma sample occurs because of differences in the responsiveness (sensitivity) of commercial thromboplastins to the reduction in clotting factors induced by oral anticoagulants (e.g., warfarin). Therefore, a system of standardizing the reporting of PT values through determination of an international normalized ratio (INR) was introduced by the World Health Organization (WHO) and has been recommended by the American College of Chest Physicians (ACCP) and the National Heart, Lung, and Blood Institute (NHLBI). The INR is derived from calibrations of commercial thromboplastin reagents against an international reference preparation (IRP), a sensitive thromboplastin prepared from human brain tissue. For the 3 commercial rabbit brain thromboplastins currently used in North America, a PT value of 1.3-2 times the control PT value (i.e., PT ratio of 1.3-2) is equivalent to an INR of 2-4. For other thromboplastins, the INR can be calculated from the prothrombin time ratio determined using any local thromboplastin as follows:

INR = (observed PT ratio)ISI

where the ISI (international sensitivity index) is a calibration factor that is available from the manufacturers of the thromboplastin reagent. The ISI is a measure of the responsiveness of the individual thromboplastin to the reduction in vitamin K-dependent coagulation factors; the lower the ISI, the more responsive the reagent and the closer the derived INR will be to the observed prothrombin time ratio. Current data suggest that the ISIs of most thromboplastin reagents used in the US range from 1.8-2.8. The INR is the prothrombin time ratio that would be obtained if the WHO reference thromboplastin, which by definition has an ISI of 1, were used to assess prothrombin time.

The generally accepted therapeutic PT range has been 1.5-2.5 times the control value in seconds (PT ratio = 1.5-2.5) or 15-35% of the normal prothrombin activity; however, this range was determined from studies in which sensitive human brain thromboplastin was used. Recent studies with the less sensitive rabbit brain thromboplastin reagents currently used in the US indicate that a lower therapeutic range may be appropriate for most thromboembolic conditions and may minimize the risk of bleeding.

The INR should be determined regularly in all patients receiving warfarin. The manufacturers recommend that INR determinations be performed daily after initiation of warfarin therapy until the INR stabilizes in the therapeutic range. ACCP states that INR determinations usually are performed daily in hospitalized patients until the INR is in the therapeutic range for at least 2 consecutive days; in outpatients, initial INR determinations may be reduced from daily to every few days until a stable response has been achieved. The frequency of INR determinations should be based on clinical judgment and patient response, but generally is every 1-4 weeks. In patients with consistently stable INRs, ACCP has suggested an INR testing interval of up to 12 weeks.

For adequate anticoagulation control, additional INR determinations should be performed when different warfarin preparations (e.g., proprietary versus nonproprietary [generic]) are interchanged and when concomitant drug therapy is added, discontinued, or taken irregularly. Heparin prolongs the PT/INR, and caution should be observed in evaluating the INR and/or PT ratio in patients receiving concomitant therapy with warfarin and heparin. Valid PT/INR determinations can usually be made during concurrent heparin therapy if blood samples for the test are drawn at least 4-6 hours after an IV injection or 12-24 hours after a subcutaneous injection of heparin. The PT/INR may not be substantially prolonged by heparin when the drug is administered by continuous IV infusion and blood samples for the test may be obtained at any time during the infusion. Warfarin may prolong the activated partial thromboplastin time (aPTT), even in the absence of heparin. However, during initial therapy with warfarin, the interference with heparin anticoagulation is of minimal clinical importance.

Safety and efficacy of warfarin therapy can be improved by increasing the quality of laboratory control. Available data indicate that the proportion of time in the therapeutic INR range is increased in patients managed by anticoagulation clinics and patients in whom anticoagulation is managed with the assistance of computer programs compared with patients receiving usual monitoring by their primary care clinician. Self-management of warfarin therapy is suggested by ACCP as an alternative to outpatient INR monitoring in patients who are motivated and can demonstrate competency in self-management strategies, including the use of self-testing equipment.

Factors Influencing Anticoagulant Response

A number of factors, including concomitant therapy with drugs or dietary or herbal supplements (see Drug Interactions) and changes in diet, environment (prolonged hot weather), physical state, and genetic variations in warfarin metabolism and/or sensitivity may alter an individual's response to warfarin therapy. Factors reported to increase response, prolong the PT/INR, and increase the risk of hemorrhage include vitamin K deficiency caused by decreased dietary intake, alterations in intestinal flora, or malabsorption states; scurvy; malnutrition or cachexia; small body size; hepatic dysfunction; moderate to severe renal impairment; hypermetabolic states such as fever or hyperthyroidism; infectious disease; carcinoma; collagen disease; congestive heart failure; diarrhea; biliary obstruction; old age; debility; menstruation and menstrual disorders; radiation therapy; initial hypoprothrombinemia; and decreased clearance of warfarin as a result of variations in genes responsible for warfarin metabolism.

Factors reported to decrease response to coumarin anticoagulants and shorten the PT/INR include increased intake or GI absorption of vitamin K; GI states that result in decreased anticoagulant absorption; diabetes mellitus; edema; hyperlipidemia; hypothyroidism; and visceral carcinoma. In addition, 2 types of resistance to warfarin have been reported. Rarely, familial resistance to warfarin, apparently resulting from variations in the anticoagulant-vitamin K receptor site, has been reported and appears to be inherited as an autosomal dominant trait. In individuals with familial resistance to warfarin, absorption and metabolism of the drugs are unaltered but 10-20 times the usual anticoagulant dosage may be required to achieve therapeutic effects. These patients also demonstrate increased sensitivity to antidotal effects of phytonadione. Another type of warfarin resistance appears to involve an increased rate of warfarin metabolism and excretion.

Pharmacogenomics

Variations in the genes responsible for warfarin metabolism or pharmacodynamic response may affect warfarin dosage requirements. Over 30% of European and Caucasian populations have one or more variant alleles encoding cytochrome P-450 (CYP) isoenzyme 2C9 (CYP2C9), the enzyme principally responsible for metabolism of S-warfarin, and such alleles are associated with reduced clearance of warfarin.(See Pharmacokinetics: Elimination.) Patients with one or more variant CYP2C9 alleles (e.g., CYP2C9*2, CYP2C9*3) are at increased risk of excessive anticoagulation (e.g., INR exceeding 3) and bleeding and require lower dosages of warfarin, particularly during initiation of therapy.

Warfarin inhibits vitamin K epoxide reductase, which is a vitamin K-cycle enzyme complex controlling the regeneration of reduced vitamin K from vitamin K epoxide. Reduced vitamin K is an essential cofactor involved in the formation of vitamin K-dependent clotting factors.(See Pharmacology.) Limited evidence suggests that variations in the gene that encodes vitamin K epoxide reductase, vitamin K epoxide reductase complex subunit 1 (VKORC1), may have an even larger impact on warfarin dosage than CYP2C9 genetic variations. Common polymorphisms in non-coding regions of the VKORC1 gene contribute substantially to warfarin dosage variability across the normal dosage range. Asians appear to be more sensitive than Caucasians to the anticoagulant effect of warfarin and may require lower initial and maintenance dosages. In an uncontrolled study in Chinese patients receiving warfarin for various indications and on a stable warfarin sodium dosage for at least 1 month, the average daily dosage required to maintain an INR of 2-2.5 was 3.3 mg. Age also was an important determinant of warfarin dosage (inverse correlation) in these patients, as were body weight and underlying disease (positive correlations). A single nucleotide polymorphism of VKORC1 that identifies a low-dose and a high-dose warfarin phenotype has been found to associate with optimal warfarin dosage in both European and Asian patients. The reduced average warfarin maintenance dosage requirement in Asian individuals is largely related to the relatively rare occurrence of the high-dose allele in this ethnic group.

Several dosing algorithms for warfarin have been developed that take into account genetic variations in CYP2C9 and VKORC1 genes and individual clinical factors (e.g., age, height, body weight, interacting drugs, indication for warfarin therapy). In one such model in Caucasian patients, approximately 30, 40, or 55% of the variability in warfarin dosage could be attributed to variations in the VKORC1 gene alone, variations in CYP2C9 and VKORC1 genes, or variations in both of these genes plus inclusion of individual clinical factors, respectively.

Laboratory tests (e.g., Nanosphere Verigene Warfarin Metabolism Nucleic Acid Test, Warfarin DoseAdvise Genetic Test) currently are available to determine if patients have certain VKORC1 or CYP2C9 gene variants that may influence their response to warfarin. Clinicians may consider incorporating information obtained from genetic testing along with individual clinical factors to improve their estimate of initial warfarin dosage. The availability and reliability of genetic tests vary, and clinicians should check with their local or reference clinical laboratory to obtain more information about specific tests. Genetic information does not replace regular INR monitoring (see Dosage: Laboratory Monitoring and Dosage Adjustment, in Dosage and Administration), and results of genetic testing, which currently require several days to obtain, should not delay initiation of warfarin therapy.

Although limited data have suggested that genetic testing could improve safety and potentially lower costs associated with warfarin therapy by lowering the risk of bleeding or ischemic complications from inappropriate dosing, current evidence does not appear to support routine use of such testing. In addition, genetic testing has not been shown to be cost-effective. ACCP currently recommends against the routine use of genetic testing to guide initial dosage selection of warfarin.

Initial Dosage

The appropriate initial dosage of warfarin varies widely among different patients; dosage must be individualized taking into account factors such as age, race, body weight, sex, genotype, concomitant drugs, and the specific indication being treated. In patients whose CYP2C9 and VKORC1 genotypes are not known, the manufacturers state that the usual initial dosage of warfarin sodium is 2-5 mg daily. For patients with known CYP2C9 and VKORC1 genotypes, the manufacturers suggest that initial dosage of warfarin may be determined based on expected maintenance dosages observed in clinical studies of patients with various combinations of these gene variants.(See Table 1.)

Table 1. Expected Daily Maintenance Dosages of Warfarin Sodium Based on CYP2C9 and VKORC1 Genotypesa
VKORC1 CYP2C9 *1/*1 *1/*2 *1/*3 *2/*2 *2/*3 *3/*3
GG 5-7 mg 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg
AG 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg
AA 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg

a Manufacturers suggest using these expected maintenance dosage ranges to estimate initial daily dosage of warfarin sodium in patients with known CYP2C9 and VKORC1 genotypes. Dosage ranges are derived from multiple published clinical studies. VKORC1-1639G > A (rs9923231) variant is used in this table; other co-inherited VKORC1 variants also may be important determinants of warfarin sodium dosage.

Routine use of warfarin loading doses is not recommended by the manufacturers because such practice may increase the risk of hemorrhage or other complications and does not offer more rapid protection against clot formation. However, there is some evidence suggesting that use of a 10-mg loading dose may be a safe and effective approach in reducing the time to therapeutic INR. ACCP therefore suggests that in patients sufficiently healthy to be treated as outpatients, an initial dosage of 10 mg daily for the first 2 days may be administered, with subsequent dosing based on INR determinations.

Smaller initial dosages (e.g., 2-5 mg of warfarin sodium daily) result in less fluctuation in the degree of anticoagulation and decrease the risk of hemorrhage. Low initial dosages should be considered for geriatric and/or debilitated patients.(See Cautions: Geriatric Precautions.) Lower initial dosages also should be considered in patients with certain genetic variations in CYP2C9 and/or VKORC1 gene(s), which are associated with reduced warfarin clearance or altered pharmacodynamic response. Asians also appear to require lower initial and maintenance dosages than Caucasians, resulting in part from such genetic variations.(See Pharmacogenomics under Dosage: Factors Influencing Anticoagulant Response, in Dosage and Administration.)

Transferring from Parenteral Anticoagulation to Warfarin

When warfarin is indicated for follow-up therapy after initial treatment with a parenteral anticoagulant (e.g., heparin, a low molecular weight heparin, fondaparinux), therapy with the parenteral anticoagulant is usually continued until an adequate response to warfarin is obtained as indicated by INR determinations. The manufacturers recommend that heparin and warfarin be used concurrently for at least 4-5 days until the desired INR has been attained, after which the parenteral anticoagulant may be discontinued. In adults with acute deep-vein thrombosis (DVT) or pulmonary embolism (PE), ACCP recommends that heparin, a low molecular weight heparin, or fondaparinux be used concurrently with warfarin for at least 5 days and until the INR is at least 2 for 24 hours or longer.

In children with venous thromboembolism in whom long-term warfarin therapy is being considered, warfarin should be initiated on the same day as heparin or a low molecular weight heparin, and such therapy should be overlapped for at least 5 days and until the INR is therapeutic.

When warfarin is indicated for follow-up therapy after a nonheparin anticoagulant (e.g., argatroban, lepirudin) in the treatment of heparin-induced thrombocytopenia (HIT), therapy with warfarin and the nonheparin anticoagulant should be overlapped for a minimum of 5 days until an adequate response to warfarin is obtained as indicated by INR determinations. Warfarin therapy should be initiated only after substantial recovery from acute HIT has occurred (i.e., platelet counts of at least 150,000/mm).

Conversion from anticoagulation with argatroban to warfarin is more complex than with other direct thrombin inhibitors (e.g., lepirudin) since combined therapy with argatroban and warfarin prolongs the INR beyond that produced by warfarin alone. The INR should be determined daily during concurrent argatroban and warfarin therapy. The manufacturer of argatroban recommends using the aPTT to monitor the effects of argatroban during conversion to warfarin.

For an argatroban infusion rate of 2 mcg/kg per minute, argatroban therapy should be discontinued when the INR on combined therapy exceeds 4. Overshooting the target INR should be avoided, as supratherapeutic INRs during concomitant therapy with direct thrombin inhibitors and warfarin have been associated with necrosis or gangrene of the skin or limbs. The INR should be determined 4-6 hours after discontinuance of argatroban infusion during warfarin monotherapy. If INR is below the desired therapeutic range, argatroban infusion should be resumed. Attempts to discontinue argatroban should be repeated daily and until the INR (4-6 hours after discontinuance of argatroban) on warfarin alone is in therapeutic range.

For argatroban infusion rates exceeding 2 mcg/kg per minute, the infusion rate should be reduced temporarily to 2 mcg/kg per minute, and the procedure just described should be reinstituted for conversion to therapy. INR should be repeated 4-6 hours after reduction of the argatroban infusion.

Maintenance Dosage

Maintenance dosage of warfarin sodium varies greatly among patients and should be based on INR determinations. The manufacturers state that the usual maintenance dosage of warfarin sodium is 2-10 mg daily for patients in whom CYP2C9 and VKORC1 genotypes are not known. Although dosage requirements may remain constant in an individual patient, genetic variations in warfarin metabolism or sensitivity or changes in clinical state, concurrent drug therapy, or diet may necessitate adjustment of dosage. For patients with known CYP2C9 and VKORC1 genotypes, the manufacturers suggest expected maintenance dosages observed in clinical studies of patients with various combinations of these gene variants.(See Initial Dosage under Dosage and Administration: Dosage.) Lower initial and maintenance dosages should be considered for geriatric and/or debilitated patients. Because of inherited increased sensitivity and/or reduced metabolism of warfarin, Asians also appear to require lower initial and maintenance dosages of warfarin than Caucasians. Acquired or inherited warfarin resistance is rare but should be suspected if large daily dosages of warfarin sodium are required to maintain INR within a normal therapeutic range.(See Pharmacology.) Changes in anticoagulant dosage should be made in small increments, and patient response should be carefully monitored with clinical observation and INR determinations. If a previously stable patient presents with a single subtherapeutic or supratherapeutic INR (not exceeding 0.5 above or below the therapeutic range), ACCP suggests that the current dosage of warfarin be continued and the INR retested within 1-2 weeks.

The manufacturers state that warfarin dosage in pediatric patients varies based on age, with infants generally having the highest, and adolescents having the lowest dosage requirements to maintain therapeutic INRs. When warfarin is used in children, a target INR range of 2-3 generally is suggested by ACCP for most indications except in the setting of prosthetic cardiac valves where adherence to the adult recommendations is suggested.

In general, for prophylaxis or treatment of DVT and PE or for prophylaxis in most patients with acute myocardial infarction (MI), atrial fibrillation, valvular heart disease, or bioprosthetic heart valves, many clinicians recommend adjustment of warfarin dosage to maintain a moderate intensity of anticoagulation (INR of 2-3). (See Treatment and Secondary Prevention under Uses: Deep-Vein Thrombosis and Pulmonary Embolism.) In contrast, a higher intensity of anticoagulation may be necessary in patients with first-generation or mitral prosthetic mechanical heart valves, and many clinicians suggest maintaining an INR of 2.5-3.5 in such patients. An INR exceeding 4 appears to provide no additional therapeutic benefit in most patients and is associated with a higher risk of bleeding complications.

When warfarin is used for the prevention of stroke and systemic embolism in patients with atrial fibrillation, the dosage should be adjusted to maintain a target INR of 2.5 (range 2-3). In patients with atrial fibrillation or atrial flutter who require prolonged anticoagulation prior to cardioversion, warfarin dosage usually is adjusted to achieve a target INR range of 2-3 for at least 3 weeks before and at least 4 weeks after pharmacologic or electrical cardioversion.

In patients with mitral valve disease associated with rheumatic fever who have concurrent atrial fibrillation, left atrial thrombus, or a history of systemic embolism (e.g., stroke), ACCP recommends warfarin anticoagulation adjusted to prolong the INR to a target of 2.5 (range 2-3). In patients with rheumatic mitral valve disease who have left atrial hypertrophy (left atrial diameter exceeding 5.5 cm) and normal sinus rhythm, warfarin anticoagulation at a target INR of 2.5 (range 2-3) is suggested.

In patients being considered for percutaneous mitral valvotomy who have evidence of left atrial thrombus (confirmed by transesophageal echocardiography [TEE]), ACCP recommends treatment with warfarin (target INR 3, range 2.5-3.5) and postponement of the procedure.

At least 3 months of warfarin (INR range of 2-3) and aspirin therapy (not exceeding 100 mg daily) is recommended following acute ST-segment elevation MI (STEMI) in patients who are at high risk of systemic or pulmonary embolism (e.g., large anterior STEMI, a history of previous thromboembolism, intracardiac thrombus, atrial fibrillation, or substantial heart failure).

For secondary prevention of cardioembolic cerebral ischemic events in patients with transient ischemic attacks or ischemic stroke and concurrent atrial fibrillation, warfarin anticoagulation to maintain a target INR of 2.5 (range 2-3) may be used long-term, provided no contraindications to therapy exist. In patients at high risk for recurrent stroke from other cardiac sources (e.g., prosthetic mechanical heart valves, recent MI, left ventricular thrombus, dilated cardiomyopathies, marantic endocarditis, extensive wall-motion abnormalities), ACC and AHA recommend warfarin anticoagulation to maintain a target INR of 2.5 (range 2-3) with concomitant low-dose aspirin.

In patients with acute cerebral venous sinus thrombosis provoked by a transient risk factor, AHA, the American Stroke Association (ASA), and other experts suggest continuation of anticoagulation with warfarin (after initial heparin or low molecular weight heparin therapy) for 3-6 months, with dosage adjusted to maintain a target INR of 2-3. In patients with unprovoked cerebral venous sinus thrombosis, AHA and ASA suggest continuing warfarin therapy for 6-12 months (target INR of 2-3). Indefinite anticoagulation with warfarin may be considered following an initial episode of cerebral venous sinus thrombosis in patients with severe thrombophilia and in patients with recurrent cerebral venous sinus thrombosis, venous thrombosis occurring after acute cerebral venous sinus thrombosis, or other permanent risk factors for recurrent thrombosis (target INR of 2-3).

Warfarin dosed to a target INR of 2.5 (range 2-3) also is recommended in patients with a patent foramen ovale and cryptogenic stroke who have evidence of DVT.

Long-term warfarin anticoagulation is required in patients with mechanical heart valves. In general, a target INR of 2.5 (range 2-3) is suggested with warfarin therapy in patients with a mechanical heart valve in the aortic position, while a higher intensity of anticoagulation (target INR 3; range 2.5-3.5) is recommended in those with a mechanical heart valve in the mitral position. A higher intensity of warfarin anticoagulation also may be considered in patients with mechanical heart valves in both the aortic and mitral positions. ACCP recommends the addition of an antiplatelet agent such as low-dose aspirin (e.g., 50-100 mg daily) to warfarin therapy in all patients with mechanical heart valves who are at low risk of bleeding.

Warfarin therapy (target INR 2.5; range 2-3) is suggested by ACCP in patients with bioprosthetic heart valves in the mitral position, at least for the first 3 months after valve insertion; after the first 3 months, patients may be switched to aspirin therapy provided they are in normal sinus rhythm. However, long-term warfarin therapy (INR 2.5, range 2-3) may be indicated in some patients with bioprosthetic heart valves who have additional risk factors for thromboembolism (e.g., atrial fibrillation, prior thromboembolism, left ventricular dysfunction, hypercoagulable states); the addition of aspirin therapy also may be considered in such high-risk patients.

During the early postoperative period following insertion of a mechanical heart valve, ACCP suggests bridging anticoagulation with heparin or a low molecular weight heparin until the patient is stable on warfarin therapy.(See Initial Dosage under Dosage and Administration: Dosage.)

In patients with prosthetic heart valves who develop infective endocarditis, ACCP suggests temporary discontinuance of warfarin therapy at the time of presentation for treatment until it is clear that invasive procedures will not be required and the patient is stable without signs of neurologic complications.

For long-term control of HIT with or without thrombosis, warfarin is administered for follow-up treatment after therapy with a nonheparin anticoagulant (e.g., argatroban, lepirudin). Conversion to warfarin therapy should be initiated only after substantial recovery from acute HIT has occurred (i.e., platelet counts at least 150,000/mm). Warfarin therapy should be overlapped with the nonheparin anticoagulant for a minimum of 5 days and until the INR is within the target therapeutic range.

The optimum duration of warfarin therapy must be determined by the condition being treated and its severity. For the treatment of DVT or PE, full-dose heparin, a low molecular weight heparin, or fondaparinux is used initially with warfarin until a stable INR is achieved, then warfarin generally is continued (with dosage adjusted to maintain an INR of 2-3) as follow-up anticoagulant therapy for at least 3 months. After 3 months, the risks versus benefits of extended therapy (defined by ACCP as treatment beyond 3 months without a scheduled stop date) should be evaluated in individual patients.(See Treatment and Secondary Prevention under Uses: Deep-Vein Thrombosis and Pulmonary Embolism.)

Although it has been suggested that there is an increased risk of thrombosis or rebound thromboembolism following abrupt discontinuance of warfarin therapy, some studies suggest that there is no increased incidence of arterial or venous thromboembolism when anticoagulant therapy is stopped abruptly rather than tapered over a few weeks.

Managing Anticoagulation in Patients Requiring Invasive Procedures

Temporary interruption of long-term warfarin therapy may be required in patients undergoing surgery or other invasive procedures to minimize the risk of perioperative bleeding. The decision whether to interrupt therapy should be based on an assessment of the patient's risk for thromboembolism versus risk of perioperative bleeding, taking into account individual patient- and surgery-related factors. Temporary discontinuance of warfarin usually is required for major surgical or invasive procedures, but may not be necessary for minor procedures associated with a low risk of bleeding (e.g., minor dental procedures, minor dermatologic procedures, cataract surgery).

In patients who require temporary interruption of warfarin prior to surgery, ACCP recommends that the drug be discontinued approximately 5 days prior to surgery. Warfarin may be resumed approximately 12-24 hours postoperatively when adequate hemostasis is achieved. Bridging anticoagulation (administration of a short-acting anticoagulant consisting of a low molecular weight heparin or IV heparin during the period of interruption of warfarin therapy) may be considered in some patients who are at particularly high risk of thromboembolism without warfarin therapy. The decision to administer bridging anticoagulation should be individualized based on the patient's risk of thromboembolism versus risk of bleeding. ACCP states that bridging therapy generally is unnecessary for patients other than those at highest risk for stroke and/or venous thromboembolism (e.g., patients with mechanical heart valves, atrial fibrillation, or a venous thromboembolic event with additional risk factors for venous thromboembolism). For additional information on the perioperative management of patients receiving warfarin, including risk stratification methods, consult the most recent ACCP Evidence-based Clinical Practice Guidelines on Antithrombotic Therapy and Prevention of Thrombosis available at http://www.chestnet.org.

Cautions

Hemorrhage

Hemorrhage, the most common adverse effect of coumarin-derivative anticoagulants (e.g., warfarin), is an extension of the pharmacologic action of the drugs and may range from minor local ecchymoses to major hemorrhagic complications, which occasionally result in death. Massive hemorrhage, if it occurs, most frequently involves the GI tract or genitourinary sites but may involve the spinal cord or cerebral, pericardial, pulmonary, adrenal, or hepatic sites. Although hemorrhage results principally from overdosage or excessive prolongation of the prothrombin time (PT), hemorrhagic complications may occur when the PT is in the usual therapeutic range and frequently result from the presence of occult lesions. Hemorrhage is more likely to occur during the initiation of warfarin therapy and with higher dosages (which result in higher international normalized ratios [INRs]). Risk factors for hemorrhage include a high intensity of anticoagulation (INR exceeding 4), patient age 65 years or older, highly variable INRs, history of GI bleeding, hypertension, cerebrovascular disease, serious heart disease, anemia, malignancy, trauma, renal insufficiency, concomitant drugs that may increase PT/INR response, and a long duration of warfarin therapy.(See Pharmacology and see Pharmacokinetics: Elimination.) Regular monitoring of INR should be performed in all patients receiving warfarin therapy.(See Dosage: Laboratory Monitoring and Dosage Adjustment, in Dosage and Administration.) Patients at high risk of bleeding may benefit from more frequent monitoring, use of lower dosages with careful dosage adjustment to the desired INR, and a shorter duration of therapy. A severe elevation (exceeding 50 seconds) in activated partial thromboplastin time (aPTT) with a PT ratio or INR in the desired range reportedly may suggest an increased risk of postoperative hemorrhage.

Hemorrhagic complications may be manifested by signs or symptoms that do not indicate obvious bleeding, such as paralysis; headache; pain in the chest, abdomen, joints, muscles, or other areas; dizziness; shortness of breath; difficulty breathing or swallowing; unexplained swelling; weakness; hypotension; or unexplained shock. Paralytic ileus and intestinal obstruction also have been reported from submucosal or intramural hemorrhage. The possibility of hemorrhage should be considered in any anticoagulated patient with complaints that do not indicate an obvious diagnosis. Adrenal hemorrhage with resultant acute adrenal insufficiency also has been reported during anticoagulant therapy. Anticoagulant therapy should be discontinued in patients who develop manifestations compatible with acute adrenal hemorrhage or insufficiency. Plasma cortisol concentrations should be measured immediately and vigorous therapy with IV corticosteroids instituted promptly; delay in initiation of such therapy while awaiting laboratory confirmation of the diagnosis may result in the patient's death.

The frequency and severity of hemorrhage may be minimized by careful clinical management of the patient, including frequent PT/INR determinations. (See Laboratory Monitoring and Dosage Adjustment under Dosage and Administration: Dosage.) Early manifestations of overdosage include microscopic or gross hematuria, melena, excessive uterine or menstrual bleeding, petechiae, ecchymoses, bleeding from gums or other mucous membranes, and oozing from nicks made while shaving. If any unexpected bleeding occurs during anticoagulant therapy, the patient's condition must be critically evaluated immediately.

In the treatment of overdosage or excessive prolongation of the INR, therapy should be determined by the severity of the effect, the urgency of the need to restore normal hemostasis, and whether or not therapy with the anticoagulant is to be maintained. The American College of Chest Physicians (ACCP) suggests the use of oral phytonadione in patients with an INR of greater than 10 and no evidence of bleeding; routine use of phytonadione generally is not recommended for INR values between 4.5 and 10 with no evidence of bleeding.

In patients with major bleeding associated with warfarin therapy, ACCP suggests the use of 4-factor prothrombin complex concentrate rather than fresh frozen plasma for rapid reversal of anticoagulation, with additional use of phytonadione (administered at a dosage of 5-10 mg by slow IV infusion). Several hours are usually required for the effects of phytonadione to occur whether the drug is administered orally or parenterally. Purified factor IX preparations (e.g., factor IX [human]) should not be used because they cannot increase the levels of prothrombin, factor VII, and factor X that are also depressed by warfarin treatment.

Phytonadione, if given in excessive dosage, may make the patient unresponsive for several days or weeks to subsequent warfarin therapy and probably should not be used in patients with minor hemorrhage in whom the drug must be continued.

Necrosis

Potentially fatal tissue necrosis and/or gangrene of skin or other tissues with subcutaneous infarction, vasculitis, and local thrombosis have occurred rarely in patients receiving a coumarin derivative, including warfarin. This reaction, which can occur on the first exposure to these drugs or during a subsequent course of therapy, usually appears early (e.g., 1-10 days) after initiation of therapy; tissue damage occurs principally at sites of fat tissue such as the abdomen, breasts, buttocks, and thighs. Most cases of warfarin-induced necrosis have been reported in women. The necrotic lesions generally begin as painful, erythematous patches on the skin that progress rapidly to dark, hemorrhagic areas. Necrosis may involve skin, soft tissue, and muscle; gangrene and, frequently, infection follow. In severe cases, surgical debridement of the affected tissue, skin grafting, or amputation may be necessary.

Possible limb ischemia, necrosis, and gangrene may occur in patients with heparin-induced thrombocytopenia (HIT) when warfarin is substituted for heparin treatment or continued after heparin discontinuance. In some patients, amputation of the involved area and/or death have occurred. Warfarin should be used with caution. Clinicians should consider delaying warfarin therapy until thrombin generation is adequately controlled and thrombocytopenia has resolved (i.e., platelet counts at least 150,000/mm and stable).

Patients with hereditary, familial, or clinical deficiencies of protein C or its cofactor, protein S, appear to have an increased risk of developing necrosis during warfarin therapy; however, necrosis can occur in the absence of protein C deficiency. It has been suggested that necrotic reactions occur because initiation of warfarin therapy causes plasma concentrations of protein C to decrease more rapidly than plasma concentrations of factors II, IX, and X. Protein C generally inhibits coagulation by inactivating factors V and VIII and facilitating fibrinolysis; therefore, a rapid decrease in plasma concentrations of protein C results in a hypercoagulable state. Warfarin-induced necrosis generally occurs when the hypercoagulable state is maximal. If necrosis occurs during therapy with warfarin, decisions regarding diagnostic testing and therapy must be made on an individualized basis. If necrosis is suspected to be induced by warfarin and is not associated with HIT, the drug should be discontinued, vitamin K (phytonadione) or fresh frozen plasma should be administered, and alternative anticoagulant therapy (e.g., heparin) should be considered both to treat the underlying thromboembolic disease and possibly to prevent additional microvascular thrombosis.(See Cautions: Precautions and Contraindications.) In addition, protein C concentrate or epoprostenol (prostacyclin) reportedly has been used with some success to treat warfarin-induced necrosis.

It has been suggested that if warfarin therapy is discontinued and heparin therapy initiated or continued before actual tissue necrosis occurs (e.g., at the first patient complaint of pain or discomfort in a particular skin area), it may be possible to limit the extent of tissue damage. In addition, initiation of anticoagulant therapy with heparin for 4-5 days before initiation of warfarin therapy or overlapping therapy with the 2 drugs for 5-6 days may minimize the risk of warfarin-induced necrosis.

Purple Toes Syndrome and Cholesterol Microembolization

Some evidence suggests that anticoagulation with coumarin derivatives (e.g., warfarin) may enhance the release of atheromatous plaque fragments and increase the risk of complications; some cases have progressed to necrosis and death. The most common visceral organs involved are the kidneys, followed by the pancreas, spleen, and liver. A distinct syndrome resulting from microemboli to the feet is known as ''purple toes syndrome.'' Purple toes syndrome usually occurs 3-10 weeks or later following initiation of therapy with warfarin or related compounds (e.g., dicumarol [no longer commercially available in the US]) This syndrome typically is characterized by a purplish or mottled discoloration of the plantar surfaces and sides of the toes, which blanches on moderate pressure and fades with elevation of the legs; other characteristics may include pain and tenderness of the toes and waxing and waning of the color over time. Although purple toes syndrome reportedly is reversible, discontinuance of warfarin therapy is recommended in patients who develop this complication; some cases of purple toes syndrome have progressed to gangrene or necrosis, requiring debridement of the affected area and/or amputation. Systemic atheroembolism may be characterized by a variety of other manifestations depending on the site of microembolization, including livedo reticularis, rash, gangrene, abrupt and intense pain in the leg, foot, or toes, foot ulcers, myalgia, penile gangrene, abdominal pain, flank or back pain, hematuria, renal insufficiency, hypertension, cerebral ischemia, spinal cord infarction, pancreatitis, symptoms simulating polyarteritis, or any other sequelae of vascular compromise caused by embolic occlusion.

Other Adverse Effects

GI disturbances such as nausea, vomiting, anorexia, flatulence/bloating, abdominal cramps, and diarrhea have been reported occasionally in patients receiving a coumarin derivative. Dermatitis (including bullous eruptions), urticaria, rash, alopecia, fever, fatigue, lethargy, malaise, pain, headache, mouth ulcers, and leukopenia have been reported occasionally and agranulocytosis, nephropathy, and increased serum concentrations of AST (SGOT), ALT (SGPT), and alkaline phosphatase and bilirubin have been reported rarely. Dizziness, taste perversion, hypotension, anemia, pallor, angina syndrome, chest pain, loss of consciousness, syncope, coma, and cold intolerance also have been reported infrequently. Minor and severe allergic/hypersensitivity reactions, including anaphylactic reactions, also have been reported infrequently. Other adverse effects reported infrequently with coumarin derivatives include vasculitis, edema, hepatitis, cholestatic hepatic injury, jaundice, asthenia, pruritus, and paresthesia, including chills and feeling cold. Priapism has been reported rarely with coumarin derivatives, and tracheal or tracheobronchial calcification has been reported rarely during long-term warfarin therapy; however, a causal relationship between these effects and the drugs has not been established.

Precautions and Contraindications

Warfarin should be used with increased caution in any condition where added risk of hemorrhage, necrosis, and/or gangrene is present.All patients receiving warfarin should be under close medical supervision, and adequate laboratory facilities for monitoring therapy (e.g., using INR) and measures for treating hemorrhage must be available. Patients must be carefully selected to ensure that they are cooperative and can communicate effectively with their clinician. Patients receiving warfarin should carry a notice stating that they are undergoing anticoagulant therapy so that medical and paramedical personnel are alerted in emergency situations. The manufacturers state that patients should be informed that all warfarin sodium preparations (proprietary and nonproprietary [generic]) represent the same drug and should not be taken concomitantly unless instructed otherwise by their clinician, since overdosage may result from inadvertent simultaneous use of equivalent preparations.

The manufacturers' patient medication guide should be available to all patients when their prescriptions for warfarin are issued.

Patients should avoid drastic changes in diet and should eat a balanced diet with a constant amount of vitamin K. Ingestion of large quantities of certain foods that contain a large amount of vitamin K (e.g., leafy green vegetables, certain vegetable oils) should be avoided. Patients should not attempt to diet during warfarin therapy without discussion with their clinician.

Patients should report any signs of bleeding (e.g., pain, swelling or discomfort; headaches, dizziness, or weakness; unusual bleeding or bruising, such as bruises that develop without known cause or grow in size), nosebleeds, bleeding gums, prolonged bleeding from cuts, increased menstrual flow or vaginal bleeding, pink or brown urine, red or black stools, bloody sputum, vomiting blood or material resembling coffee grounds) to clinicians immediately. Patients should inform their clinicians of coexisting conditions such as bleeding problems, propensity for falling, hepatic or renal dysfunction, high blood pressure, congestive heart failure, diabetes mellitus, and alcohol use or abuse. During warfarin therapy, patients should avoid activities or sports that could cause traumatic injury. Clinicians should be informed of falls or injuries, especially head injuries, during warfarin therapy.

Patients should report to their clinician symptoms of blood clots (e.g., pain, color, or temperature changes to any area of the body). Symptoms of purple toes syndrome (e.g., pain in toes, purple or dark toes) should be reported to a clinician immediately.

In patients with HIT and deep-vein thrombosis (DVT), ACCP and other clinicians recommend that warfarin therapy be delayed until thrombin generation is adequately controlled and thrombocytopenia has resolved (as indicated by evaluation of platelet count) because of the risk of venous limb ischemia, necrosis, and gangrene occurring when heparin treatment is discontinued and warfarin therapy started or continued in such patients.(See Cautions: Necrosis and see Uses: Heparin-Induced Thrombocytopenia.)

The decision to use warfarin in patients with the following conditions should be based on clinical judgment after weighing the risks and benefits of anticoagulant therapy: severe to moderate hepatic or renal impairment; infectious diseases (e.g., patients receiving antibiotic therapy) or disturbances of intestinal flora (e.g., sprue); surgery or trauma that may result in large, exposed raw surfaces or trauma that may result in internal bleeding; patients with indwelling catheters; severe to moderate hypertension; and vitamin C or vitamin K deficiency. Patients should inform their clinician of diarrhea, infections, or fevers that occur during warfarin therapy.

IM injections of concomitantly administered therapy should be administered in an upper extremity to permit easy access for manual compression, inspection for bleeding, and/or use of pressure bandages.

Patients with hereditary, familial, or clinical deficiencies of protein C or its cofactor, protein S, appear to have an increased risk of developing tissue necrosis during warfarin therapy, and the drug should be used with caution in patients with known or suspected deficiency in protein C-mediated anticoagulant response.(See Cautions: Necrosis.)

Numerous contraindications to therapy with coumarin-derivative anticoagulants (e.g., warfarin) have been recommended. In many instances, contraindications are relative rather than absolute. Contraindications should be evaluated for each patient giving consideration to the need for anticoagulant therapy, the risk of hemorrhage, the expected duration of therapy, patient reliability, and the availability of adequate laboratory facilities for patient monitoring. Since a high degree of patient cooperation is required for long-term or outpatient use of warfarin, senility, alcoholism, or psychosis may be relative contraindications to use of this drug.

Warfarin is contraindicated in patients who have hemorrhagic tendencies or blood dyscrasias. The drug also is contraindicated in patients with overt bleeding or active ulceration involving the GI, respiratory, or genitourinary tract; cerebrovascular hemorrhage; aneurysms (cerebral, dissecting aorta); pericarditis and pericardial effusions; bacterial endocarditis; eclampsia, preeclampsia, or threatened abortion; or malignant hypertension. Warfarin generally is contraindicated in patients with known hypersensitivity to the drug.

Warfarin generally is contraindicated in patients with recent or contemplated surgery of the eye or central nervous system and in those undergoing traumatic surgery resulting in large open surfaces. Many minor dental and surgical procedures, however, may be performed if necessary without undue risk of hemorrhage in patients receiving an anticoagulant if meticulous surgical hemostasis is maintained. Patients should inform their clinician of any planned surgeries or medical or dental procedures, as the dosage of warfarin may need to be adjusted or temporarily withheld.(See Managing Anticoagulation in Patients Requiring Invasive Procedures, under Dosage and Administration: Dosage.) The operative site should be sufficiently limited to permit effective use of local procedures for hemostasis (e.g., absorbable hemostatic agents, sutures, pressure dressings), if necessary. If anticoagulant therapy is administered prior to, during, or immediately following minor dental or surgical procedures, minimal anticoagulation should be maintained.

Pediatric Precautions

The manufacturers of warfarin state that safety and efficacy of the drug in children younger than 18 years of age have not been established in randomized, controlled studies. However, the drug has been used in pediatric patients for prevention and treatment of thromboembolic events. Difficulty achieving and maintaining therapeutic INRs has been reported in pediatric patients, and more frequent determinations of INR are recommended in such patients because of possible changing warfarin requirements.

Geriatric Precautions

Age reportedly does not substantially affect the pharmacokinetics of racemic warfarin, and the manufacturers state that the clearance of S-warfarin is similar in geriatric versus younger individuals. However, the clearance of R-warfarin appears to be slightly reduced in geriatric patients compared with that in younger individuals. In addition, geriatric patients appear to exhibit greater than expected anticoagulant responses (as determined by PT/INR values) to warfarin, and less warfarin is required to produce a therapeutic level of anticoagulation; the reason for this increased response has not been determined. Caution should be observed when warfarin is administered to geriatric or debilitated patients, particularly when the risk of hemorrhage is present.

Close monitoring of the INR also is recommended during warfarin therapy in geriatric patients 75 years or older with atrial fibrillation who are at high risk for thromboembolism because of the greater risk for hemorrhage in such patients. A large retrospective study suggests that the risks versus benefits of warfarin therapy for atrial fibrillation in geriatric patients 80 years of age or older may require more careful consideration. Reviews of medical records of patients with anticoagulant-associated intracerebral hemorrhage (AAICH) in a large US metropolitan area showed a substantial (approximately fivefold) increase in the annual incidence of this adverse event between 1988 and 1999 based on point estimates for the periods of January through December 1988, July 1993 through June 1994, and January through December 1999. The annual incidence of AAICH per 100,000 persons was 0.8 in 1988, 1.9 in 1993-1994, and 4.4 in 1999. Most notably, there was an even more marked increase in the rate of AAICH in patients 80 years of age or older, from 2.5 in 1988 to 45.9 in 1999. Most of this increase could be explained by an increase in warfarin use (as determined by records of warfarin shipments from wholesalers to pharmacies, clinics, and hospitals during the period studied); the annual incidences of cardioembolic ischemic stroke due to atrial fibrillation between 1993-1994 and 1999 did not change appreciably (22.0 and 20.6, respectively, per 100,000 persons). In geriatric patients, therapy with low initial and maintenance dosages of warfarin (e.g., dosage adjusted to maintain the INR at the lower end of the range of 2-3) is recommended by the manufacturers.

Pregnancy and Lactation

Pregnancy

Warfarin generally is considered contraindicated during pregnancy, although the drug has been used during the second trimester in certain pregnant women (e.g., those with older-generation prosthetic mechanical heart valves in the mitral position, patients with a history of thromboembolism) considered to be at very high risk for thromboembolism. If anticoagulant therapy is required in pregnant women, therapy with a low molecular weight heparin generally is recommended based on a more favorable adverse effect profile.

Potential risks of warfarin therapy to the fetus include bleeding and teratogenicity. Fetal or neonatal hemorrhage and intrauterine death have occurred, even when maternal PT values were within the generally accepted therapeutic range. Hypoplastic nasal structures and other abnormalities (e.g., stippled epiphyses) consistent with a diagnosis of chondrodysplasia punctata have occurred rarely in children whose mothers received warfarin during the first trimester of pregnancy. CNS abnormalities also have been reported, including dorsal midline dysplasia characterized by agenesis of the corpus callosum, Dandy-Walker malformation, and midline cerebellar atrophy. Ventral midline dysplasia, characterized by optic atrophy, and eye abnormalities have been observed. Mental retardation, blindness, and other CNS abnormalities have been reported in association with second- and third-trimester exposure to warfarin. Other teratogenic effects reported rarely following in utero exposure to the drug include urinary tract abnormalities (e.g., single kidney), asplenia, anencephaly, spina bifida, cranial nerve palsy, hydrocephalus, cardiac defects and congenital heart disease, polydactyly, deformities of toes, diaphragmatic hernia, corneal leukoma, cleft palate, cleft lip, schizencephaly, and microcephaly. Spontaneous abortion and stillbirth are known to occur, and the use of warfarin is associated with a higher risk of fetal mortality. Low birth weight and growth retardation also have been reported. Women should inform their clinicians if they are or plan to become pregnant. If a woman becomes pregnant while receiving warfarin, she should be apprised of the potential risks to the fetus.

ACCP, the American College of Cardiology (ACC), and the American Heart Association (AHA) state that there is some evidence suggesting that warfarin might not be fetopathic when administered during the first 6 weeks of pregnancy. If the decision is made to use warfarin during pregnancy, such as in women with mechanical heart valves, ACCP recommends that the drug be avoided during weeks 6-12 of gestation and close to term (to avoid anticoagulation of the fetus).

Women receiving long-term warfarin therapy should be counseled about the risks of pregnancy before pregnancy occurs. If pregnancy is still desired, ACCP suggests performing frequent pregnancy tests and substituting a low molecular weight heparin for warfarin when pregnancy is achieved.

Despite the risks of warfarin to the fetus, the drug has been used in pregnant women with prosthetic heart valves who are at an increased risk for valve thrombosis. The need for warfarin therapy must be critically evaluated in pregnant women and the risks of not administering the drug must be carefully weighed against the possible risks to both the mother and fetus. Heparin or low molecular weight heparin is considered safer for the fetus than warfarin but has been associated with an increased maternal risk for valve thrombosis, death, and major bleeding complications compared with anticoagulant therapy in women with prosthetic heart valves. Although a causal relationship has not been established and the number of patients involved appears to be small, cases of valve thrombosis resulting in death and/or requiring surgical intervention have been reported with at least one low molecular weight heparin (enoxaparin) during thromboprophylaxis in patients with prosthetic heart valves, including in pregnant women, The possibility of inadequate dosing or use of an inappropriate target aPTT range may complicate the evaluation of this data; some experts state that low molecular weight heparin may provide adequate protection against valve thrombosis if closely monitored to maintain target anti-factor Xa concentrations. As no prospective, controlled clinical trials have been performed in pregnant women with prosthetic mechanical heart valves, optimal antithrombotic therapy remains to be established.

ACCP recommends several approaches to the management of pregnant women with prosthetic heart valves. One approach is to administer heparin therapy (i.e., adjusted-dose heparin or adjusted-dose low molecular weight heparin) during the first trimester followed by conversion to warfarin therapy at week 13, and reinitiation of heparin therapy close to term. The option to continue warfarin throughout pregnancy until close to delivery may be reasonable in patients judged to be at very high risk of thromboembolism (e.g., those with a history of thromboembolism, first-generation mechanical valve in the mitral position). Experts generally suggest a target INR of 3 (range 2.5-3.5) in most pregnant women with prosthetic mechanical heart valves receiving warfarin anticoagulation. Some clinicians suggest that pregnant women close to term (e.g., 2-3 weeks prior to planned delivery) who have prosthetic mechanical heart valves and who are receiving warfarin should have therapy switched to subcutaneous adjusted-dose heparin or adjusted-dose low molecular weight heparin in order to avoid bleeding complications in the neonate secondary to the trauma of delivery. In the absence of appreciable bleeding, combined therapy with heparin and warfarin may be resumed 4-6 hours after delivery in pregnant women with prosthetic heart valves. The decision whether to use heparin during the first trimester or continue oral anticoagulation throughout pregnancy should be made after full discussion with the patient and her partner of the risks associated with available anticoagulant therapies. Low-dose aspirin may be used in conjunction with anticoagulant therapy in pregnant women with prosthetic heart valves who are at high risk of thromboembolism, although such combination therapy increases the risk of hemorrhage.

For some pregnant women with inherited thrombophilias, postpartum anticoagulation with warfarin titrated to a target INR range of 2-3 is suggested. and

Lactation

Limited data suggest that warfarin is not distributed into breast milk, is not detectable in plasma of nursing infants, and has not produced substantial coagulation abnormalities in such infants. Based on limited available data, it is considered unlikely that maternal warfarin therapy would pose a substantial risk to healthy, full-term breast-feeding infants, and the American Academy of Pediatrics (AAP), ACCP and other clinicians consider maternal warfarin therapy to be compatible with breast-feeding. ACCP recommends that warfarin therapy be continued in nursing women who are already receiving such therapy. Women should inform their clinician if they are breast-feeding or plan to breast-feed. The manufacturers state that the decision to breast-feed while receiving warfarin anticoagulation should be made only after careful consideration of the available alternatives, and women who decide to breast-feed should be monitored very carefully so that recommended PT/INRs are not exceeded. Neonates are particularly sensitive to the effects of warfarin as a result of vitamin K deficiency. Infants should be monitored with coagulation tests and have their vitamin K status evaluated before being breast-fed by women taking warfarin. The effects of warfarin in premature infants have not been evaluated.

Drug Interactions

Concurrent administration of numerous drugs or dietary or herbal supplements has been reported to affect patient response to coumarin-derivative anticoagulants (e.g., warfarin). Drugs may increase patient sensitivity to warfarin by decreasing intestinal synthesis or absorption of vitamin K or affecting distribution of the vitamin; decreasing the rate of anticoagulant metabolism by competing for sites of metabolism or inhibiting the function or synthesis of metabolic enzymes; increasing affinity of the anticoagulant for receptor sites; decreasing synthesis and/or increasing catabolism of functional blood coagulation factors II, VII, IX, and X; interfering with other components of normal hemostasis such as platelet function or fibrinolysis; and by producing ulcerogenic effects. Drugs may competitively or noncompetitively interfere with protein binding of warfarin, producing increased concentrations of unbound anticoagulant and potentiation of anticoagulant effects. In some instances, this is only a temporary effect and a shortened plasma half-life of the anticoagulant results from an increased rate of metabolism and renal clearance of the anticoagulant, and the prothrombin time (PT) may return to therapeutic levels after several days of concomitant therapy. Certain drugs may decrease patient response to warfarin by decreasing absorption of the anticoagulant; increasing the rate of metabolism of the anticoagulant by enzyme induction; or by increasing synthesis of functional blood coagulation factors II, VII, IX, and X. Some dietary or herbal supplements contain naturally occurring coumarins or salicylates that may have anticoagulant, antiplatelet, or fibrinolytic effects; these supplements would be expected to increase the anticoagulant effects of concomitantly administered warfarin. Certain dietary or herbal supplements also may decrease response to warfarin, possibly as a result of induction of hepatic microsomal enzymes (e.g., St. John's wort) or because of procoagulant effects (e.g., coenzyme Q10).

Because of the complexity of individual patient sensitivity (e.g., genetic factors), multiple interacting mechanisms with some drugs, the dependency of the extent of the interaction on the dosage and duration of therapy, and the possible administration of several interacting drugs simultaneously, it is often difficult to predict the direction and degree of the ultimate effect of concurrent drug administration on anticoagulant response. Tables 2 and 3 show a list of drugs that reportedly may increase or decrease patient response to coumarin derivatives (e.g., warfarin).

Table 2. Drugs That May Increase Response to Coumarin Derivatives (e.g., Warfarin)
acetaminophen ezetimibe pantoprazole
*alcohol (acute intoxication) fenofibrate *pentoxifylline
allopurinol fenoprofen calcium phenylbutazone
aminosalicylic acid fluoroquinolone anti-infectives pravastatin
*amiodarone fluoxetine propafenone
anabolic steroids flutamide propoxyphene
argatroban fluvastatin propylthiouracil
aspirin fluvoxamine quinidine
atenolol gefitinib quinine
atorvastatin gemfibrozil *rabeprazole
azithromycin glucagon salicylates
bivalirudin ibuprofen sertraline
capecitabine indomethacin streptokinase
cefixime influenza virus vaccine sulfinpyrazone
celecoxib isoniazid sulfonamides
chloral hydrate ketoprofen sulindac
chloramphenicol lansoprazole tamoxifen
cimetidine lepirudin tetracycline
cisapride lovastatin thiazides
co-trimoxazole meclofenamate thyroid drugs
danazol mefenamic acid tramadol
diazoxide methylthiouracil tricyclic antidepressants
diflunisal *metronidazole *urokinase
*disulfiram miconazole valdecoxib
erythromycin nalidixic acid vitamin E
esomeprazole neomycin (oral) zafirlukast
ethacrynic acid oxandrolone zileuton

concurrent use probably should be avoided, if possible

Table 3. Drugs that May Decrease Response to Coumarin Derivatives (e.g., Warfarin)
*alcohol (chronic alcoholism) ethchlorvynol raloxifene
aminoglutethimide glutethimide rifampin
atorvastatin griseofulvin spironolactone
*barbiturates mercaptopurine sucralfate
carbamazepine methaqualone trazodone
clozapine nafcillin vitamin K
corticosteroids *oral contraceptives containing estrogen
corticotropin pravastatin

concurrent use probably should be avoided, if possible

Warfarin is metabolized by cytochrome P-450 (CYP) isoenzymes CYP2C9, 2C19, 2C8, 2C18, 1A2, and 3A4; the S-enantiomer is metabolized principally by CYP2C9, while the R-enantiomer is metabolized by CYP1A2 and 3A4. Because the S-enantiomer of warfarin is about 2-5 times more potent than R-warfarin, drugs that preferentially alter (i.e., increase or decrease) the metabolism of S-warfarin are more likely to be associated with alterations in PT or the international normalized ratio (INR). Drugs that inhibit CYP2C9, CYP1A2, or CYP3A4 can potentially increase exposure and response to warfarin; conversely, drugs that induce CYP2C9, CYP1A2, or CYP3A4 can potentially decrease exposure and response to warfarin.(See Table 4.) INR should be closely monitored in patients who initiate, discontinue, or change dosages of concomitant drugs that affect these CYP isoenzymes.

Table 4. CYP Interactions with Warfarin
Enzyme Inhibitors Inducers*
CYP2C9 amiodarone, capecitabine, co-trimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

list of drugs is not all-inclusive

Risk of bleeding may be increased when warfarin is used concomitantly with other drugs that can also increase bleeding risk.(See Table 5.) Patients should be monitored closely whenever such drugs are used concomitantly with warfarin. While the manufacturers of warfarin state that NSAIAs, including selective cyclooxygenase-2 (COX-2) inhibitors, may be used with close monitoring in patients receiving warfarin, some experts (e.g., the American College of Chest Physicians [ACCP]) suggest that such concomitant therapy be avoided. NSAIAs can inhibit platelet aggregation and cause GI bleeding and peptic ulceration and/or perforation, in addition to specific drug interactions that might affect the PT. ACCP also suggests that concomitant administration of warfarin and antiplatelet agents should be avoided unless the benefit is known or is highly likely to be greater than the potential harm from bleeding; patients in whom benefit may potentially outweigh risk include those with mechanical heart valves, acute coronary syndrome, or patients who have undergone recent coronary artery stent placement or bypass surgery.

Table 5. Drugs that Can Increase Bleeding Risk
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal anti-inflammatory agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin-reuptake inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

Changes in INR have been reported in patients receiving certain antibiotics or antifungal agents concomitantly with warfarin; however, clinical pharmacokinetic studies have not shown consistent effects of these drugs on plasma concentrations of warfarin. The manufacturer states that INR should be monitored closely whenever any antibiotic or antifungal agent is initiated or discontinued in patients receiving warfarin.

Altered coagulation parameters and/or bleeding, sometimes fatal, have been reported in patients receiving capecitabine concomitantly with coumarin-derivative anticoagulants (e.g., warfarin). In patients stabilized on coumarin-derivative anticoagulants, increased PT/INR and/or bleeding episodes have occurred within several days to months following initiation of capecitabine therapy; similar events have been reported in at least a few patients within 1 month following discontinuance of capecitabine. This increased anticoagulant response appears to occur because of inhibition of the CYP2C9 isoenzyme involved in warfarin metabolism by capecitabine. Age exceeding 60 years and a diagnosis of cancer may predispose patients to the development of coagulopathy. Capecitabine and warfarin should be used concomitantly with caution. If capecitabine is used concomitantly with warfarin, PT/INR should be monitored frequently in order to facilitate anticoagulant dosage adjustments if necessary.

Concurrent use of oxandrolone, an anabolic androgenic steroid, with warfarin may result in unexpectedly large increases in the PT/INR. In a study in healthy individuals, oxandrolone increased the mean half-life and area under the blood concentration-time curve (AUC) of warfarin (affecting both S- and R-enantiomers similarly); microscopic hematuria and/or gingival bleeding also occurred in some individuals. A reduction of 80-85% in the mean daily warfarin dosage was required in these individuals to maintain a target INR of 1.5. When oxandrolone therapy is initiated, changed, or discontinued in patients receiving warfarin, patients should be monitored closely for occult bleeding and with laboratory tests (i.e., PT/INR) in order to facilitate dosage adjustments as necessary and diminish the risk of serious bleeding.

In one study, administration of antacids containing magnesium hydroxide or aluminum hydroxide concomitantly with warfarin had no effect on absorption of the anticoagulant.

Concurrent administration of cholestyramine with warfarin results in decreased absorption of the anticoagulant. In addition, cholestyramine has been shown to decrease the plasma half-life of warfarin by interfering with enterohepatic circulation of the drug. However, because vitamin K absorption may also be decreased by cholestyramine, the net effect of concurrent anticoagulant and cholestyramine therapy is difficult to predict. Concurrent use of cholestyramine and warfarin probably should be avoided, if possible.

Concomitant use of lomitapide with warfarin resulted in increased exposure to warfarin and a 22% increase in INR. If lomitapide is used concomitantly with warfarin, the manufacturer of lomitapide states that INR should be monitored regularly, particularly following adjustments in lomitapide dosage, and dosage of warfarin should be adjusted as clinically indicated.

Chronic ingestion of large doses of acetaminophen has been reported to potentiate the effects of coumarin-derivative anticoagulants (e.g., warfarin). Conflicting data exist and the clinical importance of such an interaction has been questioned. Large dosages of acetaminophen (exceeding 1.5 g per day) may augment the anticoagulant effect of warfarin. In addition, results of an observational study in patients stabilized on warfarin therapy indicate an association between ingestion of even low to moderate dosages of acetaminophen (7 or more 325-mg tablets weekly) and excessively high INR values. Some clinicians suggest that additional monitoring of INR values may be prudent in patients receiving warfarin therapy following initiation of, and during sustained therapy with, large doses of acetaminophen.

Concomitant administration of vaginal miconazole creams or suppositories with acenocoumarol or warfarin for approximately 3 days has resulted in an increased PT/INR and/or bleeding. Additional monitoring of INR values and appropriate dosage adjustments may be required in patients receiving concomitant intravaginal miconazole therapy.

Some clinicians state that alcohol ingestion should be avoided in patients receiving warfarin. However, other clinicians suggest that patients receiving warfarin therapy may consume alcohol in small amounts (e.g., 1-2 drinks occasionally) but that chronic heavy consumption (e.g., defined as greater than 720 mL of beer, 300 mL of wine, or 60 mL of liquor daily) should be avoided. The effects of moderate alcohol consumption (e.g., 1-2 drinks daily) on adverse events or anticoagulation control in patients receiving long-term therapeutic anticoagulation with warfarin has not been well studied. In 2 studies in a small number of healthy young men, daily ingestion of 300-600 mL of wine in the fasting or unfasting state on a short-term basis (21 days) did not affect plasma warfarin concentrations or therapeutic hypoprothrombinemia (maintained at 25-35% of normal prothrombin activity as measured by one-stage prothrombin time). However, numerous patient-specific factors affect response to warfarin, including, age, vitamin K status, concomitant disease (e.g., hepatic dysfunction, fat malabsorption, hyperthyroidism, fever), and hereditary resistance; therefore, lack of evidence of a warfarin-alcohol interaction in healthy individuals may not preclude such interactions in individual patients. Acute ingestion of alcohol has been reported to enhance hypoprothrombinemia and prolong INR by inhibiting warfarin metabolism, reducing its clearance, and/or displacing it from plasma proteins, while long-term use of alcohol (e.g., chronic alcoholism) may reduce anticoagulant effects by inducing CYP isoenzymes (e.g., CYP2E1, CYP3A4, CYP1A2) and warfarin metabolism. Alcohol also has antiplatelet effects that may increase bleeding risk with warfarin without affecting INR.

Dietary and herbal supplements also have been reported to increase or decrease the effects of warfarin, in some cases through CYP-mediated interactions (e.g., echinacea, grapefruit juice, gingko, goldenseal, St. John's wort). (See Tables 6and 7.) In general, caution should be exercised when dietary or herbal supplements are used in patients receiving warfarin, and additional INR monitoring is recommended whenever these products are initiated or discontinued; limited information is available regarding the interaction potential of these products with warfarin.

Table 6. Dietary or Herbal Supplements that May Increase Response to Coumarin Derivatives (e.g., Warfarin)
agrimony chamomile (German and Roman) parsley
alfalfa clove passion flower
aloe gel *cranberry pau d'arco
Angelica sinensis (dong quai) dandelion policosanol
aniseed fenugreek poplar
arnica feverfew prickly ash (Northern)
asa foetida garlic quassia
aspen German sarsaparilla red clover
black cohosh ginger senega
black haw Ginkgo biloba sweet clover
bladder wrack (Fucus) ginseng (Panax) sweet woodruff
bogbean horse chestnut tamarind
boldo horseradish tonka beans
bromelains inositol nicotinate wild carrot
buchu licorice wild lettuce
capsicum meadowsweet willow
cassia nettle wintergreen
celery onion
Table 7. Dietary or Herbal Supplements that May Decrease Response to Coumarin Derivatives (e.g., Warfarin)
agrimony goldenseal St. John's wort
coenzyme Q10 (ubidecarenone) mistletoe yarrow
ginseng (Panax)

Several case reports have suggested a possible interaction between warfarin and cranberry juice; in these reports, the effects of warfarin appeared to be potentiated by cranberry juice or a cranberry product, in some cases resulting in clinically important bleeding events. However, confounding factors were present in many of these cases and prospective controlled studies generally have not been able to confirm this interaction. Results of several studies, including a randomized, double-blind trial evaluating the effects of daily consumption of 240 mL of cranberry juice over a 2-week period in 30 patients stabilized on warfarin therapy, showed no evidence of any clinically important pharmacokinetic or pharmacodynamic interaction. The amounts of cranberry juice ingested varied among these studies, but generally were lower than those described in the case reports. It is possible that this interaction may be dose dependent, with response elicited by ingestion of large quantities of cranberry juice. Although available data do not appear to support a clinically important interaction between warfarin and cranberry juice, clinicians should be aware of the possibility of such an interaction and monitor closely for changes in INR and manifestations of bleeding in patients consuming cranberry juice concurrently with warfarin.

In addition to the drugs and other substances (e.g., dietary or herbal supplements, foods) mentioned above, many other drugs have been reported to alter the response to coumarin-derivative anticoagulants; however, either the clinical importance of these reports has not been established or the reports have not been substantiated. Caution must be observed when any drug is added to or deleted from the therapeutic regimen of a patient receiving warfarin; the PT should be determined more frequently than usual and appropriate dosage adjustments made. In addition, patients should be warned not to initiate or discontinue nonprescription drugs, herbal supplements, or drugs prescribed by other physicians without first informing their primary physician or pharmacist. Patients should inform their clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements.

Pharmacokinetics

Absorption

Warfarin sodium is rapidly and extensively absorbed from the GI tract, but considerable interindividual variation in absorption exists. Absorption of oral warfarin sodium is dissolution-rate controlled, and the rate and extent of absorption of the drug may vary from one commercially available tablet to another. Studies using warfarin sodium indicate that the rate, but not the extent, of absorption of the drug is decreased by the presence of food in the GI tract. Warfarin also is absorbed percutaneously, and severe toxicity has occurred from repeated skin contact with rodenticides containing the drug.

Peak plasma concentrations of warfarin usually are attained within 4 hours; studies in healthy individuals indicate that peak drug concentrations are achieved 90 minutes after administration. However, plasma warfarin concentrations are not necessarily related to antithrombogenic effects and are not useful determinants of anticoagulant dosage requirements. Peak plasma drug concentrations may be achieved earlier following IV administration of warfarin than with oral administration; however, IV administration does not result in an enhanced anticoagulant response or an earlier onset of anticoagulant effect.

Although, with adequate dosage, synthesis of vitamin K-dependent coagulation factors is affected soon after absorption of warfarin (e.g., within 24 hours), depletion of circulating functional coagulation factors must occur before therapeutic effects of the drug become apparent. Antithrombogenic effects may not occur until 2-7 days following initiation of warfarin therapy. Similarly, there is a period of latency following discontinuance of the drug until blood concentrations of functional vitamin K-dependent coagulation factors return to pretreatment levels. Onset of antithrombogenic effects is similar whether warfarin is administered orally, IM, or IV. Doses of warfarin exceeding those required to affect synthesis of coagulation factors IX and X will not hasten the onset of action but may prolong duration of action after the drug is discontinued.

Distribution

Warfarin is 99% bound to plasma proteins, principally albumin. Uptake of the drug by erythrocytes is variable. Studies in animals indicate that in addition to the liver, the drug is distributed to lungs, spleen, and kidneys. Warfarin crosses the placenta, and fetal plasma drug concentrations may be equal to maternal plasma concentrations. Based on a one-compartment model and assuming complete bioavailability, the estimated volumes of distribution for R- and S-warfarin and racemic warfarin are similar.

Limited data suggest that warfarin is not distributed into milk in humans. In one study, warfarin was not detected in the milk of 13 nursing women or in the plasma of their breast-fed infants following 30- or 40-mg initial doses and daily maintenance dosage of 2-12 mg of the drug. (See Cautions: Pregnancy and Lactation.)

Elimination

The effective elimination half-life of warfarin averages about 40 hours and shows considerable interindividual variation (range: 20-60 hours); plasma half-life of the drug generally is independent of dose. The clearance of the R-enantiomer of warfarin is about 50% that of the S-enantiomer; since the volumes of distribution of the enantiomers are similar, the half-life of R-warfarin (e.g., 37-89 hours) is longer than that of S-warfarin (e.g., 21-43 hours).

Racemic warfarin is stereoselectively metabolized by hepatic cytochrome P-450 (CYP) microsomal enzymes to inactive metabolites. The CYP isoenzymes involved in warfarin metabolism include CYP2C9, CYP2C19, CYP2C8, CYP2C18, CYP1A2, and CYP3A4. Individual patients vary greatly in the rate at which they metabolize warfarin. R-Warfarin is metabolized by CYP1A2 and CYP3A4 isoenzymes to diastereoisomeric alcohols, which are excreted principally in urine. The metabolites of R-warfarin have some anticoagulant activity but considerably less than the parent compound. S-Warfarin is metabolized principally by oxidation via the CYP2C9 isoenzyme to the inactive metabolite 7-hydroxywarfarin, which is excreted in bile. The CYP2C9 isoenzyme appears to be the principal hepatic cytochrome P-450 isoenzyme that modulates the in vivo anticoagulant activity of warfarin.

The degree of activity of the CYP2C9 isoenzyme is under genetic control and is subject to individual variation. Patients who are homozygous for the CYP2C9*1 (wild-type) allele (about 80% of Caucasians) have normal enzyme activity (i.e., extensive metabolizers), and standard warfarin dosing regimens are adequate in such patients.(See Dosage: Initial Dosage, in Dosage and Administration.) However, approximately 11 or 7% of Caucasians are intermediate (e.g., CYP2C9*2 allele) or poor (e.g., CYP2C9*3 allele) metabolizers of warfarin, respectively; clearance of S-warfarin, the predominant active form of the drug, is reduced in such patients. Therefore, patients with variant CYP2C9 alleles are at increased risk of bleeding and excessive anticoagulation (e.g., INR exceeding 3) and require lower dosages of warfarin, particularly during initiation of therapy. The CYP2C9*2 and CYP2C9*3 alleles reduce metabolism of warfarin by about 30-50 and 90%, respectively. Other CYP2C9 variant alleles associated with reduced enzymatic activity occur less frequently, including CYP2C9*5, CYP2C9*6, and CYP2C9*11 alleles in African populations and CYP2C9*5, CYP2C9*9, and CYP2C9*11 alleles in Caucasians.

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