COUMADIN® TABLETS (Warfarin Sodium Tablets, USP) CrystallineCOUMADIN® FOR INJECTION (Warfarin Sodium for Injection, USP)

Anticoagulant

Warfarin sodium can cause major or fatalbleeding. Bleeding is more likely to occur during the starting period andwith a higher dose (resulting in a higher INR). Risk factors for bleedinginclude high intensity of anticoagulation (INR >4.0), age ≥65, highly variableINRs, history of gastrointestinal bleeding, hypertension, cerebrovasculardisease, serious heart disease, anemia, malignancy, trauma, renal insufficiency,concomitant drugs (see PRECAUTIONS ),and long duration of warfarin therapy. Regular monitoring of INR should beperformed on all treated patients. Those at high risk of bleeding may benefitfrom more frequent INR monitoring, careful dose adjustment to desired INR,and a shorter duration of therapy. Patients should be instructed about preventionmeasures to minimize risk of bleeding and to report immediately to physicianssigns and symptoms of bleeding (see PRECAUTIONS:Information for Patients ).

COUMADIN(crystalline warfarin sodium) is an anticoagulant which acts by inhibitingvitamin K-dependent coagulation factors. Chemically, it is 3-(α-acetonylbenzyl)-4-hydroxycoumarinand is a racemic mixture of the R- and S-enantiomers.Crystalline warfarin sodium is an isopropanol clathrate. The crystallizationof warfarin sodium virtually eliminates trace impurities present in amorphouswarfarin. Its empirical formula is CHNaO,and its structural formula may be represented by the following:

Crystallinewarfarin sodium occurs as a white, odorless, crystalline powder, is discoloredby light and is very soluble in water; freely soluble in alcohol; very slightlysoluble in chloroform and in ether.

COUMADINTablets for oral use also contain:

COUMADIN for Injection is supplied as a sterile, lyophilizedpowder, which, after reconstitution with 2.7 mL sterile Water for Injection,contains:

COUMADIN and other coumarin anticoagulantsact by inhibiting the synthesis of vitamin K dependent clotting factors, whichinclude Factors II, VII, IX and X, and the anticoagulant proteins C and S.Half-lives of these clotting factors are as follows: Factor II - 60 hours,VII - 4 to 6 hours, IX - 24 hours, and X - 48 to 72 hours. The half-livesof proteins C and S are approximately 8 hours and 30 hours, respectively.The resultant in vivo effect is a sequential depression ofFactor VII, Protein C, Factor IX, Protein S, and Factor X and II activities.Vitamin K is an essential cofactor for the post ribosomal synthesis of thevitamin K dependent clotting factors. The vitamin promotes the biosynthesisof γ-carboxyglutamic acid residues in the proteins which are essential forbiological activity.

Warfarin is thought to interfere withclotting factor synthesis by inhibition of the C1 subunit of the vitamin Kepoxide reductase (VKORC1) enzyme complex, thereby reducing the regenerationof vitamin K epoxide. The degree of depression isdependent upon the dosage administered and, in part, by the patient's VKORC1genotype. Therapeutic doses of warfarin decrease the total amount of the activeform of each vitamin K dependent clotting factor made by the liver by approximately30% to 50%.

An anticoagulation effect generally occurswithin 24 hours after drug administration. However, peak anticoagulant effectmay be delayed 72 to 96 hours. The duration of action of a single dose ofracemic warfarin is 2 to 5 days. The effects of COUMADIN may become more pronouncedas effects of daily maintenance doses overlap. Anticoagulants have no directeffect on an established thrombus, nor do they reverse ischemic tissue damage.However, once a thrombus has occurred, the goal of anticoagulant treatmentis to prevent further extension of the formed clot and prevent secondary thromboemboliccomplications which may result in serious and possibly fatal sequelae.

COUMADIN is a racemic mixture of the R-and S-enantiomers. The S-enantiomer exhibits2 to 5 times more anticoagulant activity than the R-enantiomerin humans, but generally has a more rapid clearance.

COUMADINis essentially completely absorbed after oral administration with peak concentrationgenerally attained within the first 4 hours.

There are no differences in the apparentvolumes of distribution after intravenous and oral administration of singledoses of warfarin solution. Warfarin distributes into a relatively small apparentvolume of distribution of about 0.14 liter/kg. A distribution phase lasting6 to 12 hours is distinguishable after rapid intravenous or oral administrationof an aqueous solution. Using a one compartment model, and assuming completebioavailability, estimates of the volumes of distribution of R- and S-warfarinare similar to each other and to that of the racemate. Concentrations in fetalplasma approach the maternal values, but warfarin has not been found in humanmilk (see WARNINGS: Lactation ). Approximately99% of the drug is bound to plasma proteins.

Theelimination of warfarin is almost entirely by metabolism. COUMADIN is stereoselectivelymetabolized by hepatic microsomal enzymes (cytochrome P-450) to inactive hydroxylatedmetabolites (predominant route) and by reductases to reduced metabolites (warfarinalcohols). The warfarin alcohols have minimal anticoagulant activity. Themetabolites are principally excreted into the urine; and to a lesser extentinto the bile. The metabolites of warfarin that have been identified includedehydrowarfarin, two diastereoisomer alcohols, 4′-, 6-, 7-, 8- and 10-hydroxywarfarin.The cytochrome P-450 isozymes involved in the metabolism of warfarin include2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. 2C9 is likely to be the principal formof human liver P-450 which modulates the in vivo anticoagulantactivity of warfarin.

The S-enantiomerof warfarin is mainly metabolized to 7-hydroxywarfarin by CYP2C9, a polymorphicenzyme. The variant alleles CYP2C9*2 and CYP2C9*3 result in decreased invitro CYP2C9 enzymatic 7-hydroxylation of S-warfarin. The frequenciesof these alleles in Caucasians are approximately 11% and 7% for CYP2C9*2 andCYP2C9*3, respectively. Patients with one or moreof these variant CYP2C9 alleles have decreased S-warfarin clearance (Table1).

Other CYP2C9 alleles associated with reduced enzymaticactivity occur at lower frequencies, including *5, *6, and *11 alleles inpopulations of African ancestry and *5, *9, and *11 alleles in Caucasians.

Theterminal half-life of warfarin after a single dose is approximately 1 week;however, the effective half-life ranges from 20 to 60 hours, with a mean ofabout 40 hours. The clearance of R-warfarin is generally half that of S-warfarin,thus as the volumes of distribution are similar, the half-life of R-warfarinis longer than that of S-warfarin. The half-life of R-warfarin ranges from37 to 89 hours, while that of S-warfarin ranges from 21 to 43 hours. Studieswith radiolabeled drug have demonstrated that up to 92% of the orally administereddose is recovered in urine. Very little warfarin is excreted unchanged inurine. Urinary excretion is in the form of metabolites.

A meta-analysis of 9 qualified studiesincluding 2775 patients (99% Caucasian) was performed to examine the clinicaloutcomes associated with CYP2C9 gene variants in warfarin-treated patients. Inthis meta-analysis, 3 studies assessed bleeding risks and 8 studies assesseddaily dose requirements. The analysis suggested an increased bleeding riskfor patients carrying either the CYP2C9*2 or CYP2C9*3 alleles. Patients carryingat least one copy of the CYP2C9*2 allele required a mean daily warfarin dosethat was 17% less than the mean daily dose for patients homozygous for theCYP2C9*1 allele. For patients carrying at least one copy of the CYP2C9*3 allele,the mean daily warfarin dose was 37% less than the mean daily dose for patientshomozygous for the CYP2C9*1 allele.

In an observationalstudy, the risk of achieving INR >3 during the first 3 weeks of warfarin therapywas determined in 219 Swedish patients retrospectively grouped by CYP2C9 genotype.The relative risk of overanticoagulation as measured by INR >3 during thefirst 2 weeks of therapy was approximately doubled for those patients classifiedas *2 or *3 compared to patients who were homozygous for the *1 allele.

Warfarinreduces the regeneration of vitamin K from vitamin K epoxide in the vitaminK cycle, through inhibition of vitamin K epoxide reductase (VKOR), a multiproteinenzyme complex. Certain single nucleotide polymorphisms in the VKORC1 gene(especially the –1639G>A allele) have been associated with lower dose requirementsfor warfarin. In 201 Caucasian patients treated with stable warfarin doses,genetic variations in the VKORC1 gene were associated with lower warfarindoses. In this study, about 30% of the variance in warfarin dose could beattributed to variations in the VKORC1 gene alone; about 40% of the variancein warfarin dose could be attributed to variations in VKORC1 and CYP2C9 genescombined. About 55% of the variability in warfarindose could be explained by the combination of VKORC1 and CYP2C9 genotypes,age, height, body weight, interacting drugs, and indication for warfarin therapyin Caucasian patients. Similar observations havebeen reported in Asian patients.

Patients60 years or older appear to exhibit greater than expected PT/INR responseto the anticoagulant effects of warfarin. The cause of the increased sensitivityto the anticoagulant effects of warfarin in this age group is unknown. Thisincreased anticoagulant effect from warfarin may be due to a combination ofpharmacokinetic and pharmacodynamic factors. Racemic warfarin clearance maybe unchanged or reduced with increasing age. Limited information suggeststhere is no difference in the clearance of S-warfarin in the elderly versusyoung subjects. However, there may be a slight decrease in the clearance ofR-warfarin in the elderly as compared to the young. Therefore, as patientage increases, a lower dose of warfarin is usually required to produce a therapeuticlevel of anticoagulation.

Asianpatients may require lower initiation and maintenance doses of warfarin. Onenon-controlled study conducted in 151 Chinese outpatients reported a meandaily warfarin requirement of 3.3±1.4 mg to achieve an INR of 2 to 2.5. Thesepatients were stabilized on warfarin for various indications. Patient agewas the most important determinant of warfarin requirement in Chinese patientswith a progressively lower warfarin requirement with increasing age.

Renal clearance is considered to bea minor determinant of anticoagulant response to warfarin. No dosage adjustmentis necessary for patients with renal failure.

Hepatic dysfunction can potentiate theresponse to warfarin through impaired synthesis of clotting factors and decreasedmetabolism of warfarin.

The administration of COUMADIN via theintravenous (IV) route should provide the patient with the same concentrationof an equal oral dose, but maximum plasma concentration will be reached earlier.However, the full anticoagulant effect of a dose of warfarin may not be achieveduntil 72 to 96 hours after dosing, indicating that the administration of IVCOUMADIN should not provide any increased biological effect or earlier onsetof action.

In five prospective randomized controlledclinical trials involving 3711 patients with non-rheumatic AF, warfarin significantlyreduced the risk of systemic thromboembolism including stroke (see Table 2).The risk reduction ranged from 60% to 86% in all except one trial (CAFA: 45%)which stopped early due to published positive results from two of these trials.The incidence of major bleeding in these trials ranged from 0.6% to 2.7% (seeTable 2). Meta-analysis findings of these studies revealed that the effectsof warfarin in reducing thromboembolic events including stroke were similarat either moderately high INR (2.0-4.5) or low INR (1.4-3.0). There was asignificant reduction in minor bleeds at the low INR. Similar data from clinicalstudies in valvular atrial fibrillation patients are not available.

WARIS (The Warfarin Re-Infarction Study)was a double-blind, randomized study of 1214 patients 2 to 4 weeks post-infarctiontreated with warfarin to a target INR of 2.8 to 4.8. [But note that a lowerINR was achieved and increased bleeding was associated with INRs above 4.0;(see DOSAGE AND ADMINISTRATION ).] Theprimary endpoint was a combination of total mortality and recurrent infarction.A secondary endpoint of cerebrovascular events was assessed. Mean follow-upof the patients was 37 months. The results for each endpoint separately, includingan analysis of vascular death, are provided in the following table:

WARIS II (The Warfarin, Aspirin, Re-Infarction Study)was an open-label, randomized study of 3630 patients hospitalized for acutemyocardial infarction treated with warfarin target INR 2.8 to 4.2, aspirin160 mg/day, or warfarin target INR 2.0 to 2.5 plus aspirin 75 mg/day priorto hospital discharge. There were approximately four times as many major bleedingepisodes in the two groups receiving warfarin than in the group receivingaspirin alone. Major bleeding episodes were not more frequent among patientsreceiving aspirin plus warfarin than among those receiving warfarin alone,but the incidence of minor bleeding episodes was higher in the combined therapygroup. The primary endpoint was a composite of death, nonfatal reinfarction,or thromboembolic stroke. The mean duration of observation was approximately4 years. The results for WARIS II are provided in the following table.

In a prospective, randomized, open-label,positive-controlled study in 254 patients, thethromboembolic-free interval was found to be significantly greater in patientswith mechanical prosthetic heart valves treated with warfarin alone comparedwith dipyridamole-aspirin (p<0.005) and pentoxifylline-aspirin (p<0.05)treated patients. Rates of thromboembolic events in these groups were 2.2,8.6, and 7.9/100 patient years, respectively. Major bleeding rates were 2.5,0.0, and 0.9/100 patient years, respectively.

In aprospective, open label, clinical trial comparing moderate (INR 2.65) vs.high intensity (INR 9.0) warfarin therapies in 258 patients with mechanicalprosthetic heart valves, thromboembolism occurred with similar frequency inthe two groups (4.0 and 3.7 events/100 patient years, respectively). Majorbleeding was more common in the high intensity group (2.1 events/100patient years) vs. 0.95 events/100 patient years in the moderate intensitygroup.

In a randomizedtrial in 210 patients comparing two intensities of warfarin therapy (INR 2.0-2.25vs. INR 2.5-4.0) for a three-month period following tissue heart valve replacement,thromboembolism occurred with similar frequency in the two groups (major embolicevents 2.0% vs. 1.9%, respectively, and minor embolic events 10.8% vs. 10.2%,respectively). Major bleeding complications were more frequent with the higherintensity (major hemorrhages 4.6%) vs. none in the lower intensity.

COUMADIN is indicated for the prophylaxisand/or treatment of venous thrombosis and its extension, and pulmonary embolism.

COUMADINis indicated for the prophylaxis and/or treatment of the thromboembolic complicationsassociated with atrial fibrillation and/or cardiac valve replacement.

COUMADINis indicated to reduce the risk of death, recurrent myocardial infarction,and thromboembolic events such as stroke or systemic embolization after myocardialinfarction.

Anticoagulation is contraindicated inany localized or general physical condition or personal circumstance in whichthe hazard of hemorrhage might be greater than the potential clinical benefitsof anticoagulation, such as:

COUMADINis contraindicated in women who are or may become pregnant because the drugpasses through the placental barrier and may cause fatal hemorrhage to thefetus in utero. Furthermore, there have been reports of birthmalformations in children born to mothers who have been treated with warfarinduring pregnancy.

Embryopathy characterized by nasalhypoplasia with or without stippled epiphyses (chondrodysplasia punctata)has been reported in pregnant women exposed to warfarin during the first trimester.Central nervous system abnormalities also have been reported, including dorsalmidline dysplasia characterized by agenesis of the corpus callosum, Dandy-Walkermalformation, and midline cerebellar atrophy. Ventral midline dysplasia, characterizedby optic atrophy, and eye abnormalities have been observed. Mental retardation,blindness, and other central nervous system abnormalities have been reportedin association with second and third trimester exposure. Although rare, teratogenicreports following in utero exposure to warfarin include urinarytract anomalies such as single kidney, asplenia, anencephaly, spina bifida,cranial nerve palsy, hydrocephalus, cardiac defects and congenital heart disease,polydactyly, deformities of toes, diaphragmatic hernia, corneal leukoma, cleftpalate, cleft lip, schizencephaly, and microcephaly.

Spontaneousabortion and stillbirth are known to occur and a higher risk of fetal mortalityis associated with the use of warfarin. Low birth weight and growth retardationhave also been reported.

Women of childbearing potentialwho are candidates for anticoagulant therapy should be carefully eva luatedand the indications critically reviewed with the patient. If the patient becomespregnant while taking this drug, she should be apprised of the potential risksto the fetus, and the possibility of termination of the pregnancy should bediscussed in light of those risks.

Hemorrhagic tendencies or blooddyscrasias.

Recent or contemplated surgeryof: (1) central nervous system; (2) eye; (3) traumatic surgery resultingin large open surfaces.

Bleeding tendencies associatedwith active ulceration or overt bleeding of: (1) gastrointestinal,genitourinary or respiratory tracts; (2) cerebrovascular hemorrhage; (3) aneurysms-cerebral,dissecting aorta; (4) pericarditis and pericardial effusions; (5) bacterialendocarditis.

Threatened abortion, eclampsiaand preeclampsia.

Inadequate laboratory facilities.

Unsupervisedpatients with senility, alcoholism, or psychosis or other lack of patientcooperation.

Spinal puncture and otherdiagnostic or therapeutic procedures with potential for uncontrollable bleeding.

Miscellaneous: majorregional, lumbar block anesthesia, malignant hypertension and known hypersensitivityto warfarin or to any other components of this product.

The most serious risks associated withanticoagulant therapy with warfarin sodium are hemorrhage in any tissue ororgan (see BLACK BOX WARNING )and, less frequently (<0.1%), necrosis and/or gangrene of skin and othertissues. Hemorrhage and necrosis have in some cases been reported to resultin death or permanent disability. Necrosis appears to be associated with localthrombosis and usually appears within a few days of the start of anticoagulanttherapy. In severe cases of necrosis, treatment through debridement or amputationof the affected tissue, limb, breast or penis has been reported. Careful diagnosisis required to determine whether necrosis is caused by an underlying disease.Warfarin therapy should be discontinued when warfarin is suspected to be thecause of developing necrosis and heparin therapy may be considered for anticoagulation.Although various treatments have been attempted, no treatment for necrosishas been considered uniformly effective. See below for information on predisposingconditions. These and other risks associated with anticoagulant therapy mustbe weighed against the risk of thrombosis or embolization in untreated cases.

Itcannot be emphasized too strongly that treatment of each patient is a highlyindividualized matter. COUMADIN (Warfarin Sodium), a narrow therapeutic range(index) drug, may be affected by factors such as other drugs and dietary vitaminK. Dosage should be controlled by periodic determinations of prothrombin time(PT)/International Normalized Ratio (INR). Determinations of whole blood clottingand bleeding times are not effective measures for control of therapy. Heparinprolongs the one-stage PT. When heparin and COUMADIN are administered concomitantly,refer below to Conversion From Heparin Therapy for recommendations.

Increasedcaution should be observed when COUMADIN is administered in the presence ofany predisposing condition where added risk of hemorrhage, necrosis, and/organgrene is present.

Anticoagulation therapy with COUMADINmay enhance the release of atheromatous plaque emboli, thereby increasingthe risk of complications from systemic cholesterol microembolization, includingthe “purple toes syndrome.” Discontinuation of COUMADIN therapy is recommendedwhen such phenomena are observed.

Systemic atheroemboliand cholesterol microemboli can present with a variety of signs and symptomsincluding purple toes syndrome, livedo reticularis, rash, gangrene, abruptand 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 simulatingpolyarteritis, or any other sequelae of vascular compromise due to embolicocclusion. The most commonly involved visceral organs are the kidneys followedby the pancreas, spleen, and liver. Some cases have progressed to necrosisor death.

Purple toes syndrome is a complication oforal anticoagulation characterized by a dark, purplish or mottled color ofthe toes, usually occurring between 3 to 10 weeks, or later, after the initiationof therapy with warfarin or related compounds. Major features of this syndromeinclude purple color of plantar surfaces and sides of the toes that blancheson moderate pressure and fades with elevation of the legs; pain and tendernessof the toes; waxing and waning of the color over time. While the purple toessyndrome is reported to be reversible, some cases progress to gangrene ornecrosis which may require debridement of the affected area, or may lead toamputation.

COUMADIN should be used with cautionin patients with heparin-induced thrombocytopenia and deep venous thrombosis.Cases of venous limb ischemia, necrosis, and gangrene have occurred in patientswith heparin-induced thrombocytopenia and deep venous thrombosis when heparintreatment was discontinued and warfarin therapy was started or continued.In some patients sequelae have included amputation of the involved area and/ordeath.

The decision to administer anticoagulantsin the following conditions must be based upon clinical judgment in whichthe risks of anticoagulant therapy are weighed against the benefits:

Lactation: Based on very limited published data,warfarin has not been detected in the breast milk of mothers treated withwarfarin. The same limited published data report that some breast-fed infants,whose mothers were treated with warfarin, had prolonged prothrombin times,although not as prolonged as those of the mothers. The decision to breast-feedshould be undertaken only after careful consideration of the available alternatives.Women who are breast-feeding and anticoagulated with warfarin should be verycarefully monitored so that recommended PT/INR values are not exceeded. Itis prudent to perform coagulation tests and to eva luate vitamin K status ininfants before advising women taking warfarin to breast-feed. Effects in prematureinfants have not been eva luated.

Severe to moderatehepatic or renal insufficiency.

Infectiousdiseases or disturbances of intestinal flora: sprue, antibiotic therapy.

Trauma whichmay result in internal bleeding.

Surgery or trauma resultingin large exposed raw surfaces.

Indwelling catheters.

Severeto moderate hypertension.

Known or suspecteddeficiency in protein C mediated anticoagulant response: Hereditaryor acquired deficiencies of protein C or its cofactor, protein S, have beenassociated with tissue necrosis following warfarin administration. Not allpatients with these conditions develop necrosis, and tissue necrosis occursin patients without these deficiencies. Inherited resistance to activatedprotein C has been described in many patients with venous thromboembolic disordersbut has not yet been eva luated as a risk factor for tissue necrosis. The riskassociated with these conditions, both for recurrent thrombosis and for adversereactions, is difficult to eva luate since it does not appear to be the samefor everyone. Decisions about testing and therapy must be made on an individualbasis. It has been reported that concomitant anticoagulation therapy withheparin for 5 to 7 days during initiation of therapy with COUMADIN may minimizethe incidence of tissue necrosis. Warfarin therapy should be discontinuedwhen warfarin is suspected to be the cause of developing necrosis, and heparintherapy may be considered for anticoagulation.

Miscellaneous: polycythemiavera, vasculitis, and severe diabetes.

Periodicdetermination of PT/INR is essential. (See DOSAGE ANDADMINISTRATION: Laboratory Control.) Numerous factors, aloneor in combination including changes in diet, medications, botanicals, andgenetic variations in the CYP2C9 and VKORC1 enzymes (see CLINICALPHARMACOLOGY: Pharmacogenomics ) may influence the response ofthe patient to warfarin.

Itis generally good practice to monitor the patient’s response with additionalPT/INR determinations in the period immediately after discharge from the hospital,and whenever other medications, including botanicals, are initiated, discontinuedor taken irregularly. The following factors are listed for reference; however,other factors may also affect the anticoagulant response.

Drugsmay interact with COUMADIN through pharmacodynamic or pharmacokinetic mechanisms.Pharmacodynamic mechanisms for drug interactions with COUMADIN are synergism(impaired hemostasis, reduced clotting factor synthesis), competitive antagonism(vitamin K), and altered physiologic control loop for vitamin K metabolism(hereditary resistance). Pharmacokinetic mechanisms for drug interactionswith COUMADIN are mainly enzyme induction, enzyme inhibition, and reducedplasma protein binding. It is important to note that some drugs may interactby more than one mechanism.

Thefollowing factors, alone or in combination, may be responsible for INCREASEDPT/INR response:

ENDOGENOUS FACTORS:

EXOGENOUS FACTORS:

Potentialdrug interactions with COUMADIN are listed below by drug class and by specificdrugs.

Thefollowing factors, alone or in combination, may be responsible for DECREASEDPT/INR response:

ENDOGENOUS FACTORS:

EXOGENOUS FACTORS:

Potentialdrug interactions with COUMADIN (Warfarin Sodium) are listedbelow by drug class and by specific drugs.