Warfarin Sodium (Page 4 of 9)


The most serious risks associated with anticoagulant therapy with warfarin sodium are hemorrhage in any tissue or organ12 (see BLACK BOX WARNING) and, less frequently (<0.1%), necrosis and/or gangrene of skin and other tissues. Hemorrhage and necrosis have in some cases been reported to result in death or permanent disability. Necrosis appears to be associated with local thrombosis and usually appears within a few days of the start of anticoagulant therapy. In severe cases of necrosis, treatment through debridement or amputation of the affected tissue, limb, breast or penis has been reported. Careful diagnosis is required to determine whether necrosis is caused by an underlying disease. Warfarin therapy should be discontinued when warfarin is suspected to be the cause of developing necrosis and heparin therapy may be considered for anticoagulation. Although various treatments have been attempted, no treatment for necrosis has been considered uniformly effective. See below for information on predisposing conditions. These and other risks associated with anticoagulant therapy must be weighed against the risk of thrombosis or embolization in untreated cases.

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

Increased caution should be observed when warfarin is administered in the presence of any predisposing condition where added risk of hemorrhage, necrosis, and/or gangrene is present.

Anticoagulation therapy with warfarin may enhance the release of atheromatous plaque emboli, thereby increasing the risk of complications from systemic cholesterol microembolization, including the “purple toes syndrome.” Discontinuation of warfarin therapy is recommended when such phenomena are observed.

Systemic atheroemboli and cholesterol microemboli can present with a variety of signs and symptoms including purple toes syndrome, 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 due to embolic occlusion. The most commonly involved visceral organs are the kidneys followed by the pancreas, spleen, and liver. Some cases have progressed to necrosis or death.

Purple toes syndrome is a complication of oral anticoagulation characterized by a dark, purplish or mottled color of the toes, usually occurring between 3-10 weeks, or later, after the initiation of therapy with warfarin or related compounds. Major features of this syndrome include purple color of plantar surfaces and sides of the toes that blanches on moderate pressure and fades with elevation of the legs; pain and tenderness of the toes; waxing and waning of the color over time. While the purple toes syndrome is reported to be reversible, some cases progress to gangrene or necrosis which may require debridement of the affected area, or may lead to amputation.

Warfarin should be used with caution in patients with heparin-induced thrombocytopenia and deep venous thrombosis. Cases of venous limb ischemia, necrosis, and gangrene have occurred in patients with heparin-induced thrombocytopenia and deep venous thrombosis when heparin treatment was discontinued and warfarin therapy was started or continued. In some patients sequelae have included amputation of the involved area and/or death13.

The decision to administer anticoagulants in the following conditions must be based upon clinical judgment in which the 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 with warfarin. 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-feed should be undertaken only after careful consideration of the available alternatives. Women who are breast-feeding and anticoagulated with warfarin should be very carefully monitored so that recommended PT/INR values are not exceeded. It is prudent to perform coagulation tests and to evaluate vitamin K status in infants before advising women taking warfarin to breast-feed. Effects in premature infants have not been evaluated.

Severe to moderate hepatic or renal insufficiency.

Infectious diseases or disturbances of intestinal fora: sprue, antibiotic therapy.

Trauma which may result in internal bleeding.

Surgery or trauma resulting in large exposed raw surfaces.

Indwelling catheters.

Severe to moderate hypertension.

Known or suspected deficiency in protein C mediated anticoagulant response: Hereditary or acquired deficiencies of protein C or its cofactor, protein S, have been associated with tissue necrosis following warfarin administration. Not all patients with these conditions develop necrosis, and tissue necrosis occurs in patients without these deficiencies. Inherited resistance to activated protein C has been described in many patients with venous thromboembolic disorders but has not yet been evaluated as a risk factor for tissue necrosis. The risk associated with these conditions, both for recurrent thrombosis and for adverse reactions, is difficult to evaluate since it does not appear to be the same for everyone. Decisions about testing and therapy must be made on an individual basis. It has been reported that concomitant anticoagulation therapy with heparin for 5 to 7 days during initiation of therapy with warfarin may minimize the incidence of tissue necrosis. Warfarin therapy should be discontinued when warfarin is suspected to be the cause of developing necrosis, and heparin therapy may be considered for anticoagulation.

Miscellaneous: polycythemia vera, vasculitis, and severe diabetes.


Periodic determination of PT/INR is essential. (see DOSAGE AND ADMINISTRATION: Laboratory Control.)

Numerous factors, alone or in combination including changes in diet, medications, botanicals, and genetic variations in the CYP2C9 and VKORC1 enzymes (see CLINICAL PHARMACOLOGY: Pharmacogenomics) may influence the response of the patient to warfarin.

Drug-Drug and Drug-Disease Interactions

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

Drugs may interact with warfarin through pharmacodynamic or pharmacokinetic mechanisms. Pharmacodynamic mechanisms for drug interactions with warfarin 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 interactions with warfarin are mainly enzyme induction, enzyme inhibition, and reduced plasma protein binding. It is important to note that some drugs may interact by more than one mechanism.

The following factors, alone or in combination, may be responsible for INCREASED PT/INR response:


blood dyscrasias — see CONTRAINDICATIONScancercollagen vascular diseasecongestive heart failure diarrheaelevated temperaturehepatic disorders infectious hepatitis jaundice hyperthyroidismpoor nutritional statesteatorrheavitamin K deficiency


Potential drug interactions with warfarin sodium are listed below by drug class and by specific drugs.

Classes of Drugs
5-lipoxygenase InhibitorAdrenergic Stimulants, CentralAlcohol Abuse Reduction PreparationsAnalgesicsAnesthetics, InhalationAntiandrogenAntiarrhythmics†Antibiotics† Aminoglycosides (oral) Cephalosporins, parenteral Macrolides Miscellaneous Penicillins, intravenous, high dose Quinolones (fluoroquinolones) Sulfonamides, long acting TetracyclinesAnticoagulantsAnticonvulsants†Antidepressants†Antimalarial AgentsAntineoplastics†Antiparasitic/Antimicrobials Antiplatelet Drugs/EffectsAntithyroid Drugs†Beta-Adrenergic BlockersCholelitholytic AgentsDiabetes Agents, OralDiuretics†Fungal Medications, Intravaginal, Systemic†Gastric Acidity and Peptic Ulcer Agents†Gastrointestinal Prokinetic Agents Ulcerative Colitis AgentsGout Treatment AgentsHemorrheologic AgentsHepatotoxic DrugsHyperglycemic AgentsHypertensive Emergency AgentsHypnotics†Hypolipidemics† Bile Acid-Binding Resins† Fibric Acid Derivatives HMG-CoA Reductase Inhibitors† Leukotriene Receptor AntagonistMonoamine Oxidase InhibitorsNarcotics, prolongedNonsteroidal Anti- Inflammatory AgentsProton Pump InhibitorsPsychostimulantsPyrazolonesSalicylatesSelective Serotonin Reuptake InhibitorsSteroids, Adrenocortical†Steroids, Anabolic (17-Alkyl Testosterone Derivatives)ThrombolyticsThyroid DrugsTuberculosis Agents†Uricosuric AgentsVaccinesVitamins†
Specific Drugs Reported
also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations†Increased and decreased PT/INR responses have been reported.
acetaminophenalcohol†allopurinolaminosalicylic acidamiodarone HClargatrobanaspirinatenololatorvastatin†azithromycinbivalirudincapecitabinecefamandolecefazolincefoperazonecefotetancefoxitinceftriaxonecelecoxibcerivastatinchenodiolchloramphenicolchloral hydrate†chlorpropamidecholestyramine†cimetidineciprofloxacincisaprideclarithromycinclofibratecyclophosphamide†danazoldextrandextrothyroxinediazoxide diclofenacdicumaroldiflunisaldisulfiramdoxycyclineerythromycinesomeprazoleethacrynic acidezetimibefenofibratefenoprofenfluconazolefluorouracilfluoxetineflutamidefluvastatinfluvoxaminegefitinibgemifibrozilglucagonhalothaneheparinibuprofenifosfamideindomethacininfluenza virus vaccineitraconazoleketoprofenketorolaclansoprazolelepirudinlevamisolelevofloxacinlevothyroxineliothyronine lovastatinmefenamic acidmethimazole†methyldopamethylphenidatemethylsalicylate ointment (topical)metronidazolemiconazole (intravaginal, oral, systemic)moricizine hydrochloride†nalidixic acidnaproxenneomycinnorfloxacinofloxacinolsalazineomeprazoleoxandroloneoxaprozinoxymetholonepantoprazoleparoxetinepenicillin G, intravenouspentoxifyllinephenylbutazonephenytoin†piperacillinpiroxicampravastatin†prednisone†propafenone propoxyphenepropranololpropylthiouracil†quinidinequininerabeprazoleranitidine†rofecoxibsertralinesimvastatinstanozololstreptokinasesulfamethizolesulfamethoxazolesulfinpyrazonesulfisoxazolesulindactamoxifentetracyclinethyroidticarcillinticlopidinetissue plasminogen activator (t-PA)tolbutamidetramadoltrimethoprim/ sulfamethoxazoleurokinasevaldecoxibvalproatevitamin Ewarfarin overdosezafirlukastzileuton

The following factors, alone or in combination, may be responsible for DECREASED PT/INR response:


edemahereditary coumarin resistancehyperlipemia hypothyroidismnephrotic syndrome


Potential drug interactions with warfarin sodium are listed below by drug class and by specific drugs.

Classes of Drugs
Adrenal Cortical Steroid InhibitorsAntacidsAntianxiety AgentsAntiarrhythmics†Antibiotics†Anticonvulsants†Antidepressants†AntihistaminesAntineoplastics† Antipsychotic MedicationsAntithyroid Drugs†BarbituratesDiuretics†Enteral Nutritional SupplementsFungal Medications, Systemic†Gastric Acidity and Peptic Ulcer Agents†Hypnotics† Hypolipidemics† Bile Acid-Binding Resins† HMG-CoA Reductase Inhibitors†ImmunosuppressivesOral Contraceptives, Estrogen ContainingSelective Estrogen Receptor ModulatorsSteroids, Adrenocortical†Tuberculosis Agents†Vitamins†
Specific Drugs Reported
also: diet high in vitamin K unreliable PT/INR determinations†Increased and decreased PT/INR responses have been reported.
alcohol†aminoglutethimideamobarbitalatorvastatin†azathioprinebutabarbitalbutalbitalcarbamazepinechloral hydrate†chlordiazepoxidechlorthalidone cholestyramine†clozapinecorticotropincortisonecyclophosphamide†dicloxacillinethchlorvynolglutethimidegriseofulvinhaloperidolmeprobamate 6-mercaptopurinemethimazole†moricizine hydrochloride†nafcillinparaldehydepentobarbitalphenobarbitalphenytoin†pravastatin†prednisone†primidone propylthiouracil†raloxifeneranitidine†rifampinsecobarbitalspironolactonesucralfatetrazodonevitamin C (high dose)vitamin Kwarfarin underdosage

Because a patient may be exposed to a combination of the above factors, the net effect of warfarin sodium on PT/INR response may be unpredictable. More frequent PT/INR monitoring is therefore advisable. Medications of unknown interaction with coumarins are best regarded with caution. When these medications are started or stopped, more frequent PT/INR monitoring is advisable.

It has been reported that concomitant administration of warfarin and ticlopidine may be associated with cholestatic hepatitis.

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