Coumadin (Warfarin Sodium) - Warnings and Precautions

WARNINGS

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. COUMADIN (Warfarin Sodium), a narrow therapeuticrange (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 COUMADIN are administered concomitantly, refer below to Conversion From Heparin Therapy for recommendations.

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

Anticoagulation therapy with COUMADIN 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 COUMADIN 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.

COUMADIN 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 death.¹³

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 flora: 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 COUMADIN 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.

PRECAUTIONS

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 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 interactions with COUMADIN 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:

ENDOGENOUS FACTORS:

blood dyscrasias -    see CONTRAINDICATIONS cancer collagen vascular disease congestive heart failure

diarrhea elevated temperature hepatic disorders    infectious hepatitis    jaundice

hyperthyroidism poor nutritional state steatorrhea vitamin K deficiency

EXOGENOUS FACTORS:

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

Classes of Drugs
5-lipoxygenase Inhibitor Adrenergic Stimulants, Central Alcohol Abuse Reduction    Preparations Analgesics Anesthetics, Inhalation Antiandrogen Antiarrhythmics† Antibiotics†    Aminoglycosides (oral)    Cephalosporins, parenteral    Macrolides    Miscellaneous    Penicillins, intravenous, high dose    Quinolones (fluoroquinolones)    Sulfonamides, long acting    Tetracyclines Anticoagulants Anticonvulsants† Antidepressants† Antimalarial Agents Antineoplastics† Antiparasitic/Antimicrobials	Antiplatelet Drugs/Effects Antithyroid Drugs† Beta-Adrenergic Blockers Cholelitholytic Agents Diabetes Agents, Oral Diuretics† Fungal Medications,    Intravaginal, Systemic† Gastric Acidity and Peptic    Ulcer Agents† Gastrointestinal    Prokinetic Agents    Ulcerative Colitis Agents Gout Treatment Agents Hemorrheologic Agents Hepatotoxic Drugs Hyperglycemic Agents Hypertensive Emergency Agents Hypnotics† Hypolipidemics†    Bile Acid-Binding Resins†    Fibric Acid Derivatives    HMG-CoA Reductase Inhibitors†	Leukotriene Receptor Antagonist Monoamine Oxidase Inhibitors Narcotics, prolonged Nonsteroidal Anti-Inflammatory    Agents Proton Pump Inhibitors Psychostimulants Pyrazolones Salicylates Selective Serotonin Reuptake    Inhibitors Steroids, Adrenocortical† Steroids, Anabolic (17-Alkyl    Testosterone Derivatives) Thrombolytics Thyroid Drugs Tuberculosis Agents† Uricosuric Agents Vaccines Vitamins†

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.
Specific Drugs Reported
acetaminophen alcohol† allopurinol aminosalicylic acid amiodarone HCl argatroban aspirin atenolol atorvastatin† azithromycin bivalirudin capecitabine cefamandole cefazolin cefoperazone cefotetan cefoxitin ceftriaxone celecoxib cerivastatin chenodiol chloramphenicol chloral hydrate† chlorpropamide cholestyramine† cimetidine ciprofloxacin cisapride clarithromycin clofibrate COUMADIN overdose cyclophosphamide† danazol dextran dextrothyroxine diazoxide diclofenac dicumarol diflunisal disulfiram doxycycline erythromycin esomeprazole ethacrynic acid ezetimibe	fenofibrate fenoprofen fluconazole fluorouracil fluoxetine flutamide fluvastatin fluvoxamine gefitinib gemfibrozil glucagon halothane heparin ibuprofen ifosfamide indomethacin influenza virus vaccine itraconazole ketoprofen ketorolac lansoprazole lepirudin levamisole levofloxacin levothyroxine liothyronine lovastatin mefenamic acid methimazole† methyldopa methylphenidate methylsalicylate ointment (topical) metronidazole miconazole (intravaginal, oral,    systemic) moricizine hydrochloride† nalidixic acid naproxen neomycin norfloxacin ofloxacin olsalazine omeprazole oxandrolone oxaprozin	oxymetholone pantoprazole paroxetine penicillin G, intravenous pentoxifylline phenylbutazone phenytoin† piperacillin piroxicam pravastatin† prednisone† propafenone propoxyphene propranolol propylthiouracil† quinidine quinine rabeprazole ranitidine† rofecoxib sertraline simvastatin stanozolol streptokinase sulfamethizole sulfamethoxazole sulfinpyrazone sulfisoxazole sulindac tamoxifen tetracycline thyroid ticarcillin ticlopidine tissue plasminogen activator (t-PA) tolbutamide tramadol trimethoprim/sulfamethoxazole urokinase valdecoxib valproate vitamin E zafirlukast zileuton

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

ENDOGENOUS FACTORS:

edema hereditary coumarin resistance hyperlipemia

hypothyroidism nephrotic syndrome

EXOGENOUS FACTORS:

Potential drug interactions with COUMADIN (Warfarin Sodium) are listed below by drug class and by specific drugs.

Classes of Drugs
Adrenal Cortical Steroid Inhibitors Antacids Antianxiety Agents Antiarrhythmics† Antibiotics† Anticonvulsants† Antidepressants† Antihistamines Antineoplastics† Antipsychotic Medications	Antithyroid Drugs† Barbiturates Diuretics† Enteral Nutritional Supplements Fungal Medications, Systemic† Gastric Acidity and Peptic Ulcer    Agents† Hypnotics† Hypolipidemics†    Bile Acid-Binding Resins†    HMG-CoA Reductase Inhibitors†	Immunosuppressives Oral Contraceptives, Estrogen    Containing Selective Estrogen Receptor    Modulators Steroids, Adrenocortical† Tuberculosis Agents† Vitamins†

also:  diet high in vitamin K          unreliable PT/INR determinations
†Increased and decreased PT/INR responses have been reported.
Specific Drugs Reported
alcohol† aminoglutethimide amobarbital atorvastatin† azathioprine butabarbital butalbital carbamazepine chloral hydrate† chlordiazepoxide chlorthalidone cholestyramine† clozapine corticotropin cortisone	COUMADIN underdosage cyclophosphamide† dicloxacillin ethchlorvynol glutethimide griseofulvin haloperidol meprobamate 6-mercaptopurine methimazole† moricizine hydrochloride† nafcillin paraldehyde pentobarbital	phenobarbital phenytoin† pravastatin† prednisone† primidone propylthiouracil† raloxifene ranitidine† rifampin secobarbital spironolactone sucralfate trazodone vitamin C (high dose) vitamin K

Because a patient may be exposed to a combination of the above factors, the net effect of COUMADIN 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.

Botanical (Herbal) Medicines

Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with COUMADIN. Few adequate, well-controlled studies exist evaluating the potential for metabolic and/or pharmacologic interactions between botanicals and COUMADIN. Due to a lack of manufacturing standardization with botanical medicinal preparations, the amount of active ingredients may vary. This could further confound the ability to assess potential interactions and effects on anticoagulation. It is good practice to monitor the patient’s response with additional PT/INR determinations when initiating or discontinuing botanicals.

Specific botanicals reported to affect COUMADIN therapy include the following:

• Bromelains, danshen, dong quai (Angelica sinensis), garlic, Ginkgo biloba, ginseng, and cranberry products are associated most often with an INCREASE in the effects of COUMADIN.
• Coenzyme Q₁₀ (ubidecarenone) and St. John’s wort are associated most often with a DECREASE in the effects of COUMADIN.

Some botanicals may cause bleeding events when taken alone (e.g., garlic and Ginkgo biloba) and may have anticoagulant, antiplatelet, and/or fibrinolytic properties. These effects would be expected to be additive to the anticoagulant effects of COUMADIN. Conversely, other botanicals may have coagulant properties when taken alone or may decrease the effects of COUMADIN.

Some botanicals that may affect coagulation are listed below for reference; however, this list should not be considered all-inclusive. Many botanicals have several common names and scientific names. The most widely recognized common botanical names are listed.

Botanicals that contain coumarins with potential anticoagulant effects:
Agrimony1 Alfalfa Angelica (Dong Quai) Aniseed Arnica Asafoetida Bogbean2 Boldo Buchu Capsicum3 Cassia4	Celery Chamomile (German and Roman) Dandelion4 Fenugreek Horse Chestnut Horseradish Licorice4 Meadowsweet2 Nettle Parsley	Passion Flower Prickly Ash (Northern) Quassia Red Clover Sweet Clover Sweet Woodruff Tonka Beans Wild Carrot Wild Lettuce

Miscellaneous botanicals with anticoagulant properties:
Bladder Wrack (Fucus)	Pau d’arco

Botanicals that contain salicylate and/or have antiplatelet properties:
Agrimony1 Aloe Gel Aspen Black Cohosh Black Haw Bogbean2 Cassia4 Clove	Dandelion4 Feverfew Garlic5 German Sarsaparilla Ginger Ginkgo Biloba Ginseng (Panax) 5 Licorice4	Meadowsweet2 Onion5 Policosanol Poplar Senega Tamarind Willow Wintergreen

Botanicals with fibrinolytic properties:
Bromelains Capsicum3	Garlic5 Ginseng (Panax) 5	Inositol Nicotinate Onion5

1Contains coumarins, has antiplatelet properties, and may have coagulant properties due to possible Vitamin K content.
2Contains coumarins and salicylate.
3Contains coumarins and has fibrinolytic properties.
4Contains coumarins and has antiplatelet properties.
5Has antiplatelet and fibrinolytic properties.
Botanicals with coagulant properties:
Agrimony1 Goldenseal	Mistletoe Yarrow

Effect on Other Drugs

Coumarins may also affect the action of other drugs. Hypoglycemic agents (chlorpropamide and tolbutamide) and anticonvulsants (phenytoin and phenobarbital) may accumulate in the body as a result of interference with either their metabolism or excretion.

Considerations for Increased Bleeding Risk

COUMADIN is a narrow therapeutic range (index) drug, and additional caution should be observed when warfarin sodium is administered to certain patients. Reported risk factors for bleeding include high intensity of anticoagulation (INR >4.0), age ≥65, highly variable INRs, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, serious heart disease, anemia, malignancy, trauma, renal insufficiency, concomitant drugs (see PRECAUTIONS), and long duration of warfarin therapy. Identification of risk factors for bleeding and certain genetic variations in CYP2C9 and VKORC1 in a patient may increase the need for more frequent INR monitoring and the use of lower warfarin doses (see CLINICAL PHARMACOLOGY: Metabolism and DOSAGE AND ADMINISTRATION). Bleeding is more likely to occur during the starting period and with a higher dose of COUMADIN (resulting in a higher INR).

Intramuscular (I.M.) injections of concomitant medications should be confined to the upper extremities which permits easy access for manual compression, inspections for bleeding and use of pressure bandages.

Caution should be observed when COUMADIN (or warfarin) is administered concomitantly with nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, to be certain that no change in anticoagulation dosage is required. In addition to specific drug interactions that might affect PT/INR, NSAIDs, including aspirin, can inhibit platelet aggregation, and can cause gastrointestinal bleeding, peptic ulceration and/or perforation.

Information for Patients

The objective of anticoagulant therapy is to decrease the clotting ability of the blood so that thrombosis is prevented, while avoiding spontaneous bleeding. Effective therapeutic levels with minimal complications are in part dependent upon cooperative and well-instructed patients who communicate effectively with their physician. Patients should be advised: Strict adherence to prescribed dosage schedule is necessary. Do not take or discontinue any other medication, including salicylates (e.g., aspirin and topical analgesics), other over-the-counter medications, and botanical (herbal) products except on advice of the physician. Avoid alcohol consumption. Do not take COUMADIN during pregnancy and do not become pregnant while taking it (see CONTRAINDICATIONS). Avoid any activity or sport that may result in traumatic injury. Prothrombin time tests and regular visits to physician or clinic are needed to monitor therapy. Carry identification stating that COUMADIN is being taken. If the prescribed dose of COUMADIN is forgotten, notify the physician immediately. Take the dose as soon as possible on the same day but do not take a double dose of COUMADIN the next day to make up for missed doses. The amount of vitamin K in food may affect therapy with COUMADIN. Eat a normal, balanced diet maintaining a consistent amount of vitamin K. Avoid drastic changes in dietary habits, such as eating large amounts of green leafy vegetables. You should also avoid intake of cranberry juice or any other cranberry products. Notify your healthcare provider if any of these products are part of your normal diet. Contact physician to report any illness, such as diarrhea, infection or fever. Notify physician immediately if any unusual bleeding or symptoms occur. Signs and symptoms of bleeding include: pain, swelling or discomfort, prolonged bleeding from cuts, increased menstrual flow or vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or dark brown urine, red or tar black stools, headache, dizziness, or weakness. If therapy with COUMADIN is discontinued, patients should be cautioned that the anticoagulant effects of COUMADIN may persist for about 2 to 5 days. Patients should be informed that all warfarin sodium, USP, products represent the same medication, and should not be taken concomitantly, as overdosage may result. A Medication Guide¹⁴ should be available to patients when their prescriptions for warfarin sodium are issued.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity and mutagenicity studies have not been performed with COUMADIN. The reproductive effects of COUMADIN have not been evaluated. The use of warfarin during pregnancy has been associated with the development of fetal malformations in humans (see CONTRAINDICATIONS).

Use in Pregnancy

Pregnancy Category X

See CONTRAINDICATIONS.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 18 have not been established in randomized, controlled clinical trials. However, the use of COUMADIN in pediatric patients is well-documented for the prevention and treatment of thromboembolic events. Difficulty achieving and maintaining therapeutic PT/INR ranges in the pediatric patient has been reported. More frequent PT/INR determinations are recommended because of possible changing warfarin requirements.

Geriatric Use

Patients 60 years or older appear to exhibit greater than expected PT/INR response to the anticoagulant effects of warfarin (see CLINICAL PHARMACOLOGY). COUMADIN is contraindicated in any unsupervised patient with senility. Caution should be observed with administration of warfarin sodium to elderly patients in any situation or physical condition where added risk of hemorrhage is present. Lower initiation and maintenance doses of COUMADIN are recommended for elderly patients (see DOSAGE AND ADMINISTRATION).