warnings
WARNINGS The most serious risks associated with anticoagulant therapy with warfarin sodium are hemorrhage in any tissue or organ 5 (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)/lnternational Normalized Ratio (INR) or other suitable coagulation tests. 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. Caution should be observed when warfarin sodium is administered in any situation or in the presence of any predisposing condition where added risk of hemorrhage, necrosis, and/or gangrene is present. Anticoagulation therapy with warfarin sodium 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 sodium 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 to 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. Heparin-induced thrombocytopenia Warfarin sodium 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 6 . A severe elevation (>50 seconds) in activated partial thromboplastin time (aPTT) with a PT/INR in the desired range as been identified as an indication of increased risk of postoperative hemorrhage. 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 reports 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 breastfeed should be undertaken only after careful consideration of the available alternatives.Women who are breastfeeding 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 at risk for bleeding tendencies 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 warfarin sodium 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. Minor and severe allergic/hypersensitivity reactions and anaphylactic reactions have been reported. In patients with acquired or inherited warfarin resistance, decreased therapeutic responses to warfarin sodium have been reported. Exaggerated therapeutic responses have been reported in other patients. Patients with congestive heart failure may exhibit greater than expected PT/INR response to warfarin sodium, thereby requiring more frequent laboratory monitoring, and reduced doses of warfarin sodium. Concomitant use of anticoagulants with streptokinase or urokinase is not recommended and may be hazardous. Please note recommendations accompanying these preparations.)