Warfarin Sodium (Page 3 of 8)

4 CONTRAINDICATIONS

Warfarin sodium is contraindicated in:

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Pregnancy

Warfarin sodium is contraindicated in women who are pregnant except in pregnant women with mechanical heart valves, who are at high risk of thromboembolism [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1)]. Warfarin sodium can cause fetal harm when administered to a pregnant woman. Warfarin sodium exposure during pregnancy causes a recognized pattern of major congenital malformations (warfarin embryopathy and fetotoxicity), fatal fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality. If warfarin sodium is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

Warfarin sodium is contraindicated in patients with:

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Hemorrhagic tendencies or blood dyscrasias
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Recent or contemplated surgery of the central nervous system or eye, or traumatic surgery resulting in large open surfaces [see Warnings and Precautions (5.7)]
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Bleeding tendencies associated with:
− Active ulceration or overt bleeding of the gastrointestinal, genitourinary, or respiratory tract
− Central nervous system hemorrhage
− Cerebral aneurysms, dissecting aorta
− Pericarditis and pericardial effusions
− Bacterial endocarditis
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Threatened abortion, eclampsia, and preeclampsia
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Unsupervised patients with conditions associated with potential high level of non-compliance
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Spinal puncture and other diagnostic or therapeutic procedures with potential for uncontrollable bleeding
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Hypersensitivity to warfarin or to any other components of this product (e.g., anaphylaxis) [see Adverse Reactions (6)]
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Major regional or lumbar block anesthesia
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Malignant hypertension

5 WARNINGS AND PRECAUTIONS

The 7.5 mg tablets contain FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible individuals. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

5.1 Hemorrhage

Warfarin sodium can cause major or fatal bleeding. Bleeding is more likely to occur within the first month. Risk factors for bleeding include high intensity of anticoagulation (INR > 4), age greater than or equal to 65, history of highly variable INRs, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, anemia, malignancy, trauma, renal impairment, certain genetic factors [see Clinical Pharmacology (12.5)], certain concomitant drugs [see Drug Interactions (7)], and long duration of warfarin therapy.

Perform regular monitoring of INR in all treated patients. Those at high risk of bleeding may benefit from more frequent INR monitoring, careful dose adjustment to desired INR, and a shortest duration of therapy appropriate for the clinical condition. However, maintenance of INR in the therapeutic range does not eliminate the risk of bleeding.

Drugs, dietary changes, and other factors affect INR levels achieved with warfarin sodium therapy. Perform more frequent INR monitoring when starting or stopping other drugs, including botanicals, or when changing dosages of other drugs [see Drug Interactions (7)].

Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding [see Patient Counseling Information (17)].

5.2 Tissue Necrosis

Necrosis and/or gangrene of skin and other tissues is an uncommon but serious risk (< 0.1%). Necrosis may be associated with local thrombosis and usually appears within a few days of the start of warfarin sodium therapy. In severe cases of necrosis, treatment through debridement or amputation of the affected tissue, limb, breast, or penis has been reported.

Careful clinical evaluation is required to determine whether necrosis is caused by an underlying disease. Although various treatments have been attempted, no treatment for necrosis has been considered uniformly effective. Discontinue warfarin sodium therapy if necrosis occurs. Consider alternative drugs if continued anticoagulation therapy is necessary.

5.3 Calciphylaxis

Fatal and serious calciphylaxis or calcium uremic arteriolopathy has been reported in patients with and without end-stage renal disease. When calciphylaxis is diagnosed in these patients, discontinue warfarin sodium and treat calciphylaxis as appropriate. Consider alternative anticoagulation therapy.

5.4 Systemic Atheroemboli and Cholesterol Microemboli

Anticoagulation therapy with warfarin sodium may enhance the release of atheromatous plaque emboli. Systemic atheroemboli and cholesterol microemboli can present with a variety of signs and symptoms depending on the site of embolization. The most commonly involved visceral organs are the kidneys followed by the pancreas, spleen, and liver. Some cases have progressed to necrosis or death. A distinct syndrome resulting from microemboli to the feet is known as “purple toes syndrome.” Discontinue warfarin sodium therapy if such phenomena are observed. Consider alternative drugs if continued anticoagulation therapy is necessary.

5.5 Limb Ischemia, Necrosis, and Gangrene in Patients with HIT and HITTS

Do not use warfarin sodium as initial therapy in patients with heparin-induced thrombocytopenia (HIT) and with heparin-induced thrombocytopenia with thrombosis syndrome (HITTS). Cases of limb ischemia, necrosis, and gangrene have occurred in patients with HIT and HITTS 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. Treatment with warfarin sodium may be considered after the platelet count has normalized.

5.6 Use in Pregnant Women with Mechanical Heart Valves

Warfarin sodium can cause fetal harm when administered to a pregnant woman. While warfarin sodium is contraindicated during pregnancy, the potential benefits of using warfarin sodium may outweigh the risks for pregnant women with mechanical heart valves at high risk of thromboembolism. In those individual situations, the decision to initiate or continue warfarin sodium should be reviewed with the patient, taking into consideration the specific risks and benefits pertaining to the individual patient’s medical situation, as well as the most current medical guidelines. Warfarin sodium exposure during pregnancy causes a recognized pattern of major congenital malformations (warfarin embryopathy and fetotoxicity), fatal fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

5.7 Other Clinical Settings with Increased Risks

In the following clinical settings, the risks of warfarin sodium therapy may be increased:

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Moderate to severe hepatic impairment
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Infectious diseases or disturbances of intestinal flora (e.g., sprue, antibiotic therapy)
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Use of an indwelling catheter
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Severe to moderate hypertension
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Deficiency in protein C-mediated anticoagulant response: warfarin sodium reduces the synthesis of the naturally occurring anticoagulants, protein C and protein S. Hereditary or acquired deficiencies of protein C or its cofactor, protein S, have been associated with tissue necrosis following warfarin administration. Concomitant anticoagulation therapy with heparin for 5 to 7 days during initiation of therapy with warfarin sodium may minimize the incidence of tissue necrosis in these patients.
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Eye surgery: In cataract surgery, warfarin sodium use was associated with a significant increase in minor complications of sharp needle and local anesthesia block but not associated with potentially sight-threatening operative hemorrhagic complications. As warfarin sodium cessation or reduction may lead to serious thromboembolic complications, the decision to discontinue warfarin sodium before a relatively less invasive and complex eye surgery, such as lens surgery, should be based upon the risks of anticoagulant therapy weighed against the benefits.
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Polycythemia vera
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Vasculitis
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Diabetes mellitus

5.8 Endogenous Factors Affecting INR

The following factors may be responsible for increased INR response: diarrhea, hepatic disorders, poor nutritional state, steatorrhea, or vitamin K deficiency.

The following factors may be responsible for decreased INR response: increased vitamin K intake or hereditary warfarin resistance.

6 ADVERSE REACTIONS

The following serious adverse reactions to warfarin sodium are discussed in greater detail in other sections of the labeling:

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Hemorrhage [see Boxed Warning, Warnings and Precautions (5.1), and Overdosage (10)]
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Necrosis of skin and other tissues [see Warnings and Precautions (5.2)]
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Calciphylaxis [see Warnings and Precautions (5.3)]
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Systemic atheroemboli and cholesterol microemboli [see Warnings and Precautions (5.4)]

Other adverse reactions to warfarin sodium include:

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Immune system disorders: hypersensitivity/allergic reactions (including urticaria and anaphylactic reactions)
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Vascular disorders: vasculitis
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Hepatobiliary disorders: hepatitis, elevated liver enzymes. Cholestatic hepatitis has been associated with concomitant administration of warfarin sodium and ticlopidine.
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Gastrointestinal disorders: nausea, vomiting, diarrhea, taste perversion, abdominal pain, flatulence, bloating
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Skin disorders: rash, dermatitis (including bullous eruptions), pruritus, alopecia
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Respiratory disorders: tracheal or tracheobronchial calcification
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General disorders: chills