Warfarin Sodium (Page 3 of 9)

5.2 Tissue Necrosis

Warfarin sodium can cause necrosis and/or gangrene of skin and other tissues, which 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

Warfarin sodium can cause fatal and serious calciphylaxis or calcium uremic arteriolopathy, which 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 Acute Kidney Injury

In patients with altered glomerular integrity or with a history of kidney disease, acute kidney injury may occur with warfarin sodium, possibly in relation to episodes of excessive anticoagulation and hematuria [see Use in Specific Populations (8.6)]. More frequent monitoring of anticoagulation is advised in patients with compromised renal function.

5.5 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.

5.6 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.

5.7 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)].

5.8 Other Clinical Settings with Increased Risks

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

Moderate to severe hepatic impairment
Infectious diseases or disturbances of intestinal flora (e.g., sprue, antibiotic therapy)
Use of an indwelling catheter
Severe to moderate hypertension
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.
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.
Polycythemia vera
Vasculitis
Diabetes mellitus

5.9 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:

Hemorrhage [see Boxed Warning, Warnings and Precautions (5.1), and Overdosage (10)]
Tissue Necrosis [see Warnings and Precautions (5.2)]
Calciphylaxis [see Warnings and Precautions (5.3)]
Acute Kidney Injury [see Warnings and Precautions (5.4)]
Systemic Atheroemboli and Cholesterol Microemboli [see Warnings and Precautions (5.5)]
Limb Ischemia, Necrosis, and Gangrene in Patients with HIT and HITTS [see Warnings and Precautions (5.6)]
Other Clinical Settings with Increased Risks [see Warnings and Precautions (5.8)]

Other adverse reactions to warfarin sodium include:

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

7 DRUG INTERACTIONS

7.1 General Information

Drugs may interact with warfarin sodium through pharmacodynamic or pharmacokinetic mechanisms. Pharmacodynamic mechanisms for drug interactions with warfarin sodium are synergism (impaired hemostasis, reduced clotting factor synthesis), competitive antagonism (vitamin K), and alteration of the physiologic control loop for vitamin K metabolism (hereditary resistance). Pharmacokinetic mechanisms for drug interactions with warfarin sodium 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.

More frequent INR monitoring should be performed when starting or stopping other drugs, including botanicals, or when changing dosages of other drugs, including drugs intended for short-term use (e.g., antibiotics, antifungals, corticosteroids) [see Boxed Warning ].

Consult the labeling of all concurrently used drugs to obtain further information about interactions with warfarin sodium or adverse reactions pertaining to bleeding.

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