Warfarin for Deep Vein Thrombosis

INDICATIONS AND USAGE Warfarin sodium tablets are indicated for: • Prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism (PE). • Prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation (AF) and/or cardiac valve replacement. • Reduction in the risk of death, recurrent myocardial infarction (MI), and thromboembolic events such as stroke or systemic embolization after myocardial infarction. Limitations of Use Warfarin sodium tablets have no direct effect on an established thrombus, nor does it reverse ischemic tissue damage. Once a thrombus has occurred, however, the goals of anticoagulant treatment are to prevent further extension of the formed clot and to prevent secondary thromboembolic complications that may result in serious and possibly fatal sequelae. Warfarin sodium tablets are a vitamin K antagonist indicated for: • Prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism ( 1 ) • Prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement ( 1 ) • Reduction in the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic embolization after myocardial infarction ( 1 ) Limitations of Use Warfarin sodium tablets have no direct effect on an established thrombus, nor does it reverse ischemic tissue damage. ( 1 )

DOSAGE AND ADMINISTRATION Individualize dosing regimen for each patient, and adjust based on INR response. ( 2.1 , 2.2 ) Knowledge of genotype can inform initial dose selection. ( 2.3 ) Monitoring: Obtain daily INR determinations upon initiation until stable in the therapeutic range. Obtain subsequent INR determinations every 1 to 4 weeks. ( 2.4 ) Review conversion instructions from other anticoagulants. ( 2.8 ) 2.1 Individualized Dosing The dosage and administration of warfarin sodium tablets must be individualized for each patient according to the patient’s International Normalized Ratio (INR) response to the drug. Adjust the dose based on the patient’s INR and the condition being treated. Consult the latest evidence-based clinical practice guidelines regarding the duration and intensity of anticoagulation for the indicated conditions. 2.2 Recommended Target INR Ranges and Durations for Individual Indications An INR of greater than 4 appears to provide no additional therapeutic benefit in most patients and is associated with a higher risk of bleeding. Venous Thromboembolism (including deep venous thrombosis [DVT] and PE) Adjust the warfarin dose to maintain a target INR of 2.5 (INR range, 2 to 3) for all treatment durations. The duration of treatment is based on the indication as follows: For patients with a DVT or PE secondary to a transient (reversible) risk factor, treatment with warfarin for 3 months is recommended. For patients with an unprovoked DVT or PE, treatment with warfarin is recommended for at least 3 months. After 3 months of therapy, evaluate the risk-benefit ratio of long-term treatment for the individual patient. For patients with two episodes of unprovoked DVT or PE, long-term treatment with warfarin is recommended. For a patient receiving long-term anticoagulant treatment, periodically reassess the risk-benefit ratio of continuing such treatment in the individual patient. Atrial Fibrillation In patients with non-valvular AF, anticoagulate with warfarin to target INR of 2.5 (range, 2 to 3). In patients with non-valvular AF that is persistent or paroxysmal and at high risk of stroke (i.e., having any of the following features: prior ischemic stroke, transient ischemic attack, or systemic embolism, or 2 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended. In patients with non-valvular AF that is persistent or paroxysmal and at an intermediate risk of ischemic stroke (i.e., having 1 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended. For patients with AF and mitral stenosis, long-term anticoagulation with warfarin is recommended. For patients with AF and prosthetic heart valves, long-term anticoagulation with warfarin is recommended; the target INR may be increased and aspirin added depending on valve type and position, and on patient factors. Mechanical and Bioprosthetic Heart Valves For patients with a bileaflet mechanical valve or a Medtronic Hall (Minneapolis, MN) tilting disk valve in the aortic position who are in sinus rhythm and without left atrial enlargement, therapy with warfarin to a target INR of 2.5 (range, 2 to 3) is recommended. For patients with tilting disk valves and bileaflet mechanical valves in the mitral position, therapy with warfarin to a target INR of 3 (range, 2.5 to 3.5) is recommended. For patients with caged ball or caged disk valves, therapy with warfarin to a target INR of 3 (range, 2.5 to 3.5) is recommended. For patients with a bioprosthetic valve in the mitral position, therapy with warfarin to a target INR of 2.5 (range, 2 to 3) for the first 3 months after valve insertion is recommended. If additional risk factors for thromboembolism are present (AF, previous thromboembolism, left ventricular dysfunction), a target INR of 2.5 (range 2 to 3) is recommended. Post-Myocardial Infarction For high-risk patients with MI (e.g., those with a large anterior MI, those with significant heart failure, those with intracardiac thrombus visible on transthoracic echocardiography, those with AF, and those with a history of a thromboembolic event), therapy with combined moderate-intensity (INR, 2 to 3) warfarin plus low-dose aspirin (≤ 100 mg/day) for at least 3 months after the MI is recommended. Recurrent Systemic Embolism and Other Indications Oral anticoagulation therapy with warfarin has not been fully evaluated by clinical trials in patients with valvular disease associated with AF, patients with mitral stenosis, and patients with recurrent systemic embolism of unknown etiology. However, a moderate dose regimen (INR 2 to 3) may be used for these patients. 2.3 Initial and Maintenance Dosing The appropriate initial dosing of warfarin sodium tablets varies widely for different patients. Not all factors responsible for warfarin dose variability are known, and the initial dose is influenced by: Clinical factors including age, race, body weight, sex, concomitant medications, and comorbidities Genetic factors (CYP2C9 and VKORC1 genotypes) [see Clinical Pharmacology ( 12.5 )] Select the initial dose based on the expected maintenance dose, taking into account the above factors. Modify this dose based on consideration of patient-specific clinical factors. Consider lower initial and maintenance doses for elderly and/or debilitated patients and in Asian patients [see Use in Specific Populations ( 8.5 ) and Clinical Pharmacology ( 12.3 )] . Routine use of loading doses is not recommended as this practice may increase hemorrhagic and other complications and does not offer more rapid protection against clot formation. Individualize the duration of therapy for each patient. In general, anticoagulant therapy should be continued until the danger of thrombosis and embolism has passed [see Dosage and Administration ( 2.2 )] . Dosing Recommendations without Consideration of Genotype If the patient’s CYP2C9 and VKORC1 genotypes are not known, the initial dose of warfarin sodium tablets is usually 2 to 5 mg once daily. Determine each patient’s dosing needs by close monitoring of the INR response and consideration of the indication being treated. Typical maintenance doses are 2 to 10 mg once daily. Dosing Recommendations with Consideration of Genotype Table 1 displays three ranges of expected maintenance warfarin sodium tablets doses observed in subgroups of patients having different combinations of CYP2C9 and VKORC1 gene variants [see Clinical Pharmacology ( 12.5 )] . If the patient’s CYP2C9 and/or VKORC1 genotype are known, consider these ranges in choosing the initial dose. Patients with CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3 may require more prolonged time (> 2 to 4 weeks) to achieve maximum INR effect for a given dosage regimen than patients without these CYP variants. Table 1: Three Ranges of Expected Maintenance Warfarin Sodium Tablets Daily Doses Based on CYP2C9 and VKORC1 Genotypes † VKORC1 CYP2C9 *1/*1 *1/*2 *1/*3 *2/*2 *2/*3 *3/*3 GG 5 to 7 mg 5 to 7 mg 3 to 4 mg 3 to 4 mg 3 to 4 mg 0.5 to 2 mg AG 5 to 7 mg 3 to 4 mg 3 to 4 mg 3 to 4 mg 0.5 to 2 mg 0.5 to 2 mg AA 3 to 4 mg 3 to 4 mg 0.5 to 2 mg 0.5 to 2 mg 0.5 to 2 mg 0.5 to 2 mg † Ranges are derived from multiple published clinical studies. VKORC1−1639G > A (rs9923231) variant is used in this table. Other co-inherited VKORC1 variants may also be important determinants of warfarin dose. 2.4 Monitoring to Achieve Optimal Anticoagulation Warfarin sodium tablets have a narrow therapeutic range (index), and their action may be affected by factors such as other drugs and dietary vitamin K. Therefore, anticoagulation must be carefully monitored during warfarin sodium tablets therapy. Det

WARNINGS AND PRECAUTIONS • Tissue necrosis: Necrosis or gangrene of skin or other tissues can occur, with severe cases requiring debridement or amputation. Discontinue warfarin sodium and consider alternative anticoagulants if necessary. (5.2) • Calciphylaxis: Fatal and serious cases have occurred. Discontinue warfarin sodium and consider alternative anticoagulation therapy. ( 5.3 ) • Acute kidney injury may occur during episodes of excessive anticoagulation and hematuria. ( 5.4 ) • Systemic atheroemboli and cholesterol microemboli: Some cases have progressed to necrosis or death. Discontinue warfarin sodium if such emboli occur. ( 5.5 ) • Heparin-induced thrombocytopenia (HIT): Initial therapy with warfarin sodium in HIT has resulted in cases of amputation and death. Warfarin sodium may be considered after platelet count has normalized. ( 5.6) • Pregnant women with mechanical heart valves: Warfarin sodium may cause fetal harm; however, the benefits may outweigh the risks. ( 5.7 ) 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 >4.0), 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 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.

DRUG INTERACTIONS • Concomitant use of drugs that increase bleeding risk, antibiotics, antifungals, botanical (herbal) products, and inhibitors and inducers of CYP2C9, 1A2, or 3A4. ( 7 ) • Consult labeling of all concurrently used drugs for complete information about interactions with warfarin sodium or increased risks for bleeding. (7) 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. 7.2 CYP450 Interactions CYP450 isozymes involved in the metabolism of warfarin include CYP2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. The more potent warfarin S -enantiomer is metabolized by CYP2C9 while the R -enantiomer is metabolized by CYP1A2 and 3A4. • Inhibitors of CYP2C9, 1A2, and/or 3A4 have the potential to increase the effect (increase INR) of warfarin by increasing the exposure of warfarin. • Inducers of CYP2C9, 1A2, and/or 3A4 have the potential to decrease the effect (decrease INR) of warfarin by decreasing the exposure of warfarin. Examples of inhibitors and inducers of CYP2C9, 1A2, and 3A4 are below in Table 2; however, this list should not be considered all-inclusive. Consult the labeling of all concurrently used drugs to obtain further information about CYP450 interaction potential. The CYP450 inhibition and induction potential should be considered when starting, stopping, or changing dose of concomitant medications. Closely monitor INR if a concomitant drug is a CYP2C9, 1A2, and/or 3A4 inhibitor or inducer. Table 2: Examples of CYP450 Interactions with Warfarin Enzyme Inhibitors Inducers CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 7.3 Drugs that Increase Bleeding Risk Examples of drugs known to increase the risk of bleeding are presented in Table 3. Because bleeding risk is increased when these drugs are used concomitantly with warfarin, closely monitor patients receiving any such drug with warfarin. Table 3: Drugs that Can Increase the Risk of Bleeding Drug Class Specific Drugs Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 7.4 Antibiotics and Antifungals There have been reports of changes in INR in patients taking warfarin and antibiotics or antifungals, but clinical pharmacokinetic studies have not shown consistent effects of these agents on plasma concentrations of warfarin. Closely monitor INR when starting or stopping any antibiotic or antifungal in patients taking warfarin. 7.5 Botanical (Herbal) Products and Foods More frequent INR monitoring should be performed when starting or stopping botanicals. Few adequate, well-controlled studies evaluating the potential for metabolic and/or pharmacologic interactions between botanicals and warfarin sodium exist. 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. 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 warfarin sodium. Conversely, some botanicals may decrease the effects of warfarin sodium (e.g., co-enzyme Q 10 , St. John’s wort, ginseng). Some botanicals and foods can interact with warfarin sodium through CYP450 interactions (e.g., echinacea, grapefruit juice, ginkgo, goldenseal, St. John’s wort). The amount of vitamin K in food may affect therapy with warfarin sodium. Advise patients taking warfarin sodium to eat a normal, balanced diet maintaining a consistent amount of vitamin K. Patients taking warfarin sodium should avoid drastic changes in dietary habits, such as eating large amounts of green leafy vegetables.

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 Most common adverse reactions to warfarin sodium are fatal and nonfatal hemorrhage from any tissue or organ. (6) To report SUSPECTED ADVERSE REACTIONS, contact Taro Pharmaceuticals U.S.A., Inc., at 1-866-923-4914 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .