WARFARIN SODIUM- warfarin sodium_tablet

Warfarin acts by inhibiting the synthesis of vitamin K-dependent clotting factors, which include Factors II, VII, IX, and X, and the anticoagulant proteins C and S. Vitamin K is an essential cofactor for the post ribosomal synthesis of the vitamin K-dependent clotting factors. Vitamin K promotes the biosynthesis of gamma-carboxyglutamic acid residues in the proteins that are essential for biological activity. Warfarin is thought to interfere with clotting factor synthesis by inhibition of the C1 subunit of vitamin K epoxide reductase (VKORC1) enzyme complex, thereby reducing the regeneration of vitamin K 1 [see Clinical Pharmacology ( 12. 5 An anticoagulation effect generally occurs within 24 hours after warfarin administration. However, peak anticoagulant effect may be delayed 72 to 96 hours. The duration of action of a single dose of racemic warfarin is 2 to 5 days. The effects of warfarin sodium may become more pronounced as effects of daily maintenance doses overlap. This is consistent with the half-lives of the affected vitamin K-dependent clotting factors and anticoagulation proteins: Factor II - 60 hours, VII - 4 to 6 hours, IX - 24 hours, X - 48 to 72 hours, and proteins C and S are approximately 8 hours and 30 hours, respectively. Warfarin sodium is a racemic mixture of the R S S R Absorption Warfarin is essentially completely absorbed after oral administration, with peak concentration generally attained within the first 4 hours. Distribution Warfarin shows a volume of distribution of about 0. Approximately 99% of the drug is bound to plasma proteins. Metabolism The elimination of warfarin is almost entirely by metabolism. Warfarin is stereoselectively metabolized by hepatic cytochrome P-450 (CYP450) microsomal enzymes to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolites (warfarin alcohols) with minimal anticoagulant activity. Identified metabolites of warfarin include dehydrowarfarin, two diastereoisomer alcohols, and 4′-, 6-, 7-, 8-, and 10- hydroxywarfarin. The CYP450 isozymes involved in the metabolism of warfarin include CYP2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. CYP2C9, a polymorphic enzyme, is likely to be the principal form of human liver CYP450 that modulates the in vivo [see Clinical Pharmacology ( 12. 5 Excretion The terminal half-life of warfarin after a single dose is approximately 1 week; however, the effective half-life ranges from 20 to 60 hours, with a mean of about 40 hours. The clearance of R-warfarin is generally half that of S-warfarin, thus as the volumes of distribution are similar, the half-life of R-warfarin is longer than that of S-warfarin. The half-life of R-warfarin ranges from 37 to 89 hours, while that of S-warfarin ranges from 21 to 43 hours. Studies with radiolabeled drug have demonstrated that up to 92% of the orally administered dose is recovered in urine. Very little warfarin is excreted unchanged in urine. Urinary excretion is in the form of metabolites. Geriatric Patients Patients 60 years or older appear to exhibit greater than expected INR response to the anticoagulant effects of warfarin. The cause of the increased sensitivity to the anticoagulant effects of warfarin in this age group is unknown but may be due to a combination of pharmacokinetic and pharmacodynamic factors. Limited information suggests there is no difference in the clearance of S-warfarin; however, there may be a slight decrease in the clearance of R-warfarin in the elderly as compared to the young. Therefore, as patient age increases, a lower dose of warfarin is usually required to produce a therapeutic level of anticoagulation [see Dosage and Administration ( 2. 4 Asian Patients Asian patients may require lower initiation and maintenance doses of warfarin. A non-controlled study of 151 Chinese outpatients stabilized on warfarin for various indications reported a mean daily warfarin requirement of 3. 4 mg to achieve an INR of 2 to 2. Patient age was the most important determinant of warfarin requirement in these patients, with a progressively lower warfarin requirement with increasing age. CYP2C9 and VKORC1 Polymorphisms The S in vitro Other CYP2C9 alleles associated with reduced enzymatic activity occur at lower frequencies, including *5, *6, and *11 alleles in populations of African ancestry and *5, *9, and *11 alleles in Caucasians. Warfarin reduces the regeneration of vitamin K from vitamin K epoxide in the vitamin K cycle through inhibition of VKOR, a multiprotein enzyme complex. Certain single nucleotide polymorphisms in the VKORC1 gene (e. , en dash1639G > A) have been associated with variable warfarin dose requirements. VKORC1 and CYP2C9 gene variants generally explain the largest proportion of known variability in warfarin dose requirements. CYP2C9 and VKORC1 genotype information, when available, can assist in selection of the initial dose of warfarin [see Dosage and Administration ( 2.

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.

Individualize dosing regimen for each patient, and adjust based on INR response. 2 Knowledge of genotype can inform initial dose selection. 3 Monitoring: Obtain daily INR determinations upon initiation until stable in the therapeutic range. Obtain subsequent INR determinations every 1 to 4 weeks. 4 Review conversion instructions from other anticoagulants. 8 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. 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. , 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. , 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) is recommended. For patients with caged ball or caged disk valves, therapy with warfarin to a target INR of 3 (range, 2. 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. , 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. 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. 3 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 [see Clinical Pharmacology ( 12. 5 Table 1: Three Ranges of Expected Maintenance Warfarin Sodium Tablets Daily Doses Based on CYP2C9 and VKORC1 Genotypes dagger 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 dagger 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. 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. Determine the INR daily after the administration of the initial dose until INR results stabilize in the therapeutic range. After stabilization, maintain dosing within the therapeutic range by performing periodic INRs. The frequency of performing INR should be based on the clinical situation but generally acceptable intervals for INR determinations are 1 to 4 weeks. Perform additional INR tests when other warfarin products are interchanged with warfarin sodium tablets, as well as whenever other medications are initiated, discontinued, or taken irregularly. Heparin, a common concomitant drug, increases the INR [see Dosage and Administration ( 2. 8 7 Determinations of whole blood clotting and bleeding times are not effective measures for monitoring of warfarin sodium tablets therapy. No dosage adjustment is necessary for patients with renal failure. Monitor INR more frequently in patients with compromised renal function to maintain INR within the therapeutic range [see Warnings and Precautions ( 5. 6 The anticoagulant effect of warfarin sodium tablets persists beyond 24 hours. If a patient misses a dose of warfarin sodium tablets at the intended time of day, the patient should take the dose as soon as possible on the same day. The patient should not double the dose the next day to make up for a missed dose. Some dental or surgical procedures may necessitate the interruption or change in the dose of warfarin sodium tablets therapy. Consider the benefits and risks when discontinuing warfarin sodium tablets even for a short period of time. Determine the INR immediately prior to any dental or surgical procedure. In patients undergoing minimally invasive procedures who must be anticoagulated prior to, during, or immediately following these procedures, adjusting the dosage of warfarin sodium tablets to maintain the INR at the low end of the therapeutic range may safely allow for continued anticoagulation. Heparin Since the full anticoagulant effect of warfarin sodium tablets is not achieved for several days, heparin is preferred for initial rapid anticoagulation. During initial therapy with warfarin sodium tablets, the interference with heparin anticoagulation is of minimal clinical significance. Conversion to warfarin sodium tablets may begin concomitantly with heparin therapy or may be delayed 3 to 6 days. To ensure therapeutic anticoagulation, continue full dose heparin therapy and overlap warfarin sodium tablets therapy with heparin for 4 to 5 days and until warfarin sodium tablets has produced the desired therapeutic response as determined by INR, at which point heparin may be discontinued. As heparin may affect the INR, patients receiving both heparin and warfarin sodium tablets should have INR monitoring at least: 5 hours after the last intravenous bolus dose of heparin, or 4 hours after cessation of a continuous intravenous infusion of heparin, or 24 hours after the last subcutaneous heparin injection. Warfarin sodium tablets may increase the activated partial thromboplastin time (aPTT) test, even in the absence of heparin. A severe elevation (> 50 seconds) in aPTT with an INR in the desired range has been identified as an indication of increased risk of postoperative hemorrhage. Other Anticoagulants Consult the labeling of other anticoagulants for instructions on conversion to warfarin sodium tablets.

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 Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www. gov/medwatch.

Warfarin sodium is contraindicated in: 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. 1 [see Use in Specific Populations ( 8. 1 Warfarin sodium is contraindicated in patients with: Hemorrhagic tendencies or blood dyscrasias Recent or contemplated surgery of the central nervous system or eye, or traumatic surgery resulting in large open surfaces [see Warnings and Precautions ( 5. 8 Bleeding tendencies associated with: Threatened abortion, eclampsia, and preeclampsia Unsupervised patients with conditions associated with potential high level of non-compliance Spinal puncture and other diagnostic or therapeutic procedures with potential for uncontrollable bleeding Hypersensitivity to warfarin or to any other components of this product (e. , anaphylaxis) [see Adverse Reactions ( 6 Major regional or lumbar block anesthesia Malignant hypertension Pregnancy, except in women with mechanical heart valves ( 4 5. 1 Hemorrhagic tendencies or blood dyscrasias ( 4 Recent or contemplated surgery of the central nervous system (CNS) or eye, or traumatic surgery resulting in large open surfaces ( 4 5. 8 Bleeding tendencies associated with certain conditions ( 4 Threatened abortion, eclampsia, and preeclampsia ( 4 Unsupervised patients with potential high levels of non-compliance ( 4 Spinal puncture and other diagnostic or therapeutic procedures with potential for uncontrollable bleeding ( 4 Hypersensitivity to warfarin or any component of the product ( 4 Major regional or lumbar block anesthesia ( 4 Malignant hypertension ( 4.

Pregnant women with mechanical heart valves: Warfarin sodium may cause fetal harm; however, the benefits may outweigh the risks. 1 Lactation: Monitor breastfeeding infants for bruising or bleeding. 2 Renal Impairment: Instruct patients with renal impairment to frequently monitor their INR. 6 Risk Summary Warfarin sodium is contraindicated in women who are pregnant except in pregnant women with mechanical heart valves, who are at high risk of thromboembolism, and for whom the benefits of warfarin sodium may outweigh the risks [see Warnings and Precautions ( 5. 7 Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions In humans, warfarin crosses the placenta, and concentrations in fetal plasma approach the maternal values. Exposure to warfarin during the first trimester of pregnancy caused a pattern of congenital malformations in about 5% of exposed offspring. Warfarin embryopathy is characterized by nasal hypoplasia with or without stippled epiphyses (chondrodysplasia punctata) and growth retardation (including low birth weight). Central nervous system and eye abnormalities have also been reported, including dorsal midline dysplasia characterized by agenesis of the corpus callosum, Dandy-Walker malformation, midline cerebellar atrophy, and ventral midline dysplasia characterized by optic atrophy. Mental retardation, blindness, schizencephaly, microcephaly, hydrocephalus, and other adverse pregnancy outcomes have been reported following warfarin exposure during the second and third trimesters of pregnancy [see Contraindications ( 4 Risk Summary Warfarin was not present in human milk from mothers treated with warfarin from a limited published study. Because of the potential for serious adverse reactions, including bleeding in a breastfed infant, consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for warfarin sodium and any potential adverse effects on the breastfed infant from warfarin sodium or from the underlying maternal condition before prescribing warfarin sodium to a lactating woman. Clinical Considerations Monitor breastfeeding infants for bruising or bleeding. Data Human Data Based on published data in 15 nursing mothers, warfarin was not detected in human milk. Among the 15 full-term newborns, 6 nursing infants had documented prothrombin times within the expected range. Prothrombin times were not obtained for the other 9 nursing infants. Effects in premature infants have not been evaluated. Pregnancy Testing Warfarin sodium can cause fetal harm [see Use in Specific Populations ( 8. 1 Verify the pregnancy status of females of reproductive potential prior to initiating warfarin sodium therapy. Contraception Females Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after the final dose of warfarin sodium. Adequate and well-controlled studies with warfarin sodium have not been conducted in any pediatric population, and the optimum dosing, safety, and efficacy in pediatric patients is unknown. Pediatric use of warfarin sodium is based on adult data and recommendations, and available limited pediatric data from observational studies and patient registries. Pediatric patients administered warfarin sodium should avoid any activity or sport that may result in traumatic injury. The developing hemostatic system in infants and children results in a changing physiology of thrombosis and response to anticoagulants. Dosing of warfarin in the pediatric population varies by patient age, with infants generally having the highest, and adolescents having the lowest milligram per kilogram dose requirements to maintain target INRs. Because of changing warfarin requirements due to age, concomitant medications, diet, and existing medical condition, target INR ranges may be difficult to achieve and maintain in pediatric patients, and more frequent INR determinations are recommended. Bleeding rates varied by patient population and clinical care center in pediatric observational studies and patient registries. Infants and children receiving vitamin K-supplemented nutrition, including infant formulas, may be resistant to warfarin therapy, while human milk-fed infants may be sensitive to warfarin therapy. Of the total number of patients receiving warfarin sodium in controlled clinical trials for which data were available for analysis, 1885 patients (24. 4%) were 65 years and older, while 185 patients (2. 4%) were 75 years and older. No overall differences in effectiveness or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Patients 60 years or older appear to exhibit greater than expected INR response to the anticoagulant effects of warfarin [see Clinical Pharmacology ( 12. 3 [see Dosage and Administration ( 2. 3 Renal clearance is considered to be a minor determinant of anticoagulant response to warfarin. No dosage adjustment is necessary for patients with renal impairment. Instruct patients with renal impairment taking warfarin to monitor their INR more frequently [see Warnings and Precautions ( 5. 4 Hepatic impairment can potentiate the response to warfarin through impaired synthesis of clotting factors and decreased metabolism of warfarin. Conduct more frequent monitoring for bleeding when using warfarin sodium in these patients.

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 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. , 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. CYP450 isozymes involved in the metabolism of warfarin include CYP2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. The more potent warfarin S R 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 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 Examples of drugs known to increase the risk of bleeding are presented in Table 3 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 Non-steroidal 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 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. 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. , 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. , co-enzyme Q 10 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.

OVERDOSAGE
Bleeding (e. , appearance of blood in stools or urine, hematuria, excessive menstrual bleeding, melena, petechiae, excessive bruising or persistent oozing from superficial injuries, unexplained fall in hemoglobin) is a manifestation of excessive anticoagulation. The treatment of excessive anticoagulation is based on the level of the INR, the presence or absence of bleeding, and clinical circumstances. Reversal of warfarin sodium anticoagulation may be obtained by discontinuing warfarin sodium therapy and, if necessary, by administration of oral or parenteral vitamin K 1 The use of vitamin K 1 Prothrombin complex concentrate (PCC), fresh frozen plasma, or activated Factor VII treatment may be considered if the requirement to reverse the effects of warfarin sodium is urgent. A risk of hepatitis and other viral diseases is associated with the use of blood products; PCC and activated Factor VII are also associated with an increased risk of thrombosis. Therefore, these preparations should be used only in exceptional or life-threatening bleeding episodes secondary to warfarin sodium overdosage.
NONCLINICAL TOXICOLOGY
Carcinogenicity, mutagenicity, or fertility studies have not been performed with warfarin.
CLINICAL STUDIES
In five prospective, randomized, controlled clinical trials involving 3711 patients with non-rheumatic AF, warfarin significantly reduced the risk of systemic thromboembolism including stroke (see Table 4). The risk reduction ranged from 60% to 86% in all except one trial (CAFA: 45%), which was stopped early due to published positive results from two of these trials. The incidence of major bleeding in these trials ranged from 0. 7% (see Table 4). Table 4: Clinical Studies of Warfarin in Non-Rheumatic AF Patients 1 N Thromboembolism % Major Bleeding Study Warfarin-Treated Patients Control Patients PT Ratio INR % Risk Reduction p-value Warfarin-Treated Patients Control Patients AFASAK 335 336 1. 6 0 SPAF 210 211 1. 9 BAATAF 212 208 1. 5 CAFA 187 191 1. 6 2 to 3 45 0. 5 SPINAF 260 265 1. 5 Trials in patients with both AF and mitral stenosis suggest a benefit from anticoagulation with warfarin sodium [see Dosage and Administration ( 2. 1 - All study results of warfarin vs. control are based on intention-to-treat analysis and include ischemic stroke and systemic thromboembolism, excluding hemorrhagic stroke and transient ischemic attacks. In a prospective, randomized, open-label, positive-controlled study in 254 patients with mechanical prosthetic heart valves, the thromboembolic-free interval was found to be significantly greater in patients treated with warfarin alone compared with dipyridamole/aspirin-treated patients (p < 0. 005) and pentoxifylline/aspirin-treated patients (p < 0. The results of this study are presented in Table 5 Table 5: Prospective, Randomized, Open-Label, Positive-Controlled Clinical Study of Warfarin in Patients with Mechanical Prosthetic Heart Valves Patients Treated With Warfarin Dipyridamole/Aspirin Pentoxifylline/Aspirin Event Thromboembolism 2. 9/100 py Major Bleeding 2. 5/100 py 0/100 py 0. 9/100 py py = patient years In a prospective, open-label, clinical study comparing moderate (INR 2. 65) versus high intensity (INR 9) warfarin therapies in 258 patients with mechanical prosthetic heart valves, thromboembolism occurred with similar frequency in the two groups (4 and 3. 7 events per 100 patient years, respectively). Major bleeding was more common in the high intensity group. The results of this study are presented in Table 6 Table 6: Prospective, Open-Label Clinical Study of Warfarin in Patients with Mechanical Prosthetic Heart Valves Event Moderate Warfarin Therapy INR 2. 65 High Intensity Warfarin Therapy INR 9 Thromboembolism 4/100 py 3. 7/100 py Major Bleeding 0. 95/100 py 2. 1/100 py py = patient years In a randomized trial in 210 patients comparing two intensities of warfarin therapy (INR 2 to 2. 5 to 4) for a three month period following tissue heart valve replacement, thromboembolism occurred with similar frequency in the two groups (major embolic events 2% vs. 9%, respectively, and minor embolic events 10. 2%, respectively). Major hemorrhages occurred in 4. 6% of patients in the higher intensity INR group compared to zero in the lower intensity INR group. WARIS (The Warfarin Re-Infarction Study) was a double-blind, randomized study of 1214 patients 2 to 4 weeks post-infarction treated with warfarin to a target INR of 2. The primary endpoint was a composite of total mortality and recurrent infarction. A secondary endpoint of cerebrovascular events was assessed. Mean follow-up of the patients was 37 months. The results for each endpoint separately, including an analysis of vascular death, are provided in Table 7 Table 7: WARIS en dash Endpoint Analysis of Separate Events % Risk Warfarin Placebo Reduction Event (N = 607) (N = 607) RR (95% CI) ( p Total Patient Years of Follow-up 2018 1944 Total Mortality 94 (4. 7/100 py) 123 (6. 3/100 py) 0. 97) 24 (p = 0. 030) Vascular Death 82 (4. 1/100 py) 105 (5. 4/100 py) 0. 02) 22 (p = 0. 068) Recurrent MI 82 (4. 1/100 py) 124 (6. 85) 34 (p = 0. 001) Cerebrovascular Event 20 (1/100 py) 44 (2. 75) 54 (p = 0. 002) RR = Relative risk; Risk reduction = (1 - RR); CI = Confidence interval; MI = Myocardial infarction; py = patient years WARIS II (The Warfarin, Aspirin, Re-Infarction Study) was an open-label, randomized study of 3630 patients hospitalized for acute myocardial infarction treated with warfarin to a target INR 2. 2, aspirin 160 mg per day, or warfarin to a target INR 2 to 2. 5 plus aspirin 75 mg per day prior to hospital discharge. The primary endpoint was a composite of death, nonfatal reinfarction, or thromboembolic stroke. The mean duration of observation was approximately 4 years. The results for WARIS II are provided in Table 8 Table 8: WARIS II en dash Distribution of Events According to Treatment Group Event Aspirin (N = 1206) Warfarin (N = 1216) Aspirin plus Warfarin (N = 1208) Rate Ratio (95% CI) p No. of Events Major Bleeding a 8 33 28 3. 00 c ND Minor Bleeding d 39 103 133 3. 55 c ND Composite Endpoints e 241 203 181 0. 001 Reinfarction 117 90 69 0. 03 Thromboembolic Stroke 32 17 17 0. 03 Death 92 96 95 0. 82 a b c d e CI = confidence interval ND = not determined There were approximately four times as many major bleeding episodes in the two groups receiving warfarin than in the group receiving aspirin alone. Major bleeding episodes were not more frequent among patients receiving aspirin plus warfarin than among those receiving warfarin alone, but the incidence of minor bleeding episodes was higher in the combined therapy group.
REFERENCES
OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.
MEDICATION GUIDE
Repackaged By / Distributed By: RemedyRepack Inc. 625 Kolter Drive, Indiana, PA 15701 (724) 465-8762 Warfarin Sodium Tablets What is the most important information I should know about warfarin sodium tablets? Warfarin sodium tablets can cause bleeding which can be serious and sometimes lead to death. This is because warfarin sodium tablets are a blood thinner medicine that lowers the chance of blood clots forming in your body. You may have a higher risk of bleeding if you take warfarin sodium tablets and: are 65 years of age or older have a history of stomach or intestinal bleeding have high blood pressure (hypertension) have a history of stroke, or “mini-stroke” (transient ischemic attack or TIA) have serious heart disease have a low blood count or cancer have had trauma, such as an accident or surgery have kidney problems take other medicines that increase your risk of bleeding, including: a medicine that contains heparin other medicines to prevent or treat blood clots non-steroidal anti-inflammatory drugs (NSAIDs) take warfarin sodium for a long time. Warfarin sodium is the active ingredient in warfarin sodium tablets. Tell your healthcare provider if you take any of these medicines. Ask your healthcare provider if you are not sure if your medicine is one listed above. Many other medicines can interact with warfarin sodium tablets and affect the dose you need or increase warfarin sodium tablets side effects. Do not change or stop any of your medicines or start any new medicines before you talk to your healthcare provider. Do not take other medicines that contain warfarin sodium while taking warfarin sodium tablets. Get your regular blood test to check for your response to warfarin sodium tablets. Call your healthcare provider right away if you get any of the following signs or symptoms of bleeding problems: pain, swelling, or discomfort headaches, dizziness, or weakness unusual bruising (bruises that develop without known cause or grow in size) nosebleeds bleeding gums bleeding from cuts takes a long time to stop menstrual bleeding or vaginal bleeding that is heavier than normal pink or brown urine red or black stools coughing up blood vomiting blood or material that looks like coffee grounds Some foods and beverages can interact with warfarin sodium tablets and affect your treatment and dose. Eat a normal, balanced diet. Talk to your healthcare provider before you make any diet changes. Do not eat large amounts of leafy, green vegetables. Leafy, green vegetables contain vitamin K. Certain vegetable oils also contain large amounts of vitamin K. Too much vitamin K can lower the effect of warfarin sodium tablets. Always tell all of your healthcare providers that you take warfarin sodium tablets. Wear or carry information that you take warfarin sodium tablets. See “What are the possible side effects of warfarin sodium tablets?” for more information about side effects. What are warfarin sodium tablets? Warfarin sodium tablets are prescription medicine used to treat blood clots and to lower the chance of blood clots forming in your body. Blood clots can cause a stroke, heart attack, or other serious conditions if they form in the legs or lungs. Who should not take warfarin sodium tablets? Do not take warfarin sodium tablets if: your risk of having bleeding problems is higher than the possible benefit of treatment. you are pregnant unless you have a mechanical heart valve. you are allergic to warfarin or any of the other ingredients in warfarin sodium tablets. See the end of this leaflet for a complete list of ingredients in warfarin sodium tablets. Before taking warfarin sodium tablets, tell your healthcare provider about all of your medical conditions, including if you: have bleeding problems fall often have liver problems have kidney problems or are undergoing dialysis have high blood pressure have a heart problem called congestive heart failure have diabetes plan to have any surgery or a dental procedure are pregnant or plan to become pregnant. See “ Who should not take warfarin sodium tablets? Your healthcare provider will do a pregnancy test before you start treatment with warfarin sodium tablets. Females who can become pregnant should use effective birth control during treatment, and for at least 1 month after the last dose of warfarin sodium tablets. are breastfeeding. You and your healthcare provider should decide if you will take warfarin sodium tablets and breastfeed. Check your baby for bruising or bleeding if you take warfarin sodium tablets and breastfeed. any Tell your healthcare provider about all the medicines you take, What is the most important information I should know about warfarin sodium tablets? How should I take warfarin sodium tablets? Take warfarin sodium tablets exactly as prescribed. You must have regular blood tests and visits with your healthcare provider to monitor your condition. If you miss a dose of warfarin sodium tablets, call your healthcare provider. Do not Call your healthcare provider right away if you: take too much warfarin sodium tablets are sick with diarrhea, an infection, or have a fever fall or injure yourself, especially if you hit your head. Your healthcare provider may need to check you. What should I avoid while taking warfarin sodium tablets ? Do not do any activity or sport that may cause a serious injury. What are the possible side effects of warfarin sodium tablets? Warfarin sodium tablets may cause serious side effects, including: See “ What is the most important information I should know about warfarin sodium tablets? Death of skin tissue (skin necrosis or gangrene). Kidney problems. “Purple toes syndrome.” These are not all of the side effects of warfarin sodium tablets. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store warfarin sodium tablets? Store warfarin sodium tablets at 68° to 77°F (20° to 25°C). Keep warfarin sodium tablets in a tightly closed container. Keep warfarin sodium tablets out of the light. Follow your healthcare provider or pharmacist instructions about the right way to throw away outdated or unused warfarin sodium tablets. Females who are pregnant should not handle crushed or broken warfarin sodium tablets. Keep warfarin sodium tablets and all medicines out of the reach of children. General information about the safe and effective use of warfarin sodium tablets. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use warfarin sodium tablets for a condition for which they were not prescribed. Do not give warfarin sodium tablets to other people, even if they have the same symptoms that you have. They may harm them. You can ask your healthcare provider or pharmacist for information about warfarin sodium tablets that is written for health professionals. What are the ingredients in warfarin sodium tablets? Active ingredient: Inactive ingredients: This Medication Guide has been approved by the U.S. Food and Drug Administration. Rev. E 8/2021

REMEDYREPACK INC.

WARFARIN SODIUM- warfarin sodium_tablet Product manual source documgent