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Label: WARFARIN SODIUM - warfarin sodium tablet
- NDC Code(s): 49349-605-02
- Packager: REMEDYREPACK INC.
- This is a repackaged label.
- Source NDC Code(s): 51672-4032
- Category: HUMAN PRESCRIPTION DRUG LABEL
- DEA Schedule: None
- Marketing Status: Abbreviated New Drug Application
Drug Label Information
Updated November 3, 2011
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- BOXED WARNING(What is this?)
Warfarin sodium can cause major or fatal bleeding. Bleeding is more likely to occur during the starting period and with a higher dose (resulting in a higher INR). Risk factors for bleeding include high intensity of anticoagulation (INR >4.0), agehighly variable INRs, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, serious heart disease, anemia, malignancy, trauma, renal insufficiency, concomitant drugs (see PRECAUTIONS), and long duration of warfarin therapy. Regular monitoring of INR should be performed on all treated patients. Those at high risk of bleeding may benefit from more frequent INR monitoring, careful dose adjustment to desired INR, and a shorter duration of therapy. Patients should be instructed about prevention measures to minimize risk of bleeding and to report immediately to physicians signs and symptoms of bleeding (see PRECAUTIONS: Information for Patients).
Crystalline warfarin sodium is an anticoagulant which acts by inhibiting vitamin K-dependent coagulation factors. Chemically, it is 3-(sodium salt and is a racemic mixture of the R- and S-enantiomers. Crystalline warfarin sodium is an isopropanol clathrate. The crystallization of warfarin sodium virtually eliminates trace impurities present in amorphous warfarin. Its empirical formula is C19H15NaO4, and its structural formula may be represented by the following:
Crystalline warfarin sodium occurs as a white, odorless, crystalline powder, is discolored by light and is very soluble in water; freely soluble in alcohol; very slightly soluble in chloroform and in ether.
Warfarin Sodium Tablets, USP for oral use also contain:
All strengths:Anhydrous lactose, corn starch and magnesium stearate1 mg:D&C red #6 Barium Lake.2 mg:FD&C blue #2 Aluminum Lake, FD&C red #40 Aluminum Lake.2.5 mg:FD&C blue #2 Aluminum Lake, D&C yellow #10 Aluminum Lake.3 mg:FD&C blue #2 Aluminum Lake, FD&C red #40 Aluminum Lake, D&C yellow #10 Aluminum Lake.4 mg:FD&C blue #1 Aluminum Lake.5 mg:D&C yellow #10 Aluminum Lake, D&C red #6 Barium Lake.6 mg:D&C yellow #10 Aluminum Lake, FD&C blue #2 Aluminum Lake.7.5 mg:D&C yellow #10 Aluminum Lake.10 mg:Dye Free
Warfarin sodium tablets, USP and other coumarin anticoagulants act 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. Half-lives of these clotting factors are as follows: Factor II - 60 hours, VII - 4-6 hours, IX - 24 hours, and X - 48-72 hours. The half-lives of proteins C and S are approximately 8 hours and 30 hours, respectively. The resultant in vivo effect is a sequential depression of Factor VII, Protein C, Factor IX, Protein S, and Factor X and II activities. Vitamin K is an essential cofactor for the post ribosomal synthesis of the vitamin K dependent clotting factors. The vitamin promotes the biosynthesis ofacid residues in the proteins which are essential for biological activity.
Mechanism of Action
Warfarin is thought to interfere with clotting factor synthesis by inhibition of the C1 subunit of the vitamin K epoxide reductase (VKORC1) enzyme complex, thereby reducing the regeneration of vitamin K1 epoxide. The degree of depression is dependent upon the dosage administered and, in part, by the patient's VKORC1 genotype. Therapeutic doses of warfarin decrease the total amount of the active form of each vitamin K dependent clotting factor made by the liver by approximately 30% to 50%.
An anticoagulation effect generally occurs within 24 hours after drug 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 tablets, USP may become more pronounced as effects of daily maintenance doses overlap. Anticoagulants have no direct effect on an established thrombus, nor do they reverse ischemic tissue damage. However, once a thrombus has occurred, the goal of anticoagulant treatment is to prevent further extension of the formed clot and prevent secondary thromboembolic complications which may result in serious and possibly fatal sequelae.
Warfarin sodium tablets, USP is a racemic mixture of the R- and S-enantiomers. The S-enantiomer exhibits 2-5 times more anticoagulant activity than the R-enantiomer in humans, but generally has a more rapid clearance.
Warfarin sodium tablets, USP is essentially completely absorbed after oral administration with peak concentration generally attained within the first 4 hours.
There are no differences in the apparent volumes of distribution after intravenous and oral administration of single doses of warfarin solution. Warfarin distributes into a relatively small apparent volume of distribution of about 0.14 liter/kg. A distribution phase lasting 6 to 12 hours is distinguishable after rapid intravenous or oral administration of an aqueous solution. Using a one compartment model, and assuming complete bioavailability, estimates of the volumes of distribution of R- and S-warfarin are similar to each other and to that of the racemate. Concentrations in fetal plasma approach the maternal values, but warfarin has not been found in human milk (see WARNINGS - Lactation). Approximately 99% of the drug is bound to plasma proteins.
The S-enantiomer of warfarin is mainly metabolized to 7-hydroxywarfarin by CYP2C9, a polymorphic enzyme. The variant alleles CYP2C9*2 and CYP2C9*3 result in decreased in vitro CYP2C9 enzymatic 7-hydroxylation of S-warfarin. The frequencies of these alleles in Caucasians are approximately 11% and 7% for CYP2C9*2 and CYP2C9*3, respectively1. Patients with one or more of these variant CYP2C9 alleles have decreased S-warfarin clearance (Table 1).2
Table 1. Relationship Between S-Warfarin Clearance and CYP2C9 Genotype in Caucasian Patients
CYP2C9 GenotypeNS-Warfarin Clearance/Lean Body Weight (mL/min/kg) Mean (SD)aaSD=standard deviation. bp<0.001. Pairwise comparisons indicated significant differences among all 3 genotypes.*1/*11180.065 (0.025)b*1/*2 or *1/*3590.041 (0.021)b*2/*2, *2/*3, or *3/*3110.020 (0.011)bTotal188Other 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.
A meta-analysis of 9 qualified studies including 2775 patients (99% Caucasian) was performed to examine the clinical outcomes associated with CYP2C9 gene variants in warfarin-treated patients.3 In this meta-analysis, 3 studies assessed bleeding risks and 8 studies assessed daily dose requirements. The analysis suggested an increased bleeding risk for patients carrying either the CYP2C9*2 or CYP2C9*3 alleles. Patients carrying at least one copy of the CYP2C9*2 allele required a mean daily warfarin dose that was 17% less than the mean daily dose for patients homozygous for the CYP2C9*1 allele. For patients carrying at least one copy of the CYP2C9*3 allele, the mean daily warfarin dose was 37% less than the mean daily dose for patients homozygous for the CYP2C9*1 allele.
In an observational study, the risk of achieving INR >3 during the first 3 weeks of warfarin therapy was determined in 219 Swedish patients retrospectively grouped by CYP2C9 genotype. The relative risk of over anticoagulation as measured by INR >3 during the first 2 weeks of therapy was approximately doubled for those patients classified as *2 or *3 compared to patients who were homozygous for the *1 allele.4
Warfarin reduces the regeneration of vitamin K from vitamin K epoxide in the vitamin K cycle, through inhibition of vitamin K epoxide reductase (VKOR), a multiprotein enzyme complex. Certain single nucleotide polymorphisms in the VKORC1 gene (especially the
Patients 60 years or older appear to exhibit greater than expected PT/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. This increased anticoagulant effect from warfarin may be due to a combination of pharmacokinetic and pharmacodynamic factors. Racemic warfarin clearance may be unchanged or reduced with increasing age. Limited information suggests there is no difference in the clearance of S-warfarin in the elderly versus young subjects. 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.
Asian patients may require lower initiation and maintenance doses of warfarin. One non-controlled study conducted in 151 Chinese outpatients reported a mean daily warfarin requirement of 3.3mg to achieve an INR of 2 to 2.5. These patients were stabilized on warfarin for various indications. Patient age was the most important determinant of warfarin requirement in Chinese patients with a progressively lower warfarin requirement with increasing age.
Renal Dysfunction
Renal clearance is considered to be a minor determinant of anticoagulant response to warfarin. No dosage adjustment is necessary for patients with renal failure.
Hepatic Dysfunction
Hepatic dysfunction can potentiate the response to warfarin through impaired synthesis of clotting factors and decreased metabolism of warfarin.
The administration of warfarin via the intravenous (IV) route should provide the patient with the same concentration of an equal oral dose, but maximum plasma concentration will be reached earlier. However, the full anticoagulant effect of a dose of warfarin may not be achieved until 72-96 hours after dosing, indicating that the administration of IV warfarin should not provide any increased biological effect or earlier onset of action.
Atrial Fibrillation (AF)
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 2). The risk reduction ranged from 60% to 86% in all except one trial (CAFA: 45%) which stopped early due to published positive results from two of these trials. The incidence of major bleeding in these trials ranged from 0.6 to 2.7% (see table 2). Meta-analysis findings of these studies revealed that the effects of warfarin in reducing thromboembolic events including stroke were similar at either moderately high INR (2.0-4.5) or low INR (1.4-3.0). There was a significant reduction in minor bleeds at the low INR. Similar data from clinical studies in valvular atrial fibrillation patients are not available.
StudyN Thromboembolism % Major Bleeding Warfarin Treated PatientsControl PatientsPT RatioINR% Risk Reductionp-valueWarfarin Treated PatientsControl Patients* All study results of warfarin vs. control are based on intention-to-treat analysis and include ischemic stroke and systemic thromboembolism, excluding hemorrhage, and transient ischemic attacks.AFASAK3353361.5-2.02.8-4.2600.0270.60.0SPAF2102111.3-1.82.0-4.5670.011.91.9BAATAF2122081.2-1.51.5-2.786<0.050.90.5CAFA1871911.3-1.62.0-3.04188.8.131.52SPINAF2602651.2-1.51.4-2.8790.0012.31.5
Myocardial Infarction
DOSAGE AND ADMINISTRATION.)] The primary endpoint was a combination 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 the following table:
EventWarfarin (N=607)Placebo (N=607)RR (95%CI)% Risk Reduction (p-value)Total Patient Years of Follow-up20181944Total Mortality94 (4.7/100 py)123 (6.3/100 py)0.76 (0.60, 0.97)24 (p=0.030)Vascular Death82 (4.1/100 py)105 (5.4/100 py)0.78 (0.60,1.02)22 (p=0.068)Recurrent MI82 (4.1/100 py)124 (6.4/100 py)0.66 (0.51, 0.85)34 (p=0.001)Cerebrovascular Event20 (1.0/100 py)44 (2.3/100 py)0.46 (0.28, 0.75)54 (p=0.002)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 target INR 2.8 to 4.2, aspirin 160 mg/day, or warfarin target INR 2.0 to 2.5 plus aspirin 75 mg/day prior to hospital discharge. 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. 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 the following table8:
EventAspirin (N=1206)Warfarin (N=1216)Aspirin plus Warfarin (N=1208)Rate Ratio (95% CI)*p-value* CI denotes confidence interval. a The rate ratio is for aspirin plus warfarin as compared with aspirin. b The rate ratio is for warfarin as compared with aspirin. c Major bleeding episodes were defined as nonfatal cerebral hemorrhage or bleeding necessitating surgical intervention or blood transfusion. d Minor bleeding episodes were defined as non-cerebral hemorrhage not necessitating surgical intervention or blood transfusion. ND =not determined.No. of EventsReinfarction11790690.56 (0.41-0.78)a 0.74 (0.55-0.98)b<0.001 0.03Thromboembolic stroke3217170.52 (0.28-0.98)a 0.52 (0.28-0.97)b0.03 0.03Major Bleedingc833283.35a (ND) 4.00b (ND)ND NDMinor Bleedingd391031333.21a (ND) 2.55b (ND)ND NDDeath9296950.82
Mechanical and Bioprosthetic Heart Valves
In a prospective, randomized, open label, positive-controlled study9 in 254 patients, the thromboembolic-free interval was found to be significantly greater in patients with mechanical prosthetic heart valves treated with warfarin alone compared with dipyridamole-aspirin (p<0.005) and pentoxifylline-aspirin (p<0.05) treated patients. Rates of thromboembolic events in these groups were 2.2, 8.6, and 7.9/100 patient years, respectively. Major bleeding rates were 2.5, 0.0, and 0.9/100 patient years, respectively.
In a prospective, open label, clinical trial comparing moderate (INR 2.65) vs. high intensity (INR 9.0) warfarin therapies in 258 patients with mechanical prosthetic heart valves, thromboembolism occurred with similar frequency in the two groups (4.0 and 3.7 events/100 patient years, respectively). Major bleeding was more common in the high intensity group (2.1 events/100 patient years) vs. 0.95 events/100 patient years in the moderate intensity group.10
In a randomized trial in 210 patients comparing two intensities of warfarin therapy (INR 2.0-2.25 vs. INR 2.5-4.0) for a three month period following tissue heart valve replacement, thromboembolism occurred with similar frequency in the two groups (major embolic events 2.0% vs. 1.9%, respectively and minor embolic events 10.8% vs. 10.2%, respectively). Major bleeding complications were more frequent with the higher intensity (major hemorrhages 4.6%) vs. none in the lower intensity.11
Warfarin sodium tablets, USP are indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, and pulmonary embolism.
Warfarin sodium tablets, USP are indicated for the prophylaxis and/or treatment of the thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement.
Warfarin sodium tablets, USP are indicated to reduce the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic embolization after myocardial infarction.
Anticoagulation is contraindicated in any localized or general physical condition or personal circumstance in which the hazard of hemorrhage might be greater than the potential clinical benefits of anticoagulation, such as:
Warfarin sodium tablets, USP are contraindicated in women who are or may become pregnant because the drug passes through the placental barrier and may cause fatal hemorrhage to the fetus in utero. Furthermore, there have been reports of birth malformations in children born to mothers who have been treated with warfarin during pregnancy.
Embryopathy characterized by nasal hypoplasia with or without stippled epiphyses (chondrodysplasia punctata) has been reported in pregnant women exposed to warfarin during the first trimester. Central nervous system abnormalities also have been reported, including dorsal midline dysplasia characterized by agenesis of the corpus callosum, Dandy-Walker malformation, and midline cerebellar atrophy. Ventral midline dysplasia, characterized by optic atrophy, and eye abnormalities have been observed. Mental retardation, blindness, and other central nervous system abnormalities have been reported in association with second and third trimester exposure. Although rare, teratogenic reports following in utero exposure to warfarin include urinary tract anomalies such as single kidney, asplenia, anencephaly, spina bifida, cranial nerve palsy, hydrocephalus, cardiac defects and congenital heart disease, polydactyly, deformities of toes, diaphragmatic hernia, corneal leukoma, cleft palate, cleft lip, schizencephaly, and microcephaly.
Spontaneous abortion and stillbirth are known to occur and a higher risk of fetal mortality is associated with the use of warfarin. Low birth weight and growth retardation have also been reported.
Women of childbearing potential who are candidates for anticoagulant therapy should be carefully evaluated and the indications critically reviewed with the patient. If the patient becomes pregnant while taking this drug, she should be apprised of the potential risks to the fetus, and the possibility of termination of the pregnancy should be discussed in light of those risks.
Hemorrhagic tendencies or blood dyscrasias.
Recent or contemplated surgery of:
Bleeding tendencies associated with active ulceration or overt bleeding of:
Threatened abortion,eclampsia and preeclampsia.
Inadequate laboratory facilities.
Unsupervised patients with senility,alcoholism, psychosis or other lack of patient cooperation.
Spinal punctureand other diagnostic or therapeutic procedures with potential for uncontrollable bleeding.
Miscellaneous:major regional, lumbar block anesthesia, malignant hypertension and known hypersensitivity to warfarin or to any other components of this product.
The most serious risks associated with anticoagulant therapy with warfarin sodium are hemorrhage in any tissue or organ12 (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)/International Normalized Ratio (INR). 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 Therapyfor recommendations.
Increased caution should be observed when warfarin is administered in the presence of any predisposing condition where added risk of hemorrhage, necrosis, and/or gangrene is present.
Anticoagulation therapy with warfarin 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 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 3-10 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.
Warfarin 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 death13.
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 report 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 breast-feed should be undertaken only after careful consideration of the available alternatives. Women who are breast-feeding 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 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 fora:sprue, antibiotic therapy.
Traumawhich may result in internal bleeding.
Surgery or traumaresulting 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 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.
Periodic determination of PT/INR is essential.(see DOSAGE AND ADMINISTRATION: Laboratory Control.)
Numerous factors, alone or in combination including changes in diet, medications, botanicals, and genetic variations in the CYP2C9 and VKORC1 enzymes (see CLINICAL PHARMACOLOGY: Pharmacogenomics) may influence the response of the patient to warfarin.
Drug-Drug and Drug-Disease Interactions
Drugs may interact with warfarin through pharmacodynamic or pharmacokinetic mechanisms. Pharmacodynamic mechanisms for drug interactions with warfarin are synergism (impaired hemostasis, reduced clotting factor synthesis), competitive antagonism (vitamin K), and altered physiologic control loop for vitamin K metabolism (hereditary resistance). Pharmacokinetic mechanisms for drug interactions with warfarin 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.
The following factors, alone or in combination, may be responsible for INCREASED PT/INR response:
blood dyscrasias - see CONTRAINDICATIONScancer collagen vascular disease congestive heart failurediarrhea elevated temperature hepatic disorders infectious hepatitis jaundicehyperthyroidism poor nutritional state steatorrhea vitamin K deficiencyEXOGENOUS FACTORS:
Potential drug interactions with warfarin sodium are listed below by drug class and by specific drugs.
Classes of Drugs5-lipoxygenase Inhibitor Adrenergic Stimulants, Central Alcohol Abuse Reduction Preparations Analgesics Anesthetics, Inhalation Antiandrogen AntiarrhythmicsAntibioticsAminoglycosides (oral) Cephalosporins, parenteral Macrolides Miscellaneous Penicillins, intravenous, high dose Quinolones (fluoroquinolones) Sulfonamides, long acting Tetracyclines Anticoagulants AnticonvulsantsAntidepressantsAntimalarial Agents AntineoplasticsAntiparasitic/AntimicrobialsAntiplatelet Drugs/Effects Antithyroid DrugsBeta-Adrenergic Blockers Cholelitholytic Agents Diabetes Agents, Oral DiureticsFungal Medications, Intravaginal, SystemicGastric Acidity and Peptic Ulcer AgentsGastrointestinal Prokinetic Agents Ulcerative Colitis Agents Gout Treatment Agents Hemorrheologic Agents Hepatotoxic Drugs Hyperglycemic Agents Hypertensive Emergency Agents HypnoticsHypolipidemicsBile Acid-Binding ResinsFibric Acid Derivatives HMG-CoA Reductase InhibitorsLeukotriene Receptor Antagonist Monoamine Oxidase Inhibitors Narcotics, prolonged Nonsteroidal Anti- Inflammatory Agents Proton Pump Inhibitors Psychostimulants Pyrazolones Salicylates Selective Serotonin Reuptake Inhibitors Steroids, AdrenocorticalSteroids, Anabolic (17-Alkyl Testosterone Derivatives) Thrombolytics Thyroid Drugs Tuberculosis AgentsUricosuric Agents Vaccines Vitamins
Specific Drugs Reportedalso: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinationsand decreased PT/INR responses have been reported.acetaminophen alcoholallopurinol aminosalicylic acid amiodarone HCl argatroban aspirin atenolol atorvastatinazithromycin bivalirudin capecitabine cefamandole cefazolin cefoperazone cefotetan cefoxitin ceftriaxone celecoxib cerivastatin chenodiol chloramphenicol chloral hydratechlorpropamide cholestyraminecimetidine ciprofloxacin cisapride clarithromycin clofibrate cyclophosphamidedanazol dextran dextrothyroxine diazoxidediclofenac dicumarol diflunisal disulfiram doxycycline erythromycin esomeprazole ethacrynic acid ezetimibe fenofibrate fenoprofen fluconazole fluorouracil fluoxetine flutamide fluvastatin fluvoxamine gefitinib gemifibrozil glucagon halothane heparin ibuprofen ifosfamide indomethacin influenza virus vaccine itraconazole ketoprofen ketorolac lansoprazole lepirudin levamisole levofloxacin levothyroxine liothyroninelovastatin mefenamic acid methimazolemethyldopa methylphenidate methylsalicylate ointment (topical) metronidazole miconazole (intravaginal, oral, systemic) moricizine hydrochloridenalidixic acid naproxen neomycin norfloxacin ofloxacin olsalazine omeprazole oxandrolone oxaprozin oxymetholone pantoprazole paroxetine penicillin G, intravenous pentoxifylline phenylbutazone phenytoinpiperacillin piroxicam pravastatinprednisonepropafenonepropoxyphene propranolol propylthiouracilquinidine quinine rabeprazole ranitidinerofecoxib sertraline simvastatin stanozolol streptokinase sulfamethizole sulfamethoxazole sulfinpyrazone sulfisoxazole sulindac tamoxifen tetracycline thyroid ticarcillin ticlopidine tissue plasminogen activator (t-PA) tolbutamide tramadol trimethoprim/ sulfamethoxazole urokinase valdecoxib valproate vitamin E warfarin overdose zafirlukast zileuton The following factors, alone or in combination, may be responsible for DECREASED PT/INR response:
edema hereditary coumarin resistance hyperlipemiahypothyroidism nephrotic syndromeEXOGENOUS FACTORS:
Potential drug interactions with warfarin sodium are listed below by drug class and by specific drugs.
Classes of DrugsAdrenal Cortical Steroid Inhibitors Antacids Antianxiety Agents AntiarrhythmicsAntibioticsAnticonvulsantsAntidepressantsAntihistamines AntineoplasticsAntipsychotic Medications Antithyroid DrugsBarbiturates DiureticsEnteral Nutritional Supplements Fungal Medications, SystemicGastric Acidity and Peptic Ulcer AgentsHypnoticsHypolipidemicsBile Acid-Binding ResinsHMG-CoA Reductase InhibitorsImmunosuppressives Oral Contraceptives, Estrogen Containing Selective Estrogen Receptor Modulators Steroids, AdrenocorticalTuberculosis AgentsVitamins
Specific Drugs Reportedalso: diet high in vitamin K unreliable PT/INR determinationsand decreased PT/INR responses have been reported.alcoholaminoglutethimide amobarbital atorvastatinazathioprine butabarbital butalbital carbamazepine chloral hydratechlordiazepoxide chlorthalidonecholestyramineclozapine corticotropin cortisone cyclophosphamidedicloxacillin ethchlorvynol glutethimide griseofulvin haloperidol meprobamate6-mercaptopurine methimazolemoricizine hydrochloridenafcillin paraldehyde pentobarbital phenobarbital phenytoinpravastatinprednisoneprimidonepropylthiouracilraloxifene ranitidinerifampin secobarbital spironolactone sucralfate trazodone vitamin C (high dose) vitamin K warfarin underdosageBecause a patient may be exposed to a combination of the above factors, the net effect of warfarin sodium on PT/INR response may be unpredictable. More frequent PT/INR monitoring is therefore advisable. Medications of unknown interaction with coumarins are best regarded with caution. When these medications are started or stopped, more frequent PT/INR monitoring is advisable.
It has been reported that concomitant administration of warfarin and ticlopidine may be associated with cholestatic hepatitis.
Botanical (Herbal) Medicines
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with warfarin. Few adequate, well-controlled studies exist evaluating the potential for metabolic and/or pharmacologic interactions between botanicals and warfarin. 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. It is good practice to monitor the patient's response with additional PT/INR determinations when initiating or discontinuing botanicals.
Specific botanicals reported to affect warfarin therapy include the following:
- ●
- Bromelains, danshen, dong quai (Angelica sinensis), garlic, Ginkgo biloba, ginseng, and cranberry products are associated most often with an INCREASE in the effects of warfarin.
- ●
- Coenzyme Q10 (ubidecarenone) and St. John's wort are associated most often with a DECREASE in the effects of warfarin.
Some botanicals that may affect coagulation are listed below for reference; however, this list should not be considered all-inclusive. Many botanicals have several common names and scientific names. The most widely recognized common botanical names are listed.
1Contains coumarins, has antiplatelet properties, and may have coagulant properties due to possible Vitamin K content. 2 Contains coumarins and salicylates. 3 Contains coumarins and has fibrinolytic properties. 4 Contains coumarins and has antiplatelet properties. 5 Has antiplatelet and fibrinolytic properties.Botanicals that contain coumarins with potential anticoagulant effects:Agrimony1 Alfalfa Angelica (Dong Quai) Aniseed Arnica Asafoetida Bogbean2 Boldo Buchu Capsicum3Cassia4 Celery Chamomile (German and Roman) Dandelion4 Fenugreek Horse Chestnut Horseradish Licorice4 Meadowsweet2 NettleParsley Passion Flower Prickly Ash (Northern) Quassia Red Clover Sweet Clover Sweet Woodruff Tonka Beans Wild Carrot Wild LettuceMiscellaneous botanicals with anticoagulant properties:Bladder Wrack (Fucus)Pau d'arcoBotanicals that contain salicylate and/or have antiplatelet properties:Agrimony1 Aloe Gel Aspen Black Cohosh Black Haw Bogbean2 Cassia4 CloveDandelion4 Feverfew Garlic5 German Sarsaparilla Ginger Ginkgo Biloba Ginseng (Panax)5 Licorice4Meadowsweet2 Onion5 Policosanol Poplar Senega Tamarind Willow WintergreenBotanicals with fibrinolytic properties:Bromelains Capsicum3Garlic5 Ginseng (Panax)5Inositol Nicotinate Onion5Botanicals with coagulant properties:Agrimony1MistletoeGoldensealYarrow
Effect on Other Drugs
Coumarins may also affect the action of other drugs. Hypoglycemic agents (chlorpropamide and tolbutamide) and anticonvulsants (phenytoin and phenobarbital) may accumulate in the body as a result of interference with either their metabolism or excretion.
Considerations for Increased Bleeding Risk
Warfarin sodium is a narrow therapeutic range (index) drug, and additional caution should be observed when warfarin sodium is administered to certain patients. Reported risk factors for bleeding include high intensity of anticoagulation (INR >4.0), agehighly variable INRs, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, serious heart disease, anemia, malignancy, trauma, renal insufficiency, concomitant drugs (see PRECAUTIONS) and long duration of warfarin therapy. Identification of risk factors for bleeding and certain genetic variation in CYP2CP and VKORC1 in a patient may increase the need for more frequent INR monitoring and the use of lower warfarin doses (see CLINICAL PHARMACOLOGY: Metabolismand DOSAGE AND ADMINISTRATION). Bleeding is more likely to occur during the starting period and with a higher dose of warfarin sodium (resulting in a higher INR).
Intramuscular (I.M.) injections of concomitant medications should be confined to the upper extremities which permits easy access for manual compression, inspections for bleeding and use of pressure bandages.
Caution should be observed when warfarin is administered concomitantly with nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, to be certain that no change in anticoagulation dosage is required. In addition to specific drug interactions that might affect PT/INR, NSAIDs, including aspirin, can inhibit platelet aggregation, and can cause gastrointestinal bleeding, peptic ulceration and/or perforation.
The objective of anticoagulant therapy is to decrease the clotting ability of the blood so that thrombosis is prevented, while avoiding spontaneous bleeding. Effective therapeutic levels with minimal complications are in part dependent upon cooperative and well-instructed patients who communicate effectively with their physician. Patients should be advised: Strict adherence to prescribed dosage schedule is necessary. Do not take or discontinue any other medication, including salicylates (e.g., aspirin and topical analgesics), other over-the-counter medications and botanical (herbal) products except on advice of the physician. Avoid alcohol consumption. Do not take warfarin during pregnancy and do not become pregnant while taking it (see CONTRAINDICATIONS). Avoid any activity or sport that may result in traumatic injury. Prothrombin time tests and regular visits to physician or clinic are needed to monitor therapy. Carry identification stating that warfarin is being taken. If the prescribed dose of warfarin is forgotten, notify the physician immediately. Take the dose as soon as possible on the same day but do not take a double dose of warfarin the next day to make up for missed doses. The amount of vitamin K in food may affect therapy with warfarin. Eat a normal, balanced diet maintaining a consistent amount of vitamin K. Avoid drastic changes in dietary habits, such as eating large amounts of green leafy vegetables. You should also avoid intake of cranberry juice or any other cranberry products. Notify your health care provider if any of these products are part of your normal diet. Contact physician to report any illness, such as diarrhea, infection or fever. Notify physician immediately if any unusual bleeding or symptoms occur. Signs and symptoms of bleeding include: pain, swelling or discomfort, prolonged bleeding from cuts, increased menstrual flow or vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or dark brown urine, red or tar black stools, headache, dizziness, or weakness. If therapy with warfarin is discontinued, patients should be cautioned that the anticoagulant effects of warfarin may persist for about 2 to 5 days . Patients should be informed that all warfarin sodium, USP, products represent the same medication, and should not be taken concomitantly, as overdosage may result.A Medication Guide14 should be available to patients when their prescriptions for warfarin sodium are issued
Carcinogenicity and mutagenicity studies have not been performed with warfarin. The reproductive effects of warfarin have not been evaluated. The use of warfarin during pregnancy has been associated with the development of fetal malformations in humans (see CONTRAINDICATIONS).
Pregnancy Category X - See CONTRAINDICATIONS.
Safety and effectiveness in pediatric patients below the age of 18 have not been established in randomized, controlled clinical trials. However, the use of warfarin in pediatric patients is well-documented for the prevention and treatment of thromboembolic events. Difficulty achieving and maintaining therapeutic PT/INR ranges in the pediatric patient has been reported. More frequent PT/INR determinations are recommended because of possible changing warfarin requirements.
Patients 60 years or older appear to exhibit greater than expected PT/INR response to the anticoagulant effects of warfarin (see CLINICAL PHARMACOLOGY). Warfarin is contraindicated in any unsupervised patient with senility. Caution should be observed with administration of warfarin sodium to elderly patients in any situation or physical condition where added risk of hemorrhage is present. Lower initiation and maintenance doses of warfarin are recommended for elderly patients (see DOSAGE AND ADMINISTRATION).
Potential adverse reactions to warfarin may include:
- ●
- OVERDOSAGE-Treatment.)
- ●
- Bleeding which occurs when the PT/INR is within the therapeutic range warrants diagnostic investigation since it may unmask a previously unsuspected lesion, e.g., tumor, ulcer, etc.
- ●
- Necrosis of skin and other tissues. (See WARNINGS.)
- ●
- Adverse reactions reported infrequently include: hypersensitivity/allergic reactions, including anaphylactic reactions, systemic cholesterol microembolization, purple toes syndrome, hepatitis, cholestatic hepatic injury, jaundice, elevated liver enzymes, hypotension, vasculitis, edema, anemia, pallor, fever, rash, dermatitis, including bullous eruptions, urticaria, angina syndrome, chest pain, abdominal pain including cramping, flatulence/bloating, fatigue, lethargy, malaise, asthenia, nausea, vomiting, diarrhea, pain, headache, dizziness, loss of consciousness, syncope, coma, taste perversion, pruritus, alopecia, cold intolerance, and paresthesia including feeling cold and chills.
Priapism has been associated with anticoagulant administration, however, a causal relationship has not been established.
Signs and Symptoms
Suspected or overt abnormal bleeding (e.g., appearance of blood in stools or urine, hematuria, excessive menstrual bleeding, melena, petechiae, excessive bruising or persistent oozing from superficial injuries) are early manifestations of anticoagulation beyond a safe and satisfactory level.
Excessive anticoagulation, with or without bleeding, may be controlled by discontinuing warfarin therapy and if necessary, by administration of oral or parenteral vitamin K1. (Please see recommendations accompanying vitamin K1 preparations prior to use.)15, 16
Such use of vitamin K1 reduces response to subsequent warfarin therapy. Patients may return to a pretreatment thrombotic status following the rapid reversal of a prolonged PT/INR. Resumption of warfarin administration reverses the effect of vitamin K, and a therapeutic PT/INR can again be obtained by careful dosage adjustment. If rapid anticoagulation is indicated, heparin may be preferable for initial therapy.
If minor bleeding progresses to major bleeding, give 5 to 25 mg (rarely up to 50 mg) parenteral vitamin K1. In emergency situations of severe hemorrhage, clotting factors can be returned to normal by administering 200 to 500 mL of fresh whole blood or fresh frozen plasma, or by giving commercial Factor IX complex.
A risk of hepatitis and other viral diseases is associated with the use of these blood products; Factor IX complex is 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.
Purified Factor IX preparations should not be used because they cannot increase the levels of prothrombin, Factor VII and Factor X which are also depressed along with the levels of Factor IX as a result of warfarin treatment. Packed red blood cells may also be given if significant blood loss has occurred. Infusions of blood or plasma should be monitored carefully to avoid precipitating pulmonary edema in elderly patients or patients with heart disease.
The dosage and administration of warfarin sodium tablets, USP must be individualized for each patient according to the particular patient's PT/INR response to the drug. The dosage should be adjusted based upon the patient's PT/INR.15, 16, 17, 18, 19 The best available information supports the following recommendations for dosing of warfarin sodium tablets.
Venous Thromboembolism (including deep venous thrombosis [DVT] and pulmonary embolism [PE])
For patients with a first episode of DVT or PE secondary to a transient (reversible) risk factor, treatment with warfarin for 3 months is recommended. For patients with a first episode of idiopathic DVT or PE, warfarin is recommended for at least 6 to 12 months. For patients with two or more episodes of documented DVT or PE, indefinite treatment with warfarin is suggested. For patients with a first episode of DVT or PE who have documented antiphospholipid antibodies or who have two or more thrombophilic conditions, treatment for 12 months is recommended and indefinite therapy is suggested. For patients with a first episode of DVT or PE who have documented deficiency of antithrombin, deficiency of Protein C or Protein S, or the Factor V Leiden or prothrombin 20210 gene mutation, homocystinemia, or high Factor VIII levels (>90th percentile of normal), treatment for 6 to 12 months is recommended and indefinite therapy is suggested for idiopathic thrombosis. The risk-benefit should be reassessed periodically in patients who receive indefinite anticoagulant treatment.12, 20 The dose of warfarin should be adjusted to maintain a target INR of 2.5 (INR range, 2.0 to 3.0) for all treatment durations. These recommendations are supported by the 7th ACCP guidelines.15, 17, 21, 22
Atrial Fibrillation
Five clinical trials evaluated the effects of warfarin in patients with non-valvular atrial fibrillation (AF). Meta-analysis findings of these studies revealed that the effects of warfarin in reducing thromboembolic events including stroke were similar at either moderately high INR (2.0-4.5) or low INR (1.4-3.0). There was a significant reduction in minor bleeds at the low INR. There are no adequate and well-controlled studies in populations with atrial fibrillation and valvular heart disease. Similar data from clinical studies in valvular atrial fibrillation patients are not available. The trials in non-valvular atrial fibrillation support the American College of Chest Physicians' (7th ACCP) recommendation that an INR of 2.0-3.0 be used for warfarin therapy in appropriate AF patients.17
Oral anticoagulation therapy with warfarin is recommended in patients with persistent or paroxysmal AF (PAF) (intermittent AF) at high risk of stroke (i.e., having any of the following features: prior ischemic stroke, transient ischemic attack, or systemic embolism, age >75 years, moderately or severely impaired left ventricular systolic function and/or congestive heart failure, history of hypertension, or diabetes mellitus). In patients with persistent AF or PAF, age 65 to 75 years, in the absence of other risk factors, but who are at intermediate risk of stroke, antithrombotic therapy with either oral warfarin or aspirin, 325 mg/day, is recommended. For patients with AF and mitral stenosis, anticoagulation with oral warfarin is recommended (7th ACCP). For patients with AF and prosthetic heart valves, anticoagulation with oral warfarin should be used; the target INR may be increased and aspirin added depending on valve type and position, and on patient factors.17
Post-Myocardial Infarction
mg/day) for 3 months after the MI is suggested.23
Mechanical and Bioprosthetic Heart Valves
For all patients with mechanical prosthetic heart valves, warfarin is recommended. For patients with a St. Jude Medical (St. Paul, MN) bileaflet valve in the aortic position, a target INR of 2.5 (range, 2.0 to 3.0) is recommended. For patients with tilting disk valves and bileaflet mechanical valves in the mitral position, the 7th ACCP recommends a target INR of 3.0 (range, 2.5 to 3.5). For patients with caged ball or caged disk valves, a target INR of 3.0 (range, 2.5 to 3.5) in combination with aspirin, 75 to 100 mg/day is recommended. For patients with bioprosthetic valves, warfarin therapy with a target INR of 2.5 (range, 2.0 to 3.0) is recommended for valves in the mitral position and is suggested for valves in the aortic position for the first 3 months after valve insertion.15
Recurrent Systemic Embolism and Other Indications
Oral anticoagulation therapy has not been evaluated by properly designed clinical trials in patients with valvular disease associated with atrial fibrillation, patients with mitral stenosis, and patients with recurrent systemic embolism of unknown etiology. A moderate dose regimen (INR 2.0 to 3.0) is recommended for these patients.17
An INR of greater than 4.0 appears to provide no additional therapeutic benefit in most patients and is associated with a higher risk of bleeding.
Initial Dosage
The dosing of warfarin sodium tablets, USP must be individualized according to patient's sensitivity to the drug as indicated by the PT/INR. Use of a large loading dose may increase the incidence of hemorrhagic and other complications, does not offer more rapid protection against thrombi formation, and is not recommended. It is recommended that warfarin sodium tablets, USP therapy be initiated with a dose of 2 to 5 mg per day with dosage adjustments based on the results of PT/INR determinations.17,18 The lower initiation doses should be considered for patients with certain genetic variations in CYP2C9 and VKORC1 enzymes as well as for elderly and/or debilitated patients and patients with potential to exhibit greater than expected PT/INR responses to warfarin sodium (see CLINICAL PHARMACOLOGYand PRECAUTIONS).
Most patients are satisfactorily maintained at a dose of 2 to 10 mg daily. Flexibility of dosage is provided by breaking scored tablets in half. The individual dose and interval should be gauged by the patient's prothrombin response. Acquired or inherited warfarin resistance is rare, but should be suspected if large daily doses of warfarin sodium tablets, USP are required to maintain a patient's PT/INR within a normal therapeutic range. Lower maintenance doses are recommended for elderly and/or debilitated patients and patients with a potential to exhibit greater than expected PT/INR response to warfarin sodium tablets, USP (see PRECAUTIONS).
Duration of Therapy
The duration of therapy in each patient should be individualized. In general, anticoagulant therapy should be continued until the danger of thrombosis and embolism has passed.14, 15, 17, 18, 21, 22
Missed Dose
The anticoagulant effect of warfarin sodium tablets, USP persists beyond 24 hours. If the patient forgets to take the prescribed dose of warfarin sodium tablets, USP at the scheduled time, the dose should be taken as soon as possible on the same day. The patient should not take the missed dose by doubling the daily dose to make up for missed doses, but should refer back to his or her physician.
Laboratory Control
The PT reflects the depression of vitamin K dependent Factors VII, X and II. A system of standardizing the PT in oral anticoagulant control was introduced by the World Health Organization in 1983. It is based upon the determination of an International Normalized Ratio (INR) which provides a common basis for communication of PT results and interpretations of therapeutic ranges.24 The PT should be determined daily after the administration of the initial dose until PT/INR results stabilize in the therapeutic range. Intervals between subsequent PT/INR determinations should be based upon the physician's judgment of the patient's reliability and response to warfarin sodium tablets, USP in order to maintain the individual within the therapeutic range.Acceptable intervals for PT/INR determinations are normally within the range of one to four weeks after a stable dosage has been determined. To ensure adequate control, it is recommended that additional PT tests be done when other warfarin products are interchanged with warfarin sodium tablets, USP, as well as whenever other medications are initiated, discontinued, or taken irregularly(see PRECAUTIONS). Safety and efficacy of warfarin therapy can be improved by increasing the quality of laboratory control. Reports suggest that in usual care monitoring, patients are in therapeutic range only 33%-64% of the time. Time in therapeutic range is significantly greater (56%-93%) in patients managed by anticoagulation clinics, among self-testing and self-monitoring patients, and in patients managed with the help of computer programs.25 Self-testing patients had fewer bleeding events than patients in usual care.25
Treatment During Dentistry and Surgery
The management of patients who undergo dental and surgical procedures requires close liaison between attending physicians, surgeons and dentists.15, 19 PT/INR determination is recommended just prior to any dental or surgical procedure. In patients undergoing minimal invasive procedures who must be anticoagulated prior to, during, or immediately following these procedures, adjusting the dosage of warfarin sodium tablets, USP to maintain the PT/INR at the low end of the therapeutic range may safely allow for continued anticoagulation. The operative site should be sufficiently limited and accessible to permit the effective use of local procedures for hemostasis. Under these conditions, dental and minor surgical procedures may be performed without undue risk of hemorrhage. Some dental or surgical procedures may necessitate the interruption of warfarin therapy. When discontinuing warfarin even for a short period of time, the benefits and risks should be strongly considered.
Conversion from Heparin Therapy
Since the anticoagulant effect of warfarin sodium tablets, USP is delayed, heparin is preferred initially for rapid anticoagulation. Conversion to warfarin sodium tablets, USP may begin concomitantly with heparin therapy or may be delayed 3 to 6 days. To ensure continuous anticoagulation, it is advisable to continue full dose heparin therapy and that warfarin sodium tablets, USP therapy be overlapped with heparin for 4 to 5 days, until warfarin sodium tablets, USP has produced the desired therapeutic response as determined by PT/INR. When warfarin sodium tablets, USP has produced the desired PT/INR or prothrombin activity, heparin may be discontinued.
Warfarin sodium tablets, USP may increase the activated partial thromboplastin time (aPTT) test, even in the absence of heparin. A severe elevation (>50 seconds) in activated partial thromboplastin time (aPTT) with a PT/INR in the desired range has been identified as an indication of increased risk of postoperative hemorrhage.
During initial therapy with warfarin sodium tablets, USP, the interference with heparin anticoagulation is of minimal clinical significance.
As heparin may affect the PT/INR, patients receiving both heparin and warfarin sodium tablets, USP should have blood for PT/INR determination drawn at least:
- ●
- 5 hours after the last IV bolus dose of heparin, or
- ●
- 4 hours after cessation of a continuous IV infusion of heparin, or
- ●
- 24 hours after the last subcutaneous heparin injection.
Warfarin Sodium Tablets, USP: For oral use, single scored, imprinted numerically and packaged with potencies, colors and engravings as follows:
ColorEngravingBottles of 100Bottles of 1000Bottles of 5000Cartons of 100 1010 blister packs1 mgPink1NDC 51672-4027-1NDC 51672-4027-3NDC 51672-4027-7NDC 51672-4027-02 mgLavender2NDC-51672-4028-1NDC-51672-4028-3NDC-51672-4028-7NDC-51672-4028-02.5 mgGreen2 1/2NDC 51672-4029-1NDC 51672-4029-3NDC 51672-4029-7NDC 51672-4029-03 mgTan3NDC 51672-4030-1NDC 51672-4030-3NDC 51672-4030-7NDC 51672-4030-04 mgBlue4NDC 51672-4031-1NDC 51672-4031-3NDC 51672-4031-7NDC 51672-4031-05 mgPeach5NDC 51672-4032-1NDC 51672-4032-3NDC 51672-4032-7NDC 51672-4032-06 mgTeal6NDC 51672-4033-1NDC 51672-4033-3NDC 51672-4033-7NDC 51672-4033-07.5 mgYellow7 1/2NDC 51672-4034-1NDC 51672-4034-3NDC 51672-4034-010 mgWhite10NDC 51672-4035-1NDC 51672-4035-3NDC 51672-4035-0Warfarin Sodium Tablets, USP are available in 1, 2, 2.5, 3, 4, 5, 6, 7.5 and 10 mg of warfarin sodium, USP. They are flat beveled capsule shaped tablets, scored and engraved as described in the above table on one side, and engraved with "WARFARIN" on top of "TARO" on the other side.
Protect from light. Store at 20(68[see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP.
2. Herman D, Locatelli I, Grabnar I, et al. Influence of CYP2C9 polymorphisms, demographic factors and concomitant drug therapy on warfarin metabolism and maintenance dose. Pharmacogenomics J. 2005;5:193-202.
3. Sanderson S, Emery J, Higgins J. CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: A HuGEnet
4. Lindh JD, Lundgren S, Holm L, Alfredsson L, Rane A. Several-fold increase in risk of overanticoagulation by CYP2C9 mutations. Clin Pharmacol Ther. 2005;78:540-550.
5. Wadelius M, Chen LY, Downes K, et al. Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Pharmacogenomics J. 2005;5:262-270.
6. Veenstra DL, You JHS, Rieder MJ, et al. Association of Vitamin K epoxide reductase complex 1 (VKO-RC1) variants with warfarin dose in a Hong Kong Chinese patient population. Pharmacogenet Genomics. 2005;15:687-691.
7. Takahashi H, Wilkinson GR, Nutescu EA, et al. Different contributions of polymorphisms in VKORC1 and CYP2C9 to intra- and inter-population differences in maintenance doses of warfarin in Japanese, Caucasians and African Americans. Pharmacogenet Genomics. 2006;16:101-110.
8. Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med. 2002;347:969-974.
9. Mok CK, Boey J, Wang R, et al. Warfarin versus dipyridamole-aspirin and pentoxifylline-aspirin for prevention of prosthetic valve thromboembolism: a prospective randomized clinical trial. Circ. 1985;72:1059-1063.
10. Saour JN, Sieck JO, Mamo LA, Gallus AS. Trial of different intensities of anticoagulation in patients with prosthetic heart valves. N Engl J Med. 1990;322:428-432.
11. Turpie AG, Hirsh J, Gunstensen J, Nelson H, Gent M. Randomized comparison to two intensities of oral anticoagulant therapy after tissue heart valve replacement. Lancet. 1988;331:1242-1245.
13. Warkentin TE, Elavathil LJ, Hayward CPM, Johnston MG, Russett JI, Kelton JG. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia. Ann Intern Med. 1997;127:804-812.
14. COUMADIN Medication Guide. Princeton, NJ: Bristol-Myers Squibb Company; 2007.
15. Salem DN, Stein PD, Al-Ahmad A, et al. Antithrombotic therapy in valvular heart disease
16. American Geriatrics Society Clinical Practice Guidelines. The use of oral anticoagulants (warfarin) in older people. J Amer Geriatr Soc. 2000;48:224-227.
17. Singer DE, Albers GW, Dalen JE, Go AS, Halperin JL, Manning WJ. Antithrombotic therapy in atrial fibrillation. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:429S-456S.
18. Jaffer AK, Bragg L. Practical tips for warfarin dosing and monitoring. Cleveland Clinic J Med. 2003;70:361-371.
19. Jaffer AK, Brotman DJ, Chukwumerije N. When patients on warfarin need surgery. Cleveland Clinic J Med. 2003;70:973-984.
20. Kearon C, Ginsberg JS, Kovacs MJ, et al, for the Extended Low-Intensity Anticoagulation for Thrombo-Embolism Investigators. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for longterm prevention of recurrent venous thromboembolism. N Engl J Med. 2003;349:631-639.
21. Schulman S, Granqvist S, Holmstr
22. Ridker PM, Goldhaber SZ, Danielson E, et al, for the PREVENT Investigators. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med. 2003;348:1425-1434.
23. Harrington RA, Becker RC, Ezekowitz M, et al. Antithrombotic therapy for coronary artery disease. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:513S-548S.
24. Ansell J, Hirsh J, Pollen L, Bussey H, Jacobson A, Hylek E. The pharmacology and management of the vitamin K antagonists. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:204S-233S.
25. Heneghan C, Alonso-Coello P, Garcia-Alamino JM, Perera R, Meats E, Glasziou P. Self-monitoring of oral anticoagulation: a systematic review and meta-analysis. Lancet. 2006;367:404-411.
Warfarin Sodium Tablets, USP Crystalline
Read this Medication Guide before you start taking Warfarin Sodium (WARFARIN) and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. You and your healthcare provider should talk about WARFARIN when you start taking it and at regular checkups.
What is the most important information I should know about WARFARIN?
- ●
- Take your WARFARIN exactly as prescribed to lower the chance of blood clots forming in your body.(See " What is WARFARIN?").
- ●
- Warfarin is very important for your health, but it can cause serious and life-threatening bleeding problems.To benefit from WARFARIN and also lower your chance for bleeding problems, you must:
- ●
- Get your regular blood test to check for your response to WARFARIN. This blood test is called a PT/INR test. The PT/INR test checks to see how fast your blood clots. Your healthcare provider will decide what PT/INR numbers are best for you. Your dose of WARFARIN will be adjusted to keep your PT/INR in a target range for you.
- ●
- 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)
- ●
- nose bleeds
- ●
- 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
- ●
- Many other medicines, including prescription and non-prescription medicines, vitamins and herbal supplements can interact with WARFARIN and:
- ●
- affect the dose you need, or
- ●
- increase WARFARIN side effects.
- ●
- Do not take other medicines that contain warfarin. Warfarin is the active ingredient in WARFARIN.
- ●
- Some foods can interact with WARFARIN and affect your treatment and dose.
- ●
- Eat a normal, balanced diet.Talk to your doctor 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.
- ●
- Avoid drinking cranberry juice or eating cranberry products.
- ●
- Avoid drinking alcohol.
- ●
- Always tell all of your healthcare providers that you take WARFARIN.
- ●
- Wear or carry information that you take WARFARIN.
WARFARIN is an anticoagulant medicine. It is used to lower the chance of blood clots forming in your body. Blood clots can cause a stroke, heart attack, or other serious conditions such as blood clots in the legs or lungs.
Who should not take WARFARIN?
Do not take WARFARIN if:
- ●
- your chance of having bleeding problems is higher than the possible benefit of treatment.Your healthcare provider will decide if WARFARIN is right for you. Talk to your healthcare provider about all of your health conditions.
- ●
- you are pregnant or plan to become pregnant.WARFARIN can cause death or birth defects to an unborn baby. Use effective birth control if you can get pregnant.
- ●
- you are allergic to warfarin or to anything else in WARFARIN.
Tell your healthcare provider about all of your health conditions, including if you:
- ●
- have bleeding problems
- ●
- fall often
- ●
- have liver or kidney problems
- ●
- have high blood pressure
- ●
- have a heart problem called congestive heart failure
- ●
- have diabetes
- ●
- drink alcohol or have problems with alcohol abuse. Alcohol can affect your WARFARIN dose and should be avoided.
- ●
- are pregnant or planning to become pregnant. See "Who should not take WARFARIN?"
- ●
- are breastfeeding.Warfarin Sodium Tablets may increase bleeding in your baby. Talk to your doctor about the best way to feed your baby. If you choose to breastfeed while taking WARFARIN, both you and your baby should be carefully monitored for bleeding problems.
How should I take WARFARIN?
- ●
- Take WARFARIN exactly as prescribed. Your healthcare provider will adjust your dose from time to time depending on your response to WARFARIN.
- ●
- You must have regular blood tests and visits with your healthcare provider to monitor your condition.
- ●
- Take WARFARIN at the same time every day.You can take WARFARIN either with food or on an empty stomach.
- ●
- If you miss a dose of WARFARIN, call your healthcare provider.Take the dose as soon as possible on the same day. Do not take a double dose of WARFARIN the next day to make up for a missed dose.
- ●
- Call your healthcare provider right away if you take too many WARFARIN.
- ●
- Call your healthcare provider if you are sick with diarrhea, an infection, or have a fever.
- ●
- Tell your healthcare provider about any planned surgeries, medical or dental procedures.Your WARFARIN may have to be stopped for a short time or you may need your dose adjusted.
- ●
- Call your healthcare provider right away if you fall or injure yourself, especially if you hit your head.Your healthcare provider may need to check you.
- ●
- Do not start, stop, or change any medicine without talking with your healthcare provider.
- ●
- Do not make changes in your diet, such as eating large amounts of green, leafy vegetables.
- ●
- Do not change your weight by dieting, without first checking with your healthcare provider.
- ●
- Avoid drinking alcohol.
- ●
- Do not do any activity or sport that may cause a serious injury.
- ●
- WARFARIN is very important for your health, but it can cause serious and life-threatening bleeding problems. See " What is the most important information I should know about WARFARIN?"
- ●
- Serious side effects of WARFARIN also include:
- ●
- death of skin tissue (skin necrosis or gangrene). This can happen soon after starting WARFARIN. It happens because blood clots form and block blood flow to an area of your body. Call your healthcare provider right away if you have pain, color, or temperature change to any area of your body. You may need medical care right away to prevent death or loss (amputation) of your affected body part.
- ●
- "purple toes syndrome".Call your healthcare provider right away if you have pain in your toes and they look purple in color or dark in color.
These are not all of the side effects of WARFARIN. For more information, ask your healthcare provider or pharmacist.
How should I store WARFARIN?
- ●
- Store WARFARIN at room temperature between 68and 77Protect from light.
- ●
- Keep WARFARIN and all medicines out of the reach of children.
Medicines are sometimes prescribed for purposes not mentioned in a Medication Guide. Do not use WARFARIN for a condition for which it was not prescribed. Do not give WARFARIN to other people, even if they have the same condition. It may harm them.
This Medication Guide summarizes the most important information about WARFARIN. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about WARFARIN that was written for healthcare professionals.
If you would like more information, call 1-800-544-1449.
DRUG: Warfarin Sodium
GENERIC: Warfarin Sodium
STRENGTH:5 mg
COLOR: orange
SCORE: Two even pieces
SIZE: 11 mm
warfarin sodium tablet
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:49349-605(NDC:51672-4032) Route of Administration ORAL Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength WARFARIN SODIUM (UNII: 6153CWM0CL) (WARFARIN - UNII:5Q7ZVV76EI) WARFARIN SODIUM 5 mg Inactive Ingredients Ingredient Name Strength Anhydrous lactose (UNII: 3SY5LH9PMK) STARCH, CORN (UNII: O8232NY3SJ) magnesium stearate (UNII: 70097M6I30) D&C RED NO. 6 (UNII: 481744AI4O) D&C YELLOW NO. 10 (UNII: 35SW5USQ3G) Product Characteristics Color orange Score 2 pieces Shape BULLET (TABLET) Size 11mm Flavor Imprint Code 5;WARFARIN;TARO Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:49349-605-02 30 in 1 BLISTER PACK Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA040301 11/03/2011 Labeler - REMEDYREPACK INC. (829572556)


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F&*% it!!! We'll just merge the 3rd annual into the 4th.
F&*% it!!! We'll just merge the 3rd annual into the 4th.
Troll Tagged by Uzumaki_Tim
Manga reading list: Bleach, Naruto, Katekyo Hitman Reborn, One Piece, Code Breaker, Gamaran, Kuroko No Basket, Fairy Tail, The World God Only Knows, Kimi No Iru Machi, Good Ending, Medaka Box, Nisekoi, D.Gray-Man, Ao No Exorcist, Freezing, Magi - Labyrinth of Magic, Soul Eater, Rosario Vampire Season II, Iris Zero, Ubell Blatt, Bloody Cross, Sun-Ken Rock, and Infinite Stratos,
That, or just starting all over... >.>
The 3rd and 4th annual mangashare awards!!! O.o
Man, something tells me Mister_Death will find a job before this gets finished...
Why not just get this all over and done with and crown me Lord Supreme Ruler of the Forums?
Let's get this party started.

subset: commoncrawl


text:
(29) Customer Reviews
Price Range: USD $179.99 to $179.99
Passenger Cars
All Season
Original Equipment tires
New levels of performance for today's cars and minivans. Michelin® Energy™ LX4® tires offer improved handling and comfort to meet the increased performance demands of today's passenger cars and minivans. Bearing the name Energy, this tire offers performance characteristics that are comparable to other Michelin luxury touring products.Comfortable, pleasing rideConsistent handlingMeets the increased demands of today's cars and minivans
All orders are verified for fitment guarantee.
You'll receive an alert as soon as this item is available for order.
Treadwear poor. Had in for service, have 29K on the tires. The shop said you'd be lucky to get 5K more.... I've had much better luck with other tire models...
don't really know about snow!
Size: 225/65R17
Vehicle: 2006 Toyota Highlander Hybrid 4wd (Highlander Hybrid 4wd) with 48270 KM of Tire Wear
made this review on 5/12/2013 and is a
Confident, Experienced Driver
Absolutely the worst tread life performance of any tire I've owned in 40 years of driving. Paid $135 per tire and had to replace after 3 years/30K miles. Treadwear loss was indicative of under-inflation, however, the tire pressure was routinely checked 3X per year.
Size: 235/65R16
Vehicle: 2005 Honda Odyssey EX with 48270 KM of Tire Wear
made this review on 4/27/2013 and is a
Confident, Experienced Driver
Replaced original OEM with the LX4. Few manufactures made this size in 06 when they were installed. Tires were always noisy but I was use to passenger tires before. Only put 37k on tires when dealership noticed all four tires had dryrot. Went to authorized Michlin dealer who contacted Michelin and was awarded a 50% credit on all four tires even though they were 2 months out of the dryrot warranty and had 5/32 tread left. Michelin stands by their tires. Of additional note the tires were rotated every 5k miles and nitrogen filled replaced in December 2011.
Vehicle: 2003 Saturn VUE (VUE) with 59533 KM of Tire Wear
made this review on 12/29/2011 and is a
Cautious, Reserved Driver
Lexus RX330 - 225/65 R17 - Got them used on the vehicle, put another 40,000km, still run them. Good tires.
made this review on 10/20/2011 and is a
Confident, Experienced Driver
To see all 29 reviews on tire reviews page
All orders are verified for fitment guarantee
Verified by tire & wheel expert
We honor the fitment.
If your vehicle information is present on your order, we will verify fitment to qualify you for the 100% Fitment Guarantee. If your order arrives and the tires or wheels do not fit your vehicle, we will honor an exchange and pay for freight for the return and new set.If there are concerns about your order we will contact you about potential fitment issues.
Our Fitment Guarantee applies to orders that come with full vehicle information (Year, Make Model, Sub-Model). If you are confident that the vehicle information is not necessary for your order, we will proceed without checking fitment. However, in the event there is a fitment issue with your order, we will honor a return/exchange, as per our
return / refund policy.
You will be responsible for freight charges (both ways).


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By GARY ARRINGTONSports writer
After closing out the preseason with a win against the Union Cougars, the Emery High Lady Spartans opened region 12 play with a solid victory over the Juab Wasps. Emery defeated Union 3-1 and then defeated Juab 3-2.
Coach Kris Bell talked about her team after the victories, "This team is playing a lot better as a team, we are a lot better on digs, we have started serving better and we are talking to each other better on the court."
On Thursday of last week, Emery played Juab and won the first game 25-21. Emery scored the first point of the game and then senior Brooke Jensen served three straight points as the Spartans started quickly. Emery's lead grew to 18-11 and then to 21-12 before Juab made it close at the end.
In game two, Emery led 6-3, 11-7 and 14-9 before the Wasps rallied to narrow the gap to 16-13 and then scored seven straight points to grab the lead at 20-17. Emery cut the deficit to 24-22 before falling 25-22.
In game three, Emery again jumped out to a lead before falling at the end 25-23. Emery led 9-6 and 12-7 before Juab tied the score at 16-16. Emery took the lead back at 19-18 and 23-22 but Juab scored the last three points to grab the win.
Emery, after having just two games that they probably should have won, came out smoking in game four and won easily 25-12 as the Wasps were overcome with the play of the Spartans.Emery led 4-3, 8-5 and 14-10. After Emery scored, Jensen stepped up to serve again and the Spartans scored eight straight points in an impressive offensive display.
In game five, Emery and Juab fought back and forth throughout the game before Emery scored the last three points to win the game and the match. Hailee Rogers, who had served well all night long, served the last two points and Emery had the win.
Against Union, Emery won 25-8 in the first game, 27-25 in the second game, lost 25-22 in the third game and then won the final game 25-19.
In the first game, Union led 7-6 with the Cougars serving. Emery scored the point and then Courtney Tuttle stepped up to serve and the Spartans scored nine straight points to lead 16-7. Blayr Jeffs got a pair of serves in as Emery built the lead and then Jensen helped close out the win with five straight serves.
Game two was a long game that went back and forth and was tied at 24-24. Brittany Fauver served for Emery as they scored the final three points to win. In game three, Emery played well but could not shake the Cougars, as again the game was nip and tuck. Emery led at 21-19 but Union scored three straight points to lead 22-21. Emery tied it at 22-22 but Union then scored the final three points to win their first and only game of the night.
In game four, Emery scored the first three points before trailing at 10-9. Tuttle served three straight followed by Jeffs serving five straight and Emery went from down one to up 19-11. Jensen then served three times and the score was 23-14 before winning 25-19 as Union had one last rally in them.
Emery now hosts Delta this Tuesday night and travels to Manti Thursday night.
Coach Bell finished with, "as a team, we did not have a lot of varsity experience coming into the season but we are coming together well. The girls are playing better as a team."


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Deer Stags Brody Boys Toddler & Youth Slip-On
Sorry, this item is sold out!
Looks like you've got more shoe shopping to do - have fun!
Looks like you've got more shoe shopping to do - have fun!
Item # 233722
Your little guy will look adorably handsome in the sophisticated Brody shoe by Deer Stags.
- Smooth synthetic leather upper
- Velcro closure provides an effortless on/off
- Light padding at the tongue and collar
- Rubber sole
- Imported
- Online Exclusive!
By: Sello
Location: corona
March 13, 2013
Nice shoes
"I like these shoes but they run big a little...."
By: jbeem
Location: San Francisco
December 21, 2012
A little stiff
"They looked fine, but my son found them to be too stiff."
By: rushgurl
Location: Orlando, FL
February 03, 2012
For the Ring Bear
"My son can wear an 8.5-9, I ordered a 9.5 and it was a good thing because they fit just slightly big. I found them narrow for his foot and he doesn't have a wide foot. Cute for the price. I didn't give them 5 stars because they run narrow and the velcro strap almost didn't strap on his foot."
By: vhvh20
Location: Miami, FL
August 31, 2011
Great Fit, great price
"Perfect school shoe for boys. Easy to put on, looks great, very comfy. The price is just right!"
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We posted a few weeks ago about the way skinny jeans almost ruined the American dollar—basically because US currency was being printed on special paper made largely from denim scraps provided by the denim industry, until spandex jeans became widely popular and the quality of denim scraps themselves with compromised in an epic way. Glamour posted a write-up on this same predicament, with an inside look at the way spandex denim changed …well, everything.
"Did you know that for the longest time—since the 1800s, in fact—U.S. dollars have been printed on a cotton-paper blend supplied by Crane—yes, the stationer? And, for the longest time, since the 1800s, Crane & Co. has gotten 30 percent of its cotton in the form of denim scraps from the garment industry!
But then, in the '90s and '00s, something happened in fashion that changed the money-making business forever. That something was spandex—and it started to make its way into nearly all mass-produced jeans in the United States." (Read more)
Image via Glamour
—Michelle Christina Larsen
Tags: american currency, how dollars are made, skinny jeans, spandex blend, spandex denim, spandex jeans


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Marie Longoria >> See More Amateurs
Galleries in Full HD!
Galleries in Full HD!
Peruvian goddess Marie Longoria calls New York her home now, but was born in beautiful Lima. It's hard to look at Marie and not imagine the sensual heat of South America. Watch Marie's interview in the members area to learn more about this exotic angel....
Get this complete pictorial in stunning resolution & HD video! View Full Gallery!


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- Product Details
- Fabric Estimator
- Rewards
This is a light weight cotton print. Baby blue stripes contain a leaf pattern while cream openings have a classical etched cherub scene. Great for drapery.
Color: Cream/Baby Blue
Width: 110"
Content: 100% COTTON
Country: SPAIN
V Repeat: 18.50
H Repeat: 23.33
Learn about fabric careHOW TO CARE FOR COTTON FABRICS: Machine-wash warm or cold, tumble dry. Pull straight from the dryer to prevent wrinkles, or iron while damp. Prewash cotton fabrics before cutting out your pattern. Mood strongly recommends test-laundering a swatch, if you plan to wash your garment or home furnishings yourself.
PLEASE NOTE: The above numbers are estimations only. Please take into account garment size, lining and fabric width.


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Blowfish Doris Flat Sandal
Sorry, this item is sold out!
Looks like you've got more shoe shopping to do - have fun!
Looks like you've got more shoe shopping to do - have fun!
Item # 279858
Flat in height but high in style, the Blowfish Doris espadrille sandal is the perfect summer staple. The asymmetrical styling on this casual flat sandal will add a carefree look to your warm weather wardrobe.
- Faux leather upper
- Ankle strap and side strap with adjustable buckles
- Espadrille trim
- Synthetic sole
- Imported
- View more Women's Blowfish Shoes
By: june3
Location: maryland
April 28, 2013
very attractive and comfortable
"I ordered these sandals in black in my usual size (7M) and they fit perfectly. They work best with jeans, shorts and casual skirts. They are extremely attractive and comfortable."
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text:
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Showing 1-24 of 25 items found in Outdoors & Play
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Farm products available for purchase include plants, fresh fruits and vegetables, plus a wide variety of Amish jams and jellies. A pumpkin patch and corn maze are featured in the fall.
Our farm market features a large variety of farm fresh family grown vegetables. Our sweet corn is picked fresh every morning when its the sweetest. Tomatoes, green beans, pickling cucumbers, broccoli, zucchini and other summer squash, a variety of specialty peppers are among the fresh vegetables we grow here on our farm. If fruit is what you are looking for, you will find our homegrown muskmelon, honeydew and watermelon delicious. We also carry Michigan peaches, pears, nectarines and other in season fruit from the Midwest. We are a working family operated farm. We want you to have a day on the farm experience when you stop by during the summer or the fall. Our tractor/sand box play areas are available all during the season. Our own animals are always here for you to visit, but we do bring in more during the fall season. In the fall we have our family grown pumpkins, gourds, corn shocks, Indian corn and other specialty decorations. Of course we will still have the fall veggies, squash and more, plus the continuing of the summer treats. Know your food! Know your farmer!
Located in the heart of Illinois' Amish country, The Great Pumpkin Patch is a working farm that features beautiful gardens, including a spectacular collection of more than 5,000 mums, and offers its heirloom seeds for sale. Known for its more than 300 varieties of rare pumpkins, squash and gourds from around the globe that are grown right on the farm and displayed in its Great Pumpkin Patch from mid-September through October 31 every year. The on-site Homestead Bakery sells made-from-scratch goodies such as pies and angel food cake during spring, summer and fall.
Central Illinois' most unique farm market. Wagon rides, playground, corn maze, farm animals, Apple Express train. Farm market filled with unique gifts, fresh produce and specialty foods such as jams, salsas, soups, etc. The large bakery provides an assortment of fresh baked goods and a great lunch on weekdays. Lunch served on weekends in September and October from The Old Market Eatery.
Stade's Farm & Market is located in scenic McHenry County in Northeastern Illinois, approximately 50 miles from Chicago. We produce 2,200 acres of crops that range from traditional corn and soybeans to specialty crops including many fruits and vegetables commonly grown in Northern Illinois. Through our own farm market, we sell our fresh fruits and vegetables directly to consumers in our local area. Our goal is to provide our customers with the finest quality produce possible.
Schwartz Orchard in Mt. Vernon
This orchard features fresh-picked apples, peaches, a pumpkin patch, cider and special events for children during apple season.
Our u-pick apple orchard, located in Northern Illinois, offers family fun & entertainment in a beautiful 120 acre setting. We feature the first apple tree maze in the country, "Amaze N Apples," which is planted with 3,000 apple trees in over 4 acres, hosts 1.5 mile walking trails and 3 activity areas. We also have over 16,000 apple trees including 30 varieties of apples with new varieties being planted each spring. Also giant pumpkins, gourds and squash. Visit our Apple Barn or Harvest Barn for fresh picked apples, pumpkins and our famous apple cider slushees. And don't forget our delicious apple cider! Our Entertainment Area has no admission fee as well. Each guest can purchase Entertainment tokens good for any one of our Train, Carousel, Amaze N Apples, Apple Picking or Weekend Orchard Tour rides. Tokens may be purchased at any register or at our token booth. We are open Mid-August through Mid-November, and we feature both evening and Sunday hours in September and October.
This 94-acre farm features picnic and recreational areas, antique farm equipment, a petting zoo, pony rides and barrel train rides. In fall find a pumpkin patch, haunted barn and pig races.
Richardson Adventure Farm and Corn Maze
Home of the World's Largest Corn Maze! Theres lots to do for all ages -- slides, pedal carts, jumping pillows, a carousel, wagon rides, pig races, and a 50 tall observation tower. For an additional charge, there are pumpkins of all shapes and colors, a train ride, petting zoo, zipline, zorbing, concessions, fresh donuts, fudge, kettle corn, and more! There are 2 kids game trails where parents can take their kids into the big maze, and not get lost! Or, find all of the checkpoints and earn a beautiful, full color certificate. Open until 11pm on Fridays and Saturdays for corn-mazing at night and sitting around a campfire with hot chocolate! Reserve a campfire spot as a base camp for your group!
CITY:Spring Grove
Rendleman Orchards Farm Market
Tree ripened peaches & nectarines from July - August, and apples from September - December. This farm market is open 7 days a week with seasonal produce, preserves, pickles and other specialty food items and gifts.
CITY:Alto Pass
Features 15 historic buildings that trace the history of Kendall County plus an 1819 Chicago Burlington & Quincy caboose, a fully-stocked general store, an 1840s schoolhouse, town hall, a working blacksmith shop, the Plano Train Depot, (c. 1850s) and Yorkville Firehouse (c. 1888).
Experience the best of autumn and Christmas at Larson's Family Farm. Fall features include pick-your-own pumpkins, gourds and squash. Hayrides and bonfires available on October weekends. Harvest decorations and antiques for purchase in the Barn Store. U-pick Christmas trees, handmade evergreen wreaths and lengths of roping available in winter. Enjoy a steaming cup of hot apple cider and shop the Barn Store for antiques and Christmas decorations. Contact the farm for special event and farm tour information. Lasting memories are made at Larson's Family Farm!
Bring your family out to our 65 acre site for a day of fall fun! Open from mid-August through November, enjoy the horse drawn hay rides, kid's activity area with a barn, bale pile, tractor cab and more. Pick your own apples or stop in the store and visit the bakery for apple donuts, pies, caramel apples, fresh baked bread and fudge. Jonamac Orchard is your family's fall tradition.
The North Pole has moved to Central Illinois. Try your luck at the 6+ acre corn maze, the Grand Prix style race track, pick a pumpkin or a Christmas tree (depending on season), stop by the fascinating gift shop and, of course, see the reindeer!
Goebbert's Pumpkin Farm and Garden Center
Fall: festival with haunted house, corn maze, farm animals, and more. Spring/Summer: large selection of annuals, perennials, vegetable plants, trees, shrubs, aquatic plants, roses, planters, and gourmet food items. Admission is free - cost for some activities.
CITY:South Barrington
Open August through November, come visit our farm this fall to share in our rustic culture and enjoy a taste of the season. Many varieties of apples to taste. Also available, in season, are raspberries, pumpkins, home-made goodies, and our famous apple cider donuts. Take a horse drawn ride out to the orchard to pick your own apples too. Family tradition starts here! There's a petting zoo too.
CITY:Poplar Grove
Edwards West is a popular destination for families to enjoy the sights, tastes, and activities of an apple orchard and farm market. For a fun family outing, enjoy the experience of picking your own apples, pumpkins and raspberries. Visit the play area featuring the wooden bus and train, the corn cribs, the wagon slide and our animals in the "Petting Farm." Stroll through the over 100 year old dairy barn with displays of bright colored apples, freshly squeezed cider, fresh apple cider donuts, and wonderful gift items that are on display.
October brings pumpkins, hayrides, corn maze, train rides, farm animals, and fun. Also come see our Civil war reenactment the third weekend in October. Warrior Dash Midwest in June. On site gift shop.
Didier Farms offers a variety of vegetables and flowers in our greenhouse this spring, and our farmers market in summer. U-pick opportunities are plentiful throughout the summer, weather permitting. During our Pumpkinfest, the last week of September and all of October, we offer hayrides, pony rides, corn maze and an exotic zoo, in beautiful Lake County. Also enjoy the Buffalo Creek Mining Co, pony & camel rides, Animal Land, Pumpkin Playland, kiddie rides, Parakeet Encounter, Pig Races (Sat, Sun & Mon) Pumpkin Patch Café, homemade apple cider & pumpkin donuts made daily. Antique tractor display, fall produce, birthday parties and school groups by reservation only.
Curtis Orchard is an 80-acre apple orchard, pumpkin patch and entertainment farm offers activities for the whole family. Open July 20–December 20, the orchard country store and bakery offer a wide variety of gift and food items, including pies, fritters, apple crisp donuts and award-winning cider. Outdoor activities include seasonal apple and pumpkin picking, kids play structures, a giant slide, several mazes including the corn maze, petting zoo, toddler area, birthday parties and corporate picnics. Weekend activities include outdoor meals, live entertainment, seasonal pony rides, and an orchard wagon.
Over 45 exhibits of native Illinois wildlife and domestic farm animals; tree-shaded picnic area - seating for 300; "Exclusive Use" facility rentals; private party room; open year-round.
Bakery opens at 6:00am and Market opens at 9:00 to 5:00pm, Monday- Saturday, and Sunday 6:00 to 4:00 pm. May is spring bedding plants, summer is fresh picked vegetables and fruits. After Labor Day, on weekends, pumpkins, pedal cars, pony and wagon rides, corn maze, animal barn, jumping pillow, food stands and the last weekend in Sept. a Craft Show with live music and over 100 crafters.
Ackerman Farms, celebrating over 100 years as a working family farm, invites everyone to join us from the 3rd week in August through the 3rd week in December. We feature over 150 different varieties of pumpkins and squash in all shapes and sizes, over 25 varieties of beautiful hardy mums, and over 15 varieties of apples from our orchard - everything you need for your fall decorations and for your table. Plan to spend the afternoon with us in our family friendly corn maze, ride a hay rack, browse the gift shop and visit our friendly farm animals. At Christmas, join us for hot cider by a cozy fire and leisurely shop our wonderful Christmas selection of gifts and decor. Don't forget to call us to schedule birthday parties or class field trips.
Step back in time a few years and enjoy clean, old-fashioned outdoor fun at Abbey Farms. Unique – no haunting themes, no electronic games, no gimmicks, just clean old-fashioned outdoor fun for everyone. Enjoy three seasons of fun; fresh produce in summer, Pumpkin Daze in fall and U-pick Christmas trees in winter. Shop their fresh bakery goods, cider donuts, and other seasonal delights. Looking for a unique venue for that special occasion? Visit their new rustic-chic barn, the Nagel Emporium.


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Rachel Christa Girls Infant & Toddler Dress Shoe
Sorry, this item is sold out!
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Looks like you've got more shoe shopping to do - have fun!
Item # 276890
Your little girl will be to cute for school in these Christa Rachel dress shoes. With a fashionable floral embellished upper with mary jane velco design,this little charmer is sure to make her feel like a princess and they might just stay on.
- Synthetic/patent upper
- Floral embellished toe
- Adjustable mary jane strap for secure fit
- Rubber sole
- Imported
- Online Exclusive!
Tell us what you think!
Everyone has an opinion. Here's your chance to share yours! Be the first to write a review of this product and help your fellow shoppers pick the best of the best.


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Good product.
Verified Purchase
Good product.
Well balanced product.
Posted by Reviewer2382673 on Dec 02, 2009
I was so excited to find this product, but it turns out that the the levels of kelp and iodine are high enough to cause acne. At 60 years old, this is not a good thing. I was really disappointed and will have to return the product. I will contine to try and find somthing like this that does not contain so much of the acne causing products.
Good product.
Well balanced product.
Posted by Reviewer3316886 on Jan 28, 2013
Y Feel Better All Day every day in my 50 year old
Feel strong
Posted by Reviewer2249741 on Jul 25, 2014
I do feel strong when I take this multi!
Just one of the best!
Posted by 5334850248963276366 on Sep 14, 2014
Take one, and the simply one 50+ will do the rest!
My Multi Vitamin
Posted by Reviewer2309292 on Mar 13, 2015
I have a lot of trust in this Vitamin Supplement. I hardly even catch a cold but must have my Vitamin D levels checked. I believe though it is a really great product. Thanks.
Posted by 5742638742876960853 on Jun 28, 2013
I bought this product for my grandma but she had to discontinue because it caused her stomach problems
Have been using for a while now and really do like it for my body!
Posted by Reviewer2813750 on Apr 26, 2010
I plan on sticking with this multi for quite some time.
Super Nutrition Simply One 50+ Women Iron Free
Posted by Reviewer2558871 on Sep 22, 2010
I was told about this product by a friend and it has proven to be as good as he said it would be. I used to take liquid vitamins, but this formulation suits me much better. Super Nutrition Simply One is simply great.
Simply one 50+
Posted by Reviewer2304961 on Feb 04, 2011
This is great!!
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Mix No. 6 Story Flat
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Looks like you've got more shoe shopping to do - have fun!
Item # dsw12prod4530240
Flat in height but high in style, the Mix No. 6 Story is the perfect flat to create a look your very own. This chic snake print cap toe flat pairs perfectly under leggings or your favorite denim.
- Faux leather upper
- Snake print fabric also available
- Metallic cap toe
- Synthetic sole
- Imported
- View more Women's Mix No. 6 Shoes
By: GreenEyesIrish
Location: North Carolina
October 19, 2013
Barbie Pink!
"I adore these! They are bright pink the gold toe is perfect with it! I'm a 6/6.5 and 6.5 in these is perfect! They are incredibly comfortable. I will refrain from wearing these on rainy days though because I am not sure how well the material would hold up to a downpour."
By: MDSR
Location: Houston, TX
October 13, 2013
Super freakin' cute!
"It is a little long but the shoes are too cute! They are comfortable on initial wear."
By: RMonet
August 07, 2013
By: tdosh
Location: Atlanta
July 17, 2013
toes a bit squished
"These are cute, and haven't given me any blisters, but they do squish my toes a bit. After I wear them for a bit they will probably stretch out, and I'll probably keep wearing them because they are cute."
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One Night Stanza
Show type: Edinburgh Fringe 2002
The best of the hit Radio 4 comedy. Matt and Rory look beneath the loose covers of the everyday and ask: if love can build a bridge, can affection put up a shelf?
Older Comments
Mandy Hunter - 10/08/2002
Glorious show. Funny and intelligent and silly and surreal. Came away feeling cherished and more entertained than I've been at any other show so far.


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PHA's Scientific Leadership Council (SLC) members are leading physicians and research scientists in the pulmonary hypertension field from medical centers that include Brown University, Case Western Reserve University, The Cleveland Clinic Foundation, Columbia Presbyterian Medical Center, Georgetown, Harbor - UCLA, Harvard University, Mayo Clinic, New York University, Stanford University, Tufts University, University of Texas Southwestern, University of Colorado, University of Iowa, University of Maryland, University of Michigan, University of Pittsburgh, University of South Alabama, University of Utah, Vanderbilt University, Washington University in St. Louis, and Yale. They guide PHA's medical programs.The SLC is a global body with international members currently from the U.S., Canada and Austria.
Todd M. Bull, MDChair, Research CommitteeAssociate Professor in MedicineMedical Director, Anschutz Intensive Care UnitUniversity of Colorado HospitalDenver, COTerm Ends October 2016
Mardi Gomberg-Maitland, MD, MScDirector of RV Failure, HFpEF, and Cardio-Oncology ProgramsCo-Director of the Pulmonary Vascular Disease ProgramInova Heart and Vascular InstituteFalls Church, VA
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