Information for the Patient
Coumadin
Pharmacology
Other CYP2C9 alleles associated with reduced enzymatic activity occur at lower frequencies, including *5, *6, and *11 alleles in populations of African ancestry and *5, *9 and *11 alleles in Caucasians.
Pharmacogenomics: 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. 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.
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 -1639G>A allele) have been associated with lower dose requirements for warfarin. In 201 Caucasian patients treated with stable warfarin doses, genetic variations in the VKORC1 gene were associated with lower warfarin doses. In this study, about 30% of the variance in warfarin dose could be attributed to variations in the VKORC1 gene alone; about 40% of the variance in warfarin dose could be attributed to variations in VKORC1 and CYP2C9 genes combined. About 55% of the variability in warfarin dose could be explained by the combination of VKORC1 and CYP2C9 genotypes, age, height, body weight, interacting drugs, and indication for warfarin therapy in Caucasian patients. Similar observations have been reported in Asian patients.
Elimination: The terminal half-life of warfarin after a single dose is approximately 1 week; however, the effective half-life ranges from 20 to 60 hours, with a mean of about 40 hours. The clearance of R-warfarin is generally half that of S-warfarin, thus as the volumes of distribution are similar, the half-life of R-warfarin is longer than that of S-warfarin. The half-life of R-warfarin ranges from 37 to 89 hours, while that of S-warfarin ranges from 21 to 43 hours. Studies with radiolabeled drug have demonstrated that up to 92% of the orally administered dose is recovered in urine. Very little warfarin is excreted unchanged in urine. Urinary excretion is in the form of metabolites.
Geriatrics: Patients 60 years or older appear to exhibit greater than expected PT/INR response to the anticoagulation effects of warfarin. The cause of this increased sensitivity in this age group is not known. This increased anticoagulant effect of 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 that there is no difference in the clearance of S-warfarin in the elderly, compared to that seen in young subjects. However, there may be a slight decrease in the clearance of R-warfarin in the elderly, compared to the young. Therefore, as patient age increases, a lower dose of warfarin is usually required to produce a therapeutic level of anticoagulation.
Renal Impairment: 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 Impairment: Hepatic dysfunction can potentiate the response to warfarin through impaired synthesis of clotting factors and decreased metabolism of warfarin.
Indications
COUMADIN (warfarin sodium) is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, atrial fibrillation with embolization, and as an adjunct in the prophylaxis of systemic embolism after myocardial infarction, including stroke and reinfarction.
The following are some of the more common clinical disorders which may be associated with or predispose patients to the above indications: thrombophlebitis, congestive heart failure, surgical procedure or trauma associated with a high risk of thromboembolism, myocardial infarction, cerebral embolism.
It may also be useful as an adjunct in the treatment of transient cerebral ischemic attacks due to intravascular clotting.
Precautions
Considerations for Increased Bleeding Risk: COUMADIN 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), age ≥65, highly 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 variations in CYP2CP and VKORC1 in a patient may increase the need for more frequent INR monitoring and the use of lower warfarin doses (see Pharmacology, Metabolism and Dosage). Bleeding is more likely to occur during the starting period and with a higher dose of COUMADIN (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 COUMADIN (or 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.
Geriatrics and/or Debilitated Patients: Patients 60 years or older appear to exhibit greater than expected PT/INR response to the anticoagulant effects of warfarin (see Pharmacology, Geriatrics). COUMADIN is contraindicated in any unsupervised patient with senility. Caution should be exercised with administration of warfarin sodium to elderly and/or debilitated patients in any situation or physical condition where added risk of hemorrhage is present. Low initiation and maintenance doses of COUMADIN are recommended in the elderly (see Dosage).
Safety and effectiveness in children below 18 years of age have not been established in randomized, controlled clinical trials. However, the use of COUMADIN in pediatric patients has been documented for the prevention and treatment of thromboembolic events. Difficulty achieving and maintaining therapeutic PT ratio/INR ranges in the pediatric patient has been reported. More frequent PT ratio/INR determinations are recommended because of possible changing warfarin requirements.
Supplied
Each peach, round, biconvex tablet, one side bisected and imprinted with “COUMADIN” and “5”, and the other side blank, contains: crystalline warfarin sodium 5 mg. Nonmedicinal ingredients: FD&C Yellow No. 6 Aluminum Lake, lactose anhydrous, magnesium stearate and pregelatinized tapioca starch. Bottles of 100, 250 and 1000. Protect from light. Store at room temperature (15 to 30°C). Dispense in a tight, light-resistant container as defined in the USP.
Each tan, round, biconvex tablet, one side bisected and imprinted with “COUMADIN” and “3”, and the other side blank, contains crystalline warfarin sodium 3 mg. Nonmedicinal ingredients: FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, lactose anhydrous, magnesium stearate and pregelatinized tapioca starch. Bottles of 100 and 250. Protect from light. Store at room temperature (15 to 30°C). Dispense in a tight, light-resistant container as defined in the USP.
Each pink, round, biconvex tablet, one side bisected and imprinted with “COUMADIN” and “1”, and the other side blank, contains: crystalline warfarin sodium 1 mg. Nonmedicinal ingredients: D&C Red No. 6 Barium Lake, lactose anhydrous, magnesium stearate and pregelatinized tapioca starch. Bottles of 100, 250 and 1000. Protect from light. Store at room temperature (15 to 30°C). Dispense in a tight, light-resistant container as defined in the USP.
Each teal, round, biconvex tablet, one side bisected and imprinted with “COUMADIN” and “6”, and the other side blank, contains: crystalline warfarin sodium 6 mg. Nonmedicinal ingredients: FD&C Blue No. 1 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, lactose anhydrous, magnesium stearate and pregelatinized tapioca starch. Bottles of 100. Protect from light. Store at room temperature (15 to 30°C). Dispense in a tight, light-resistant container as defined in the USP.
Each green, round, biconvex tablet, one side bisected and imprinted with “COUMADIN” and “2 ½”, and the other side blank, contains crystalline warfarin sodium 2.5 mg. Nonmedicinal ingredients: D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, lactose anhydrous, magnesium stearate and pregelatinized tapioca starch. Bottles of 100 and 250. Protect from light. Store at room temperature (15 to 30°C). Dispense in a tight, light-resistant container as defined in the USP.
Each blue, round, biconvex tablet, one side bisected and imprinted with “COUMADIN” and “4”, and the other side blank, contains: crystalline warfarin sodium 4 mg. Nonmedicinal ingredients: FD&C Blue #1 Aluminum Lake, lactose anhydrous, magnesium stearate and pregelatinized tapioca starch. Bottles of 100 and 250. Protect from light. Store at room temperature (15 to 30°C). Dispense in a tight, light-resistant container as defined in the USP.
Each white, round, biconvex tablet, one side bisected and imprinted with “COUMADIN” and “10”, and the other side blank, contains: crystalline warfarin sodium 10 mg. Nonmedicinal ingredients: lactose anhydrous, magnesium stearate and pregelatinized tapioca starch. Dye-free. Bottles of 100. Protect from light. Store at room temperature (15 to 30°C). Dispense in a tight, light-resistant container as defined in the USP.
Each lavender, round, biconvex tablet, one side bisected and imprinted with “COUMADIN” and “2”, and the other side blank, contains: crystalline warfarin sodium 2 mg. Nonmedicinal ingredients: FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, lactose anhydrous, magnesium stearate and pregelatinized tapioca starch. Bottles of 100, 250 and 1000. Protect from light. Store at room temperature (15 to 30°C). Dispense in a tight, light-resistant container as defined in the USP.
Contraindications
COUMADIN (warfarin sodium) is contraindicated in pregnancy because the drug passes through the placental barrier and may cause fatal hemorrhage to the fetus in utero. Women of childbearing potential must take precautions not to become pregnant while on COUMADIN therapy. 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. CNS 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 CNS 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 still birth 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 the light of those risks.
Recent or contemplated surgery of: central nervous system, eye, traumatic surgery resulting in large open surfaces.
Bleeding tendencies associated with active ulceration or overt bleeding of: gastrointestinal, genitourinary or respiratory tracts, cerebrovascular hemorrhage, aneurysms—cerebral, dissecting aorta, pericarditis and pericardial effusions, bacterial endocarditis.
Threatened abortion, eclampsia and pre-eclampsia.
Inadequate laboratory facilities.
Unsupervised patients with senility, alcoholism, or psychosis or other lack of patient cooperation.
Spinal puncture and 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 COUMADIN.
Warnings
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 reports that breast-fed infants, whose mothers were treated with warfarin, had prolonged prothrombin times. 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 INR values are not exceeded. It is prudent to perform coagulation tests on infants at risk for bleeding before advising women taking warfarin to breast-feed. Effects in premature infants have not been evaluated.
Miscellaneous: Minor and severe allergic/hypersensitivity reactions and anaphylactic reactions have been reported.
In patients with acquired or inherited warfarin resistance, decreased therapeutic responses to COUMADIN have been reported. Exaggerated therapeutic responses have been reported in other patients.
Patients with congestive heart failure may become more responsive to COUMADIN, thereby requiring more frequent laboratory monitoring, and reduced doses of COUMADIN.
Concomitant use of anticoagulants with streptokinase or urokinase is not recommended and may be hazardous. (Please note recommendations accompanying these preparations.)
Adverse Effects
taste perversion.
Rare events of tracheal or tracheobronchial calcification have been reported in association with long-term warfarin therapy. The clinical significance of this event is unknown.
Priapism has been associated with anticoagulant administration, however, a causal relationship has not been established.
angina syndrome, chest pain, systemic cholesterol microembolization, purple toe syndrome, vasculitis.
dizziness, cold intolerance, coma, loss of consciousness, syncope and paresthesia, including feeling cold and chills.
alopecia, rash, pruritus, urticaria, dermatitis, including bullous eruptions.
nausea, diarrhea, abdominal pain, including cramping, flatulence/bloating, vomiting.
hypersensitivity/allergic reactions, pain, edema, asthenia, fever, headache, fatigue, lethargy, malaise, anemia, pallor.
elevated liver enzymes, hepatitis, jaundice, cholestatic hepatic injury.
Overdose
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 COUMADIN therapy and if necessary, by administration of oral or parenteral vitamin K1. (Please see recommendations accompanying vitamin K1 preparations prior to use.)
Such use of vitamin K1 reduces responses to subsequent COUMADIN therapy. Patients may return to a pretreatment thrombotic status following the rapid reversal of a prolonged PT. Resumption of warfarin administration reverses the effect of vitamin K1, and a therapeutic PT 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 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 COUMADIN 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 COUMADIN 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.
Dosage
Administration: The administration and dosage of COUMADIN (warfarin sodium) must be individualized according to the patient's responsiveness to the drug. The dosage should be adjusted according to results of the patient's PT ratio/INR. Measurement of warfarin induced effects on PT can vary substantially due to the sensitivity of different thromboplastin reagents.
Early clinical studies of oral anticoagulants, which formed the basis for recommended therapeutic ranges of 1.5 to 2.5 times control PT, used sensitive human brain thromboplastin. When using the less sensitive rabbit brain thromboplastins commonly employed in PT assays today, adjustments must be made to the targeted PT range that reflect this decrease in sensitivity.
The best available information supports the following recommendations for dosing of COUMADIN:
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 generally recommended. For patients with a first episode of idiopathic DVT or PE, warfarin is generally 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 specific risk factors (e.g. documented antiphospholipid antibodies), please refer to current treatment guidelines for recommended duration of treatment.
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.
Atrial Fibrillation: Five recent clinical trials evaluated the effects of warfarin in patients with non-valvular atrial fibrillation (AF). 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. Although clinical studies have used a wide range of warfarin dosing, a more recent study suggests that in patients with atrial fibrillation, anticoagulant prophylaxis is effective at INRs of 2.0 to 3.0. The study also shows that the risk of thromboembolic stroke may increase substantially at INR's less than 2.0. INR value should not exceed 4.0, to reduce the risk of anticoagulant-related bleeding.
Similar data from clinical studies in valvular atrial fibrillation patients are not available. The trials in non-valvular atrial fibrillation support the recommendation that an INR of 2.0-3.0 be used for long term warfarin therapy in appropriate AF patients. In cases where the risk of thromboembolism is great, such as in patients with recurrent systemic embolism, a higher INR may be required. An INR ratio of greater than 4.0 appears to provide no additional therapeutic benefit in most patients and is associated with a higher risk of bleeding. In AF patients undergoing elective cardioversion, anticoagulant therapy should be given for three weeks before cardioversion and continued until normal sinus rhythm has been maintained for four weeks.
Oral anticoagulation is recommended in patients with persistent or paroxysmal atrial fibrillation without valvular disease but at high risk of embolic 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 or congestive heart failure, history of hypertension, or diabetes mellitus. For patients at lower risk, individualized treatment is required. For patients with atrial fibrillation and valvular heart disease, especially mitral valve stenosis, anticoagulation is recommended. For patients with atrial fibrillation and prosthetic heart valves, anticoagulation is required, with the target INR generally increased, with or without aspirin added, depending of risk factors related to the replaced valve or inherent to the patient.
Post-Myocardial Infarction: For most patients following myocardial infarction and not at high risk, antithrombotic treatment should consist of aspirin alone. In patients with acute coronary syndrome that were revascularised by percutaneous coronary intervention (PCI), clopidogrel is usually added. For high-risk patients with myocardial infarction (MI), including those with a large anterior MI, significant heart failure, intracardiac thrombus visible on echocardiography, or those with a history of a thromboembolic event, therapy with combined moderate-intensity warfarin (INR 2.0 to 3.0) plus low-dose aspirin (100 mg/day) for 3 months following myocardial infarction should be considered.
Laboratory Control: The Prothrombin Time (PT) should be determined daily after the administration of the initial dose until International Normalized Ratio (INR) results stabilize in the therapeutic range. Intervals between subsequent INR determinations should be based upon the physician's judgment of the patient's reliability and response to COUMADIN in order to maintain the individual within the therapeutic range. Acceptable intervals for 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, 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.
In switching to another warfarin product, particular emphasis needs to be placed on INR control. INR outside of the therapeutic range may result in serious clinical consequences: lack of efficacy leading to thromboembolic stroke or myocardial infarction, if INR values are low, and intracranial bleeding if they are high.
Initial Dosage: The dosing of COUMADIN must be individualized according to the 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 COUMADIN therapy be initiated with a dose of 2 to 5 mg per day with dosage adjustments based on the results of PT/INR determinations. 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 COUMADIN. Elderly and Asian patients may require lower initiation and maintenance doses of COUMADIN (see Precautions).
Maintenance: 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.
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.
Missed Dose: The anticoagulant effect of COUMADIN persists beyond 24 hours. If the patient forgets to take the prescribed dose of COUMADIN 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.
Treatment during Dentistry and Surgery: The management of patients who undergo dental and surgical procedures requires close liaison between attending physicians, surgeons and dentists. PT ratio/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 COUMADIN to maintain the PT ratio/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 haemostasis. Under these conditions, dental and surgical procedures may be performed without undue risk of haemorrhage. Some dental or surgical procedures may necessitate the interruption of COUMADIN therapy. When discontinuing COUMADIN even for a short period of time, the benefits and risks should be strongly considered.
Conversion from Heparin Therapy: Since the anticoagulant effect of COUMADIN is delayed, heparin is preferred initially for rapid anticoagulation. Conversion to COUMADIN 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 COUMADIN therapy be overlapped with heparin for 4 to 5 days, until COUMADIN has produced the desired therapeutic response as determined by PT ratio/INR. When COUMADIN has produced the desired PT ratio/INR or prothrombin activity, heparin may be discontinued.
COUMADIN may increase the aPTT test, even in the absence of heparin. During initial therapy with COUMADIN, the interference with heparin anticoagulation is of minimal clinical significance.
As heparin may affect the PT, patients receiving both heparin and COUMADIN should have blood drawn for PT ratio/INR determination, at least: 5 hours after the last i.v. bolus dose of heparin; or 4 hours after cessation of a continuous i.v. infusion of heparin; or 24 hours after last s.c. heparin injection.
