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
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 CYP2C9 and VKORC1 in a patient may increase the need for more frequent INR monitoring and the use of lower warfarin doses (see CLINICAL PHARMACOLOGY: Metabolism and DOSAGE AND ADMINISTRATION). 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.
Information for Patients
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 COUMADIN 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 COUMADIN is being taken. If the prescribed dose of COUMADIN 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 COUMADIN the next day to make up for missed doses. The amount of vitamin K in food may affect therapy with COUMADIN. 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 healthcare 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 COUMADIN is discontinued, patients should be cautioned that the anticoagulant effects of COUMADIN 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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity and mutagenicity studies have not been performed with COUMADIN. The reproductive effects of COUMADIN have not been evaluated. The use of warfarin during pregnancy has been associated with the development of fetal malformations in humans (see CONTRAINDICATIONS).
Use in Pregnancy
Pregnancy Category X
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 COUMADIN 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 COUMADIN therapy. Patients may return to a pretreatment thrombotic status following the rapid reversal of a prolonged PT/INR. Resumption of COUMADIN 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 COUMADIN (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 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.
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:
COUMADIN is 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: (1) central nervous system; (2) eye; (3) traumatic surgery resulting in large open surfaces.
Bleeding tendencies associated with active ulceration or overt bleeding of: (1) gastrointestinal, genitourinary or respiratory tracts; (2) cerebrovascular hemorrhage; (3) aneurysms-cerebral, dissecting aorta; (4) pericarditis and pericardial effusions; (5) bacterial endocarditis.
Threatened abortion, eclampsia and preeclampsia.
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 this product.
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Bristol-Myers Squibb Company
Princeton, New Jersey 08543 USA
COUMADIN® and the color and configuration of COUMADIN tablets are trademarks of Bristol-Myers Squibb Pharma Company.
Copyright © Bristol-Myers Squibb Company 2007
Printed in USA
Rev August 2007
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