Warfilone (Warfarin Sodium)

WARFILONE®

Frosst

Warfarin Sodium

Oral Anticoagulant

Indications And Clinical Uses: The prophylaxis and treatment of venous thrombosis and its extension, the treatment of atrial fibrillation with embolization, heart valve prosthesis and acute peripheral arterial embolism. Also in the prophylaxis and treatment of pulmonary embolism.

In acute myocardial infarction for patients with high risk factors for thromboembolic complications and as an adjunct in the treatment of coronary occlusion. It is also recommended as an adjunct in the treatment of transient cerebral ischemic attacks and cerebral embolism.

Contra-Indications: In any localized or general physical condition or personal circumstances in which the hazard of hemorrhage might be greater than the potential clinical benefits of anticoagulation, such as:

Pregnancy: Warfarin 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. 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 and corneal leukoma.

Spontaneous abortion and stillbirth are known to occur and higher risk of fetal mortality is associated with the use of warfarin.

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 CNS; 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; aneurysm – cerebral, dissecting aorta; pericarditis and pericardial effusions; bacterial endocarditis.

Threatened abortion, eclampsia and preeclampsia.

Inadequate laboratory facilities or unsupervised senility, alcoholism, psychosis or lack of patient cooperation.

Spinal puncture and other diagnostic or therapeutic procedures with potential for uncontrollable bleeding.

Miscellaneous: Major regional, lumbar block anesthesia, and malignant hypertension.

Manufacturers’ Warnings In Clinical States: The most serious risks associated with anticoagulant therapy with warfarin are hemorrhage in any tissue or organ and, less frequently, necrosis and/or gangrene of skin and other tissues. The risk of hemorrhage is related to the level of intensity and the duration of anticoagulant therapy. 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.

Warfarin is a potent drug with a half-life of 2.5 days; therefore, its effects may become more pronounced as daily maintenance doses overlap. It cannot be emphasized too strongly that treatment of each patient is a highly individualized matter. Dosage should be controlled by periodic determinations of PT or other suitable coagulation tests. 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 to Dosage – Conversion from Heparin Therapy, for recommendations.

Caution should be observed when warfarin is administered in any situation or in the presence of any predisposing condition where added risk of hemorrhage or necrosis 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 toe syndrome”. Discontinuation of warfarin therapy is recommended when such phenomena are observed. While the “purple toe syndrome” is reported to be reversible, other complications of microembolization may not be reversible.

Administration of anticoagulants in the following conditions will be based upon clinical judgment in which the risks of anticoagulant therapy are weighed against the risk of thrombosis or embolization in untreated cases. The following may be associated with these increased risks:

Lactation: Warfarin appears in the milk of nursing mothers in an inactive form. Infants nursed by warfarin treated mothers had no change in PT. Effects in premature infants have not been evaluated.

Severe to moderate hepatic or renal insufficiency.

Infectious diseases or disturbances of intestinal flora: sprue, antibiotic therapy.

Trauma which may result in internal bleeding.

Surgery or trauma resulting in large exposed raw surfaces. Indwelling catheters.

Severe to moderate hypertension.

Known or suspected deficiency in protein C. This hereditary or acquired condition, which should be suspected if there is a history of recurrent episodes of thromboembolic disorders in the patient or in the family, has been associated with an increased risk of developing necrosis following warfarin administration. Tissue necrosis may occur in the absence of protein C deficiency. It has been reported that concurrent anticoagulant therapy with heparin for 5 to 7 days during initiation of therapy with warfarin may minimize the incidence of this reaction. 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, severe diabetes, severe allergic and anaphylactic disorders.

Patients with congestive heart failure may become more sensitive to warfarin, thereby requiring more frequent laboratory monitoring, and reduced doses of warfarin.

Concurrent use of anticoagulants with streptokinase or urokinase is not recommended and may be hazardous. (Please note recommendations accompanying these preparations.)

Precautions: Periodic determination of PT or other suitable coagulation test is essential. Numerous factors, alone or in combination, including travel, changes in diet, environment, physical state and medication may influence response of the patient to anticoagulants.

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.

It has been reported that concomitant administration of warfarin and ticlopidine may be associated with cholestatic hepatitis.

Special Risk Patients: Caution should be observed when warfarin is administered to certain patients such as elderly or debilitated or when administered in any situation or physical condition where added risk of hemorrhage is present.

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.

Close monitoring of patients receiving nonsteroidal anti-inflammatory agents (NSAIDs) is recommended to be certain that no change in anticoagulation dosage is required. In addition to specific drug interactions that might affect prothrombin time, NSAIDs can inhibit platelet aggregation, and can cause gastrointestinal bleeding, peptic ulceration and/or perforation.

Information for the Patient: The objective of anticoagulant therapy is to control the coagulation mechanism 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 physicians. Patients should be advised. Strict adherence to the prescribed dosage schedule is necessary; do not take or discontinue any other medication, except on the advice of the physician; avoid alcohol, salicylates (e.g. ASA), large amounts of green leafy vegetables, and/or drastic changes in dietary habits which may affect warfarin therapy; warfarin may cause a red-orange discoloration of alkaline urine; the patient should notify the physician: if any illness such as diarrhea, infection or fever develops; or if any unusual symptoms such as pain, swelling or discomfort appear; or if prolonged bleeding from cuts, increased menstrual flow or vaginal bleeding, nosebleeds or bleeding of gums from brushing, unusual bleeding or bruising, red or dark brown urine, red or tar black stools or diarrhea occurs.

Pregnancy: See Contraindications.

Children: Safety and effectiveness in children below 18 years of age have not been established.

Adverse Reactions: Potential adverse reactions to warfarin may include: Hemorrhage from any tissue or organ. This is a consequence of the anticoagulant effect. The signs and symptoms will vary according to the location and degree or extent of the bleeding. Hemorrhagic complications may present as paralysis; headache, chest, abdomen, joint or other pain; shortness of breath, difficult breathing or swallowing; unexplained swelling or unexplained shock. Therefore, the possibility of hemorrhage should be considered in evaluating the condition of any anticoagulated patient with complaints which do not indicate an obvious diagnosis. Bleeding during anticoagulant therapy does not always correlate with prothrombin activity (see Overdose: Symptoms and Treatment).

Bleeding which occurs when the prothrombin time 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).

Other adverse reactions are infrequent and consist of alopecia, urticaria, dermatitis, fever, nausea, diarrhea, abdominal cramping, systemic cholesterol microembolization, a syndrome called “purple toes”, cholestatic hepatic injury and hypersensitivity reactions.

Priapism has been associated with anticoagulant administration, however, a causal relationship has not been established.

Symptoms And Treatment Of Overdose: Symptoms: Suspected or overt abnormal bleeding (i.e., 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.

Treatment: 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 prior to use.)

Such use of vitamin K1 reduces responses to subsequent warfarin 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 warfarin 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.

Dosage And Administration: The administration and dosage must be individualized according to the patient’s sensitivity to the drug. The dosage should be adjusted according to results of the one-stage PT. Different thromboplastin reagents vary substantially in their responsiveness to warfarin-induced effects on PT.

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 range that reflect this decrease in sensitivity. Available clinical evidence indicates that prolongation of the PT 1.3 to 1.5 times control, when measuring with the less sensitive thromboplastin reagents, is sufficient for prophylaxis and treatment of venous thromboembolism, minimizing the risk of hemorrhage associated with more prolonged PT values. In cases where the risk of thromboembolism is great, such as patients with recurrent systemic embolism, a PT of 1.5 to 2.0 times control should be maintained. A ratio greater than 2.0 appears to provide no additional therapeutic benefit in most patients and is associated with a higher risk of bleeding.

To define the appropriate therapeutic regimen it is important to be familiar with the sensitivity of the thromboplastin reagent used in the laboratory and its relationship to the International Reference Preparation (IRP), a sensitive thromboplastin prepared from human brain.

International Reference Preparation (IRP): 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 communications of PT results and interpretations of therapeutic ranges. The INR is derived from calibrations of commercial thromboplastin reagents against a sensitive human brain thromboplastin, the International Reference Preparation (IRP).

For the 3 commercial rabbit brain thromboplastins currently used in North America, a PT ratio of 1.3 to 2.0 is equivalent to an INR of 2.0 to 4.0. For other thromboplastins, the INR can be calculated as:

INR = (observed PT ratio)SI where the ISI (International Sensitivity Index) is the calibration factor and is available from the manufacturers of the thromboplastin reagent.

The proceedings and recommendations of the 1992 Third ACCP Consensus Conference on Antithrombotic Therapy and a review article evaluate issues related to oral anticoagulant therapy and the sensitivity of thromboplastin reagents and provide additional guidance for defining the appropriate therapeutic regimen.

Laboratory Control: The PT reflects the depression of vitamin K dependent Factors VII, IX, X and II. There are several modifications of the one-stage PT and the physician should become familiar with the specific method used in the laboratory which is employed. The degree of anticoagulation indicated by any range of PTs may be altered by the type of thromboplastin used; the appropriate therapeutic range must be based on the experience of each laboratory. The PT should be determined daily after the administration of the initial dose until PT results stabilize in the therapeutic range. Intervals between subsequent PT determinations should be based upon the physician’s judgment of the patient’s reliability and response to warfarin in order to maintain the individual within the therapeutic range. Acceptable intervals for PT determinations are normally within the range of 1 to 4 weeks. To ensure adequate control, it is recommended that additional PT tests are done when other warfarin products are interchanged with warfarin.

Treatment during Dentistry and Surgery: The management of patients who undergo dental and surgical procedures requires close liaison between attending physicians, surgeons and dentists. In patients who must be anticoagulated prior to, during or immediately following dental or surgical procedures adjusting the dosage to maintain the PT at the low end of the therapeutic range, may safely allow for continued anticoagulation. The operative site should be sufficiently limited to permit the effective use of local procedures for hemostasis. Under these conditions dental and surgical procedures may be performed without undue risk of hemorrhage.

Conversion from Heparin Therapy: Since the onset of warfarin’s effect is delayed, heparin is preferred initially for rapid anticoagulation. Conversion to warfarin may begin concomitantly with heparin therapy or may be delayed 3 to 6 days. As heparin may affect the PT, patients receiving both heparin and warfarin should have blood drawn for PT 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 the last s.c. heparin injection.

When warfarin has produced the desired therapeutic range of prothrombin activity, heparin may be discontinued.

Availability And Storage: Each white, round, film-coated tablet with a score F symbol on one side and the number 5 on the other, contains: warfarin sodium USP 5 mg. Nonmedicinal ingredients: calcium phosphate dibasic, croscarmellose sodium, cornstarch, hydroxypropyl cellulose with silica, hydroxypropyl methylcellulose, magnesium stearate and microcrystalline cellulose. Bottles of 100. Keep container tightly closed. Protect from light. (Shown in Product Recognition Section)

WARFILONE® Frosst Warfarin Sodium Oral Anticoagulant

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