Warfarin

DESCRIPTION

Crystalline warfarin sodium, is an anticoagulant which acts by inhibiting vitamin K-dependent coagulation factors. Chemically, it is 3- (a-acetonylbenzyl) -4 -hydroxycoumarin 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 sodium. Its empirical formula is C₁₉H₁₅NaO₄.

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.

Coumadin Tablets

Coumadin Tablets for Oral Use Also Contain: All strengths: Lactose, starch and magnesium stearate; 1 mg: D&C Red 6; 2 mg: FD&C Blue 2 and FD&C Red 40; 2-1/2 mg: FD&C Blue 1 and D&C Yellow 10; 4 mg: FD&C Blue 1 Lake; 5 mg: FD&C Yellow 6; 7-1/2 mg: D&C Yellow 10 and FD&C Yellow 6; 10 mg: Dye Free.

Coumadin for Injection

Coumadin for Injection is supplied as a sterile, lyophilized powder, which, after reconstitution with 2.7 ml sterile Water for Injection, contains: Warfarin sodium: 2 mg/ml; Sodium Phosphate, Dibasic, Heptahydrate: 4.98 mg/ml; Sodium Phosphate, Monobasic, Monohydrate: 0.194 mg/ml Sodium Chloride: 0.1 mg/ml; Mannitol: 38.0 mg/ml; Sodium Hydroxide, as needed for pH adjustment to: 8.1 to 8.3.

CLINICAL PHARMACOLOGY

Warfarin sodium 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 Factors VII, IX, 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 of g-carboxyglutamic acid residues in the proteins which are essential for biological activity. warfarin sodium is thought to interfere with clotting factor synthesis by inhibition of the regeneration of vitamin K₁ epoxide. The degree of depression is dependent upon the dosage administered. Therapeutic doses of warfarin sodium 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 sodium is 2 to 5 days. The effects of warfarin sodium 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.

Pharmacokinetics

Warfarin sodium 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.

Absorption: Warfarin sodium is essentially completely absorbed after oral administration with peak concentration generally attained within the first 4 hours.

Distribution: There are no differences in the apparent volumes of distribution after intravenous and oral administration of single doses of warfarin sodium solution. warfarin sodium 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 sodium are similar to each other and to that of the racemate. Concentrations in fetal plasma approach the maternal values, but warfarin sodium has not been found in human milk (see WARNINGS, Lactation.) Approximately 99% of the drug is bound to plasma proteins.

Metabolism: The elimination of warfarin sodium is almost entirely by metabolism. Warfarin sodium is stereoselectively metabolized by hepatic microsomal enzymes (cytochrome P-450) to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolites (warfarin sodium alcohols). The warfarin sodium alcohols have minimal anticoagulant activity. The metabolites are principally excreted into the urine; and to a lesser extent into the bile. The metabolites of warfarin sodium that have been identified include dehydrowarfarin sodium, two diastereoisomer alcohols, 4'-, 6- , 7-, 8- and 10-hydroxywarfarin sodium. The Cytochrome P-450 isozymes involved in the metabolism of warfarin sodium include 2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. 2C9 is likely to be the principal form of human liver P-450 which modulates the in vivo anticoagulant activity of warfarin sodium.

Excretion: The terminal half-life of warfarin sodium after a single dose is approximately one week; however, the effective half-life ranges from 20 to 60 hours, with a mean of about 40 hours. The clearance of R- warfarin sodium is generally half that of S-warfarin sodium, thus as the volumes of distribution are similar, the half-life of R-warfarin sodium is longer than that of S-warfarin sodium. The half-life of R-warfarin sodium ranges from 37 to 89 hours, while that of S-warfarin sodium 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 sodium is excreted unchanged in urine. Urinary excretion is in the form of metabolites.

Elderly: There are no significant age-related differences in the pharmacokinetics of racemic warfarin sodium. Limited information suggests that there is no difference in the clearance of S-warfarin sodium in elderly versus young subjects. However, there may be a slight decrease in the clearance of R-warfarin sodium in the elderly compared to the young. Older patients (60 years or older) appear to exhibit greater than expected PT/INR response to the anticoagulant effects of warfarin sodium. As patient age increases, less warfarin sodium is required to produce a therapeutic level of anticoagulation. The cause of the increased responsiveness to warfarin sodium is not known.

Renal Dysfunction: Renal clearance is considered to be a minor determinant of anticoagulant response to warfarin sodium. No dosage adjustment is necessary for patients with renal failure.

Hepatic Dysfunction: Hepatic dysfunction can potentiate the response to warfarin sodium through impaired synthesis of clotting factors and decreased metabolism of warfarin sodium.

The administration of warfarin sodium 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 sodium may not be achieved until 72-96 hours after dosing, indicating that the administration of IV warfarin sodium should not provide any increased biological effect or earlier onset of action.

Mechanical and Bioprosthetic Heart Valves

In a prospective, randomized, open label, positive-controlled study (Mok, et al, 1985) in 254 patients, the thromboembolic-free interval was found to be significantly greater in patients with mechanical prosthetic heart valves treated with warfarin sodium alone compared with dipyridimole-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 (Saour, et al, 1990) comparing moderate (INR 2.65) vs. high intensity (INR 9.0) warfarin sodium 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.

In a randomized trial (Turpie, et al, 1988) in 210 patients comparing two intensities of warfarin sodium 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 group.

CLINICAL STUDIES

Atrial Fibrillation (AF): In five prospective randomized controlled clinical trials involving 3711 patients with nonrheumatic AF, warfarin sodium significantly reduced the risk of systemic thromboembolism including stroke (See TABLE 1) 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 1) Meta-analysis findings of these studies revealed that the effects of warfarin sodium 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.

Myocardial Infarction: WARIS (The Warfarin Sodium Re-Infarction Study) was a double-blind, randomized study of 1214 patients 2 to 4 weeks post- infarction treated with warfarin sodium to a target INR of 2.8 to 4.8. (But note that a lower INR was achieved and increased bleeding was associated with INR's above 4.0; see 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:

INDICATIONS

Warfarin sodium is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, and pulmonary embolism.

Warfarin sodium is indicated for the prophylaxis and/or treatment of the thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement.

Warfarin sodium is indicated to reduce the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic embolization after myocardial infarction.

DOSAGE AND ADMINISTRATION

The dosage and administration of warfarin sodium 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. (See Laboratory Control below for full discussion on INR.)

Venous Thromboembolism (including pulmonary embolism): Available clinical evidence indicates that an INR or 2.0-3.0 is sufficient for prophylaxis and treatment of venous thromboembolism and minimizes the risk of hemorrhage associated with higher INRs.

Atrial Fibrillation: Five recent clinical trials evaluated the effects of warfarin sodium in patients with nonvalvular atrial fibrillation (AF). Meta-analysis findings of these studies revealed that the effects of warfarin sodium 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. The trials in non-valvular atrial fibrillation support the American College of Chest Physicians' (ACCP) recommendation that an INR of 2.0-3.0 be used for long term warfarin sodium therapy in appropriate AF patients.

Post-Myocardial Infarction: In post-myocardial infarction patients, warfarin sodium therapy should be initiated early (2-4 weeks post-infarction) and dosage should be adjusted to maintain an INR of 2.5-3.5 long-term. The recommendation is based on the results of the WARIS study in which treatment was initiated 2 to 4 weeks after infarction. In patients thought to be at an increased risk of bleeding complications or on aspirin therapy, maintenance of warfarin sodium therapy at the lower end of the INR range is recommended.

Mechanical and Bioprosthetic Heart Valves: In patients with mechanical heart valves, long term prophylaxis with warfarin sodium to an INR of 2.5-3.5 is recommended. In patients with bioprosthetic heart valves, based on limited data, the American College of Chest Physicians recommends warfarin sodium therapy to an INR of 2.0-3.0 for 12 weeks after valve insertion. In patients with additional risk factors such as atrial fibrillation or prior thromboembolism, consideration should be given for longer term therapy.

Recurrent Systemic Embolism: 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 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 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. Low initiation doses are recommended for elderly and/or debilitated patients and patients with potential to exhibit greater than expected PT/INR response to warfarin sodium (See PRECAUTIONS). It is recommended that warfarin sodium therapy be initiated with a dose of 2 to 5 mg per day with dosage adjustments based on the results of PT/INR determinations.

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 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 warfarin sodium persists beyond 24 hours. If the patient forgets to take the prescribed dose of warfarin sodium 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.

Intravenous Route of Administration: Warfarin sodium for injection provides an alternate administration route for patients who cannot receive oral drugs. The I.V. dosages would be the same as those that would be used orally if the patient could take the drug by the oral route. Warfarin sodium for injection should be administered as a bolus injection over 1 to 2 minutes into a peripheral vein. It is not recommended for intramuscular administration. The vial should be reconstituted with 2.7 mL of sterile Water for Injection and inspected for particulate matter and/or discoloration immediately prior to use. Do not use if either particulate matter and/or discoloration is noted. After reconstitution, warfarin sodium for injection is chemically and physically stable for 4 hours at room temperature. It does not contain any antimicrobial preservative and, thus, care must be taken to assure the sterility of the prepared solution. The vial is not recommended for multiple use and unused solution should be discarded.

Laboratory Control

The PT reflects the depression of Vitamin K dependent Factors VII, X, and II. There are several modifications of the one-stage PT and the physician should become familiar with the specific method used in his laboratory. 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 base don the experience of each laboratory. 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 judgement of the patient's reliability and response to warfarin sodium 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 test are done when other warfarin sodium products are interchanged with warfarin sodium and also if other medications are coadministered with warfarin sodium (See PRECAUTIONS).

Different thromboplastin reagents vary substantially in their sensitivity to warfarin sodium-induced effects on PT. 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 reagent prepared from human brain.

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. The INR system of reporting is based on a logarithmic relationship between the PT ratios of the test and reference preparation. The INR is the PT ratio that would be obtained if the International Reference Preparation (IRP), which has an ISI of 1.0 were used to perform the test. Early clinical studies of oral anticoagulants, which formed the basis for recommended therapeutic ranges of 1.5 to 2.5 times control mean normal 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 INR can be calculated as:

where the ISI (International Sensitivity Index) is the correction factor in the equation that relates the PT ratio of the local reagent to the reference preparation and is a measure of the sensitivity of a given thromboplastin to reduction of Vitamin K ¾dependent coagulation factors; the lower the ISI, the more sensitive the reagent and the closer the derived INR will be to the observed PT ratio ¹

The proceedings and recommendations of the 1992 National Conference on Antithrombotic Therapy ^2-4 review and evaluate issues related to oral anticoagulant therapy and the sensitivity of thromboplastin reagents and provide additional guidelines for defining the appropriate therapeutic regimen.

The conversion of the INR to PT ratios for the less intense (INR 2.0-3.0) and more intense (INR 2.5-3.5) therapeutic range recommended by the ACCP for thromboplastins over a range of ISI values shown in TABLE 3.⁵

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/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 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 and accessible 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. Some dental or surgical procedures may necessitate the interruption of warfarin sodium therapy. When discontinuing warfarin sodium 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 is delayed, heparin is preferred initially for rapid anticoagulation. Conversion to warfarin sodium 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 the warfarin sodium therapy be overlapped with heparin for 4 to 5 days, until warfarin sodium has produced the desired therapeutic response as determined by PT/INR . When warfarin sodium has produced the desired PT/INR, heparin may be discontinued.

Warfarin sodium may increase the aPTT test. During initial therapy with warfarin sodium, the interference with heparin anticoagulation is of minimal clinical significance. As heparin may affect the PT/INR, patients receiving both heparin and warfarin sodium should have blood for PT ratio/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.

HOW SUPPLIED

Tablets: For oral use, single scored, imprinted numerically and packaged in bottles of 30, 100, 1000 and Hospital Blister Packs of 100.

Coumadin oral tablets are available in 1, 2, 2-1/2, 4, 5, 7-1/2, and 10 mg of crystalline warfarin sodium with one face inscribed with the word COUMADIN, single scored and imprinted numerically with the 1, 2, 2-1/2, 4, 5, 7-1/2, or 10 superimposed, and on the other face inscribed with the word „DuPont.„

Protect from Light. Store in carton until contents have been used. Store at controlled room temperature (59°-86°F, 15°-30° C). Dispense in a tight, light resistant container as defined in the USP.

Injection: Available for intravenous use only. Not recommended for intramuscular administration. Reconstitute with 2.7 mL of sterile Water for Injection to yield 2 mg/mL. Net contents 5.4 mg lyophilized powder. Maximum yield 2.5 mL.

Protect from light. Keep vial in box until used. Store at controlled room temperature (59°-86°F, 15°-30° C)

After reconstitution, store at controlled room temperature (59°-86°F, 15°-30° C) and use within 4 hours. Do not refrigerate. Discard any unused solution.

REFERENCES

1. Poller, L. : Laboratory Control of Anticoagulant Therapy. Seminars in Thrombosis and Hemostasis, Vol. 12, No.1, pp. 13-19, 1986.

2. Hirsh, J.: Is the Dose of Warfarin Sodium Prescribed by American Physicians Unnecessarily High? Arch Int Med, Vol. 147, pp. 769- 771, 1987.

3. Cook, D.J., Guyatt, H.G., Laupacis, A., Sackett, D.L.: Rules of Evidence and CLinical Recommendations on the Use of Antithrombotic Agents. Chest ACCP Consensus Conference on Antithrombotic Therapy. Chest, Vol. 12, (Suppl), pp.305S-311S, 1992

4. Hirsh, J., Dalen, J., Deykin, D., Poller, L.: Oral Anticoagulants Mechanism of Action. Clinical Effectiveness, and Optimal Therapeutic Range. Chest ACCP Consensus Conference on Antithrombotic Therapy. Chest, Vol.102 (Suppl), pp.312S-326S, 1992

5. Hirsh, J., M.D., F.C.C.P.: Hamilton Civic Hospitals Research Center, Hamilton, Ontario, Personal Communication.

SIDE EFFECTS

Potential Adverse Reactions To Warfarin Sodium May Include

Fatal or nonfatal hemorrhage from any tissue or organ: This is a consequence of the anticoagulant effect. The signs, symptoms, and severity will vary according to the location and degree or extent of the bleeding. Hemorrhagic complications may present as paralysis; paresthesia; headache, chest, abdomen, joint, muscule, or other pain; dizziness, shortness of breath, difficult breathing or swallowing; unexplained swelling; weakness; hypotension; 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 PT/INR . (See 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 reactions, systemic cholesterol microembolization, purple toes syndrome, vasculitis, hepatitis, cholestatic hepatic injury, jaundice, elevated liver enzymes, fever, dermatitis, including bullous eroptions, urticaria, abdominal pain including cramping, asthenia, nausea, vomiting, diarrhea, headache, pruritis, alopecia, and paresthesia.

Rare events of tracheal or tracheobronchial calcification have been reported in association with long-term warfarin sodium therapy. The clinical significance of this event is unknown.

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

DRUG INTERACTIONS

No information provided.

WARNINGS

The most serious risks associated with anticoagulant therapy with sodium warfarin sodium are hemorrhage in any tissue or organ and, less frequently(0.1%), 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 sodium therapy should be discontinued when warfarin sodium 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) 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 sodium are administered concomitantly, refer below to CONVERSION FROM HEPARIN THERAPY for recommendations.

Caution should be observed when warfarin sodium 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 sodium 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 sodium 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 stimulating 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 sodium 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.

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.

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: Warfarin sodium appears in the milk of nursing mothers in an inactive form. Infants nursed by warfarin sodium treated mothers had no change in prothrombin times (PTs). 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 Mediated Anticoagulant Response: Hereditary or acquired deficiencies of protein C or its cofactor, protein S, have been associated with tissue necrosis following warfarin sodium administration. (Tissue necrosis may occur in the absence of protein C deficiency). 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 reaction, 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 concurrent anticoagulation therapy with heparin for 5 to 7 days during initiation of therapy with warfarin sodium may minimize the incidence of tissue necrosis. Warfarin sodium therapy should be discontinued when warfarin sodium is suspected to be the cause of developing necrosis and heparin therapy may be considered for anticoagulation.

Miscellaneous: polycythemia vera, vasculitis, severe diabetes

Minor and severe allergic/hypersensitivity reactions and anaphylactic reactions have been reported.

In patients with acquired or inherited warfarin sodium resistance, decreased therapeutic responses to warfarin sodium have been reported. Exaggerated therapeutic responses have been reported in other patients.

Patients with congestive heart failure may exhibit greater than expected PT/INR response to warfarin sodium, thereby requiring more frequent laboratory monitoring, and reduced doses of warfarin sodium.

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

PRECAUTIONS

General

Periodic determination of PT/INR 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. It is generally good practice to monitor the patient's response with additional PT determinations in the period immediately after discharge from the hospital, and whenever other medications are initiated, discontinued or taken irregularly. The following factors are listed for reference; however, other factors may also affect the anticoagulant response.

Drugs may interact with warfarin sodium through pharmacodynamic or pharmacokinetic mechanisms. Pharmacodynamic mechanisms for drug interactions with warfarin sodium are synergism (impaired hemostasis, reduced clotting factor synthesis), competitive antagonism (Vitamin K), and altered physiological control loop for vitamin K metabolism (hereditary resistance). Pharmacokinetic mechanisms for drug interactions with warfarin sodium are mainly enzyme induction, enzyme inhibition, and reduced plasma protein binding. It is important to note that some drugs may interact by more than one mechanism.

The following factors, alone or in combination, may be responsible for INCREASED PT/INR response:

Endogenous Factors:

Blood Dyscrasias: See CONTRAINDICATIONS
Cancer
Collagen Vascular Disease
Congestive Heart Failure
Diarrhea
Elevated Temperature
Hepatic Disorders
Infectious Hepatitis
Jaundice
Hyperthyroidism
Poor Nutritional State
Steatorrhea
Vitamin K Deficiency

Exogenous Factors: Potential drug interactions with warfarin sodium are listed below by drug class and by specific drugs.

Classes of Drugs:
Adrenergic Stimulants, Central
Alcohol Abuse Reduction Preparations
Analgesics
Anesthetics, Inhalation
Antiarrhythmics
Antibiotics:
Aminoglycosides (oral)
Cephalosporins, paternal
Macrolides
Miscellaneous
Penicillins, intravenous, high dose
Sulfonamides, long acting
Tetracyclines
Anticoagulants
Anticonvulsants‡
Antidepressants‡
Antimalarial Agents
Antineoplastics‡
Antiparasitic/Antimicrobials
Antiplatelet Drugs/Effects
Antithyroid Drugs
Beta-Adrenergic Blockers
Bromelains
Cholelitholytic Agents
Diabetes Agents, Oral
Diuretics‡
Fungal medications, Systemic‡
Gastric Acidity and Peptic Ulcer Agents ‡
Gastrointestinal, Ulcerative ColitisAgents
Gout Treatment Agents
Hemorrheologic Agents
Hepatotoxic Drugs
Hyperglycemic Agents
Hypertensive Emergency Agents
Hypnotics‡
Monoamine Oxidase Inhibitors
Narcotics, prolonged
Non-steroidal Anti-inflammatory Agents
Pyschostimulants
Pyrazolones
Salicylates
Steroids, Adrenocortical ‡
Steroids, Anabolic (17-Alkyl Testosterone Derivatives)
Thrombolytics
Thyroid Drugs
Tuberculosis Agents‡
Uricsuric Agents
Vaccines
Vitamins‡
Specific Drugs Reported:
Acetaminophen
Alcohol‡
Allopurinol
Aminosalicylic Acid
Aminodarone HCl
Aspirin
Cefamandole
Cefazolin
Cefoperazone
Cefotetan
Cefoxitin
Ceftriaxone
Chenodiol
Chloramphenicol
Chloral Hydrate‡
Chlorpropamide
Cholestyramine‡
Cimetidine
Ciprofloxacin
Clarithromycin
Clofibrate
Coumadin Overdose
Cyclophosphamide‡
Danazol
Dextran
Dextrothyroxine
Diazoxide
Diclofenac
Dicumarol
Diflunsial
Disulfiram
Doxycycline
Erthromycin
Ethacrynic Acid
Fenoprofen
Fluconazole
Fluorouracil
Glucagon
Halothane
Heparin
Ibuprofen
Ifosamide
Indomethacin
Influenza Virus Vaccine
Itraconazole
Ketoprofen
Ketorolac
Levamisole
Levothyroxine
Liothyronine
Lovastatin
Mefenamic
Methimazole‡
Methyldopa
Methylphenidate
Methylsalicylate Ointment (Topical)
Miconazole
Moricizine HCl‡
Nalidixic Acid
Naproxen
Neomycin
Norfloxacin
Ofloxacin
Olsalazine
Omeprazole
Oxaprozin
Oxymetholone
Paroxetine
Penicillin G, intravenous
Pentoxifylline
Phenylbutazone
Phenytoin‡
Piperacillin
Piroxicam
Prednisone‡
Propafenone
Propoxyphene
Propranolol
Propylthiouracil‡
Quinidine
Quinine
Ranitidine‡
Sertaline
Simvastatin
Stanozolol
Streptokinase
Sulfamethizole
Sulfamethoxazole
Sulfinpyrazone
Sulfisoxazole
Sulindac
Tamoxifen
Tetracycline
Thyroid
Ticacillin
Ticlopidine
Tissue Plasminogen Activator (t-PA)
Tolbutamide
Trimethoprim/Sulfamethoxazole
Urokinase
Valproate
Vitamin E

‡ Increased and decreased PT/INR responses have been reported.

Other Factors Affecting Blood Elements Which May Modify Hemostasis: dietary deficiencies; prolonged hot weather; unreliable PT/INR determinations

The following factors, alone or in combination, may be responsible for DECREASED PT response :

Endogenous Factors:

Edema
Hereditary Warfarin Resistance
Hyperlipemia
Hypothyroidism
Nephrotic Syndrome

Exogenous Factors: Potential drug interactions with warfarin sodium are listed below by drug class and by specific drugs.

Classes of Drugs:
Adrenal Cortical Steroid Inhibitors
Antacids
Antianxiety Agents
Antiarrhythmics‡
Antibiotics‡
Anticonvulsants‡
Antidepressants‡
Antineoplastics‡
Antipsychotic Medications
Antithyroid Drugs‡
Barbiturates
Diuretics‡
Enteral Nutritional Supplments
Fungal Medications, Systemic
Gastric Acidity and Peptic Ulcer Agents‡
Hypnotics‡
Hypolipidemics‡
Immunosuppressives
Oral Contraceptives, Estrogen Containing
Steroids, Adrenocortical‡
Tuberculosis Agents‡
Vitamins‡
Specific Drugs Reported:
Alcohol‡
Aminoglutethimide
Amobarbital
Azathioprine
Butabarbital
Butalbital
Carbamazepine
Chloral Hydrate
Chlordiazepoxide
Chlorthalidone
Cholestyramine‡
Corticotropin
Cortisone
Coumadin Underdosage
Cyclophosphamide‡
Dicloxaxillin
Ethchlorvynol
Glutethimide
Griseofulvin
Haloperidol
Meprobamate
Methimazole‡
Moricizine HCl‡
Nafcillin
Paraldehyde
Pentobarbital
Phenobarbital
Phenytoin‡
Phenytoin‡
Phenytoin‡
Prednisone‡
Primidone
Propylthiouracil‡
Ranitidine‡
Rifampin
Secobarbital
Spironolactone
Sucralfate
Trazodone
Vitamin C (High Dose)
Vitamin K

Also: Diet high in in vitamin K and unreliable PT/INR determinations.

‡ Increased and decreased PT/INR responses have been reported.

Because a patient may be exposed to a combination of the above factors, the net effect of warfarin sodium 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 monitoring is advisable.

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

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.

Special Risk Patients: Warfarin sodium is a narrow therapeutic range (index) drug, and caution should be observed when warfarin sodium is administered to certain patients such as the elderly or debilitated or when administered in any situation or physical condition where added risk of hemorrhage is present.

Intramuscular (IM) 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 sodium 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, NSAIDS, including aspirin, can inhibit platelet aggregation, and can cause gastrointestinal bleeding, peptic ulceration and/or perforation.

Acquired or inherited warfarin sodium resistance should be suspected if large daily doses of warfarin sodium are required to maintain a patient's PT/INR within a normal therapeutic range.

Information for the Patient

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, except on advice of physician. Avoid alcohol consumption. Do not take warfarin sodium 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 the physician or clinic are needed to monitor therapy. If the prescribed dose of warfarin sodium therapy 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 sodium the next day in order to make up for the missed doses. The amount of Vitamin K in food may affect therapy with warfarin sodium. 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. Contact the physician if any illness, such as diarrhea, infection or fever develops. 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 wflow or vaginal bleeding, nosebleeds or bleeding of gums from brushing, unusual bleeding, bruising, red or dark brown urine, red or tar black stools, headache, dizziness, or weakness. If therapy with warfarin sodium is discontinued, patients should be cautioned that the anticoagulant effects of warfarin sodium may persist for about 2 to 5 days.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenicity and mutagenicity studies have not been performed with warfarin sodium. The reproductive effects of warfarin sodium have not been evaluated.

Pregnancy Category X

See CONTRAINDICATIONS.

Pediatric Use

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 sodium 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 sodium requirements.