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Warfarin Sodium, USP, is an anticoagulant which acts by inhibiting vitamin K- dependent coagulation factors. Chemically, it is 3-((alpha)-acetonylbenzyl)-4-hydroxycoumarin sodium salt and is a racemic mixture of the R and S enantiomers. Crystalline warfarin sodium is an isopropanol clathrate. The crystallization of warfarin sodium virtually eliminates trace impurities present in amorphous warfarin. Its molecular formula is C 19 H 15 NaO 4 and its molecular weight is 330.32 and its structural formula may be represented by the following:
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Crystalline warfarin sodium occurs as a white, odorless, crystalline powder, is discolored by light and is very soluble in water; freely soluble in alcohol; very slightly soluble in chloroform and in ether.
Warfarin Sodium Tablets, USP for oral use also contain:
All strengths: Anhydrous lactose, corn starch and magnesium stearate
2 mg: FD&C blue #2 Aluminum Lake, FD&C red #40 Aluminum Lake.
2.5 mg: FD&C blue #2 Aluminum Lake, D&C yellow #10 Aluminum Lake.
3 mg: FD&C blue #2 Aluminum Lake, FD&C red #40 Aluminum Lake, D&C yellow #10 Aluminum Lake.
4 mg: FD&C blue #2 Aluminum Lake.
5 mg: D&C yellow #10 Aluminum Lake, D&C red #6 Barium Lake.
6 mg: D&C yellow #10 Aluminum Lake, FD&C blue #2 Aluminum Lake.
7.5 mg: D&C yellow #10 Aluminum Lake.
10 mg: Dye Free
Crystalline 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 (gamma)-carboxyglutamic acid residues in the proteins which are essential for biological activity. Warfarin is thought to interfere with clotting factor synthesis by inhibition of the regeneration of vitamin K 1 epoxide. The degree of depression is dependent upon the dosage administered. Therapeutic doses of warfarin decrease the total amount of the active form of each vitamin K dependent clotting factor made by the liver by approximately 30% to 50%.
An anticoagulation effect generally occurs within 24 hours after drug administration. However, peak anticoagulant effect may be delayed 72 to 96 hours. The duration of action of a single dose of racemic warfarin is 2 to 5 days. The effects of crystalline 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 Crystalline 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: Crystalline 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 solution. Warfarin distributes into a relatively small apparent volume of distribution of about 0.14 liter/kg. A distribution phase lasting 6 to 12 hours is distinguishable after rapid intravenous or oral administration of an aqueous solution. Using a one compartment model, and assuming complete bioavailability, estimates of the volumes of distribution of R- and S-warfarin are similar to each other and to that of the racemate. Concentrations in fetal plasma approach the maternal values, but warfarin has not been found in human milk (see WARNINGS -- Lactation ). Approximately 99% of the drug is bound to plasma proteins.
Metabolism: The elimination of warfarin is almost entirely by metabolism. Crystalline 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 alcohols). The warfarin 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 that have been identified include dehydrowarfarin, two diastereoisomer alcohols, 4- , 6-, 7-, 8- and 10-hydroxywarfarin. The Cytochrome P-450 isozymes involved in the metabolism of warfarin 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.
Excretion The terminal half-life of warfarin 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 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.
Elderly: Patients 60 years or older appear to exhibit greater than expected PT/INR response to the anticoagulant effects of warfarin. The cause of the increased sensitivity to the anticoagulant effects of warfarin in this age group is unknown. This increased anticoagulant effect from warfarin may be due to a combination of pharmacokinetic and pharmacodynamic factors. Racemic warfarin clearance may be unchanged or reduced with increasing age. Limited information suggests there is no difference in the clearance of S-warfarin in the elderly versus young subjects. However, there may be a slight decrease in the clearance of R-warfarin in the elderly as compared to the young. Therefore, as patient age increases, a lower dose of warfarin is usually required to produce a therapeutic level of anticoagulation.
Renal Dysfunction: Renal clearance is considered to be a minor determinant of anticoagulant response to warfarin. No dosage adjustment is necessary for patients with renal failure.
Hepatic Dysfunction: Hepatic dysfunction can potentiate the response to warfarin through impaired synthesis of clotting factors and decreased metabolism of warfarin.
Atrial Fibrillation (AF): In five prospective randomized controlled clinical trials involving 3711 patients with nonrheumatic AF, warfarin 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 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.
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Myocardial Infarction: WARIS (The Warfarin Re-Infarction Study) was a double-blind, randomized study of 1214 patients 2 to 4 weeks post-infarction treated with warfarin to a target INR of 2.8 to 4.8. (But note that a lower INR was achieved and increased bleeding was associated with INRs 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:
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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 alone compared with dipyridamole-aspirin (p<0.005) and pentoxifylline-aspirin (p<0.05) treated patients. Rates of thromboembolic events in these groups were 2.2, 8.6, and 7.9/100 patient years, respectively. Major bleeding rates were 2.5, 0.0, and 0.9/100 patient years, respectively.
In a prospective, open label, clinical trial (Saour et al, 1990) comparing moderate (INR 2.65) vs. high intensity (INR 9.0) warfarin therapies in 258 patients with mechanical prosthetic heart valves, thromboembolism occurred with similar frequency in the two groups (4.0 and 3.7 events/100 patient years, respectively). Major bleeding was more common in the high intensity group (2.1 events/100 patient years) vs. 0.95 events/100 patient years in the moderate intensity group.
In a randomized trial (Turpie et al, 1988) in 210 patients comparing two intensities of warfarin therapy (INR 2.0-2.25 vs. INR 2.5-4.0) for a three month period following tissue heart valve replacement, thromboembolism occurred with similar frequency in the two groups (major embolic events 2.0% vs. 1.9%, respectively and minor embolic events 10.8% vs. 10.2%, respectively). Major bleeding complications were more frequent with the higher intensity (major hemorrhages 4.6%) vs. none in the lower intensity.
Warfarin sodium tablets, USP are indicated for the prophylaxis and/or treatment of venous thrombosis and its extension and pulmonary embolism.
Warfarin sodium tablets, USP are indicated for the prophylaxis and/or treatment of the thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement.
Warfarin sodium tablets, USP are indicated to reduce the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic embolization after myocardial infarction.
Anticoagulation is contraindicated in any localized or general physical condition or personal circumstance in which the hazard of hemorrhage might be greater than the potential clinical benefits of anticoagulation, such as:
Pregnancy Warfarin sodium tablets, USP 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 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 light of those risks.
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, 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.
The most serious risks associated with anticoagulant therapy with 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 therapy should be discontinued when warfarin is suspected to be the cause of developing necrosis and heparin therapy may be considered for anticoagulation. Although various treatments have been attempted, no treatment for necrosis has been considered uniformly effective. See below for information on predisposing conditions. These and other risks associated with anticoagulant therapy must be weighed against the risk of thrombosis or embolization in untreated cases.
It cannot be emphasized too strongly that treatment of each patient is a highly individualized matter. Warfarin, 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) ratio/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 are administered concomitantly, refer below to 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, necrosis and/or gangrene is present.
Anticoagulation therapy with warfarin may enhance the release of atheromatous plaque emboli, thereby increasing the risk of complications from systemic cholesterol microembolization, including the "purple toes syndrome." Discontinuation of warfarin therapy is recommended when such phenomena are observed.
Systemic atheroemboli and cholesterol microemboli can present with a variety of signs and symptoms including purple toes syndrome, livedo reticularis, rash, gangrene, abrupt and intense pain in the leg, foot, or toes, foot ulcers, myalgia, penile gangrene, abdominal pain, flank or back pain, hematuria, renal insufficiency, hypertension, cerebral ischemia, spinal cord infarction, pancreatitis, symptoms simulating polyarteritis, or any other sequelae of vascular compromise due to embolic occlusion. The most commonly involved visceral organs are the kidneys followed by the pancreas, spleen, and liver. Some cases have progressed to necrosis or death.
Purple toes syndrome is a complication of oral anticoagulation characterized by a dark, purplish or mottled color of the toes, usually occurring between 3-10 weeks, or later, after the initiation of therapy with warfarin or related compounds. Major features of this syndrome include purple color of plantar surfaces and sides of the toes that blanches on moderate pressure and fades with elevation of the legs; pain and tenderness of the toes; waxing and waning of the color over time. While the purple toes syndrome is reported to be reversible, some cases progress to gangrene or necrosis which may require debridement of the affected area, or may lead to amputation.
Heparin-induced thrombocytopenia: Warfarin should be used with caution in patients with heparin-induced thrombocytopenia and deep venous thrombosis. Cases of venous limb ischemia, necrosis, and gangrene have occurred in patients with heparin-induced thrombocytopenia and deep venous thrombosis when heparin treatment was discontinued and warfarin therapy was started or continued. In some patients sequelae have included amputation of the involved area and/or death (Warkentin et al, 1997).
A severe elevation (>50 seconds) in activated partial thromboplastin time (aPTT) with a PT/INR ratio 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 appears in the milk of nursing mothers in an inactive form. Infants nursed by mothers treated with warfarin sodium 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 administration. Not all patients with these conditions develop necrosis, and tissue necrosis occurs in patients without these deficiencies. Inherited resistance to activated protein C has been described in many patients with venous thromboembolic disorders but has not yet been evaluated as a risk factor for tissue necrosis. The risk associated with these conditions, both for recurrent thrombosis and for adverse reactions, is difficult to evaluate since it does not appear to be the same for everyone. Decisions about testing and therapy must be made on an individual basis. It has been reported that concurrent anticoagulation therapy with heparin for 5 to 7 days during initiation of therapy with warfarin may minimize the incidence of tissue necrosis. Warfarin therapy should be discontinued when warfarin is suspected to be the cause of developing necrosis and heparin therapy may be considered for anticoagulation.
Miscellaneous: polycythemia vera, vasculitis, and severe diabetes.
Minor and severe allergic/hypersensitivity reactions and anaphylactic reactions have been reported.
In patients with acquired or inherited warfarin resistance, decreased therapeutic responses to warfarin 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.
Concomitant use of anticoagulants with streptokinase or urokinase is not recommended and may be hazardous. (Please note recommendations accompanying these preparations.)
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 patients response with additional PT/INR 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 through pharmacodynamic or pharmacokinetic mechanisms. Pharmacodynamic mechanisms for drug interactions with warfarin are synergism (impaired hemostasis, reduced clotting factor synthesis), competitive antagonism (vitamin K), and altered physiologic control loop for vitamin K metabolism (hereditary resistance). Pharmacokinetic mechanisms for drug interactions with warfarin are mainly enzyme induction, enzyme inhibition, and reduced plasma protein binding. It is important to note that some drugs may interact by more than one mechanism.
The following factors, alone or in combination, may be responsible for INCREASED PT or INR response:
ENDOGENOUS FACTORS:
blood dyscrasias-see Contraindications
diarrhea
elevated temperature
hepatic disorders:
infectious hepatitis
jaundice
poor nutritional state
steatorrhea
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
Antiandrogen
Antiarrhythmics †
Antibiotics †
Aminoglycosides (oral)
Cephalosporins, parenteral
Macrolides
Miscellaneous
Penicillins, intravenous, high dose
Quinolones (fluoroquinolones)
Sulfonamides, long acting
Tetracyclines
Anticoagulants
Anticonvulsants †
Antidepressants †
Antimalarial Agents
Antineoplastics †
Antiparasitic/Antimicrobials
Antiplatelet Drugs/Effects
Antithyroid Drugs †
Beta-Adrenergic Blockers
Bromelains
Cholelitholytic Agents
Diuretics †
Fungal Medications, Systemic †
Gastric Acidity and Peptic Ulcer Agents †
Gastrointestinal
Prokinetic Agents
Ulcerative Colitis Agents
Hemorrheologic Agents
Hepatotoxic Drugs
Herbal Medicines
Hyperglycemic Agents
Hypertensive Emergency Agents
Hypnotics †
Hypolipidemics †
Leukotriene Receptor Antagonist
Narcotics, prolonged
Nonsteroidal Anti-Inflammatory Agents
Psychostimulants
Pyrazolones
Salicylates
Selective Serotonin Reuptake Inhibitors
Steroids, Adrenocortical †
Steroids, Anabolic (17-Alkyl Testosterone Derivatives)
Thrombolytics
Thyroid Drugs
Tuberculosis Agents
Uricosuric Agents
Vaccines
Vitamins †
Specific Drugs Reported
alcohol †
aminosalicylic acid
amiodarone HCl
atorvastatin
azithromycin
cefamandole
cefoperazone
cefotetan
cefoxitin
ceftriaxone
chloral hydrate †
cholestyramine †
ciprofloxacin
cisapride
clarithromycin
cyclophosphamide †
danshen (Chinese herb)
dextrothyroxine
fenofibrate
fenoprofen
fluconazole
fluoxetine
fluvastatin
fluvoxamine
glucagon
heparin
ifosfamide
itraconazole
ketorolac
levothyroxine
liothyronine
lovastatin
methimazole †
methyldopa
methylphenidate
methylsalicylate ointment (topical)
miconazole
moricizine hydrochloride †
naproxen
neomycin
norfloxacin
ofloxacin
olsalazine
oxaprozin
paroxetine
pentoxifylline
phenytoin †
piperacillin
piroxicam
prednisone †
propafenone
propoxyphene
propranolol
propylthiouracil †
quinine
ranitidine †
simvastatin
streptokinase
sulfamethoxazole
sulfisoxazole
tamoxifen
thyroid
ticarcillin
ticlopidine
tissue plasminogen activator (t-PA)
trimethoprim/sulfamethoxazole
valproate
vitamin E
warfarin overdose
zafirlukast
zileuton
also: other medications 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/INR response:
ENDOGENOUS FACTORS:
hereditary coumarin resistance
hyperlipemia
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 Supplements
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 †
atorvastatin
chloral hydrate †
chlordiazepoxide
cholestyramine †
cyclophosphamide †
dicloxacillin
6-mercaptopurine
methimazole †
moricizine hydrochloride †
phenytoin †
prednisone †
propylthiouracil †
ranitidine †
trazodone
vitamin C (high dose)
vitamin K
warfarin underdosage
also: diet high in vitamin K
unreliable PT/INR determinations
Because a patient may be exposed to a combination of the above factors, the net effect of warfarin sodium tablets, USP on PT/INR response may be unpredictable. More frequent PT/INR monitoring is therefore advisable. Medications of unknown interaction with coumarins are best regarded with caution. When these medications are started or stopped, more frequent PT/INR monitoring is advisable.
It has been reported that concomitant administration of warfarin and ticlopidine may be associated with cholestatic hepatitis.
Effect on Other Drugs: Warfarin 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 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 (I.M.) injections of concomitant medications should be confined to the upper extremities which permits easy access for manual compression, inspections for bleeding and use of pressure bandages.
Caution should be observed when warfarin is administered concomitantly with nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, to be certain that no change in anticoagulation dosage is required. In addition to specific drug interactions that might affect PT/INR, NSAIDs, including aspirin, can inhibit platelet aggregation, and can cause gastrointestinal bleeding, peptic ulceration and/or perforation.
Acquired or inherited warfarin resistance should be suspected if large daily doses of warfarin are required to maintain a patients PT/INR within a normal therapeutic range.
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) and other over-the-counter medications except on advice of the physician. Avoid excessive alcohol consumption. Do not take warfarin during pregnancy and do not become pregnant while taking it (see Contraindications ). Avoid any activity or sport that may result in traumatic injury. Prothrombin time tests and regular visits to physician or clinic are needed to monitor therapy. Carry identification stating that warfarin is being taken. If the prescribed dose of warfarin is forgotten, notify the physician immediately. Take the dose as soon as possible on the same day but do not take a double dose of warfarin the next day to make up for missed doses. The amount of vitamin K in food may affect therapy with warfarin. Eat a normal, balanced diet maintaining a consistent amount of vitamin K. Avoid drastic changes in dietary habits, such as eating large amounts of green leafy vegetables. Contact physician to report any illness, such as diarrhea, infection or fever. Notify physician immediately if any unusual bleeding or symptoms occur. Signs and symptoms of bleeding include: pain, swelling or discomfort, prolonged bleeding from cuts, increased menstrual flow or vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or dark brown urine, red or tar black stools, headache, dizziness, or weakness. If therapy with warfarin is discontinued, patients should be cautioned that the anticoagulant effects of warfarin may persist for about 2 to 5 days. Patients should be informed that all warfarin products represent the same medication, and should not be taken concomitantly, as overdosage may result.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity and mutagenicity studies have not been performed with warfarin. The reproductive effects of warfarin have not been evaluated.
Use in Pregnancy: 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 in pediatric patients is well-documented for the prevention and treatment of thromboembolic events. Difficulty achieving and maintaining therapeutic PT/INR ranges in the pediatric patient has been reported. More frequent PT/INR determinations are recommended because of possible changing warfarin requirements.
Geriatric Use: Patients 60 years or older appear to exhibit greater than expected PT/INR response to the anticoagulant effects of warfarin (see CLINICAL PHARMACOLOGY ). Warfarin is contraindicated in any unsupervised patient with senility. Caution should be observed with administration of warfarin sodium to elderly patients in any situation or physical condition where added risk of hemorrhage is present. Low initiation doses of warfarin are recommended for elderly patients (see DOSAGE AND ADMINISTRATION ).
Potential adverse reactions to warfarin may include:
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.
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.
Treatment: Excessive anticoagulation, with or without bleeding, may be controlled by discontinuing warfarin therapy and if necessary, by administration of oral or parenteral vitamin K 1 . (Please see recommendations accompanying vitamin K 1 preparations prior to use.)
Such use of vitamin K 1 reduces response to subsequent warfarin therapy. Patients may return to a pretreatment thrombotic status following the rapid reversal of a prolonged PT/INR. Resumption of warfarin administration reverses the effect of vitamin K, and a therapeutic PT/INR can again be obtained by careful dosage adjustment. If rapid anticoagulation is indicated, heparin may be preferable for initial therapy.
If minor bleeding progresses to major bleeding, give 5 to 25 mg (rarely up to 50 mg) parenteral vitamin K 1 . In emergency situations of severe hemorrhage, clotting factors can be returned to normal by administering 200 to 500 mL of fresh whole blood or fresh frozen plasma, or by giving commercial Factor IX complex.
A risk of hepatitis and other viral diseases is associated with the use of these blood products; Factor IX complex is also associated with an increased risk of thrombosis. Therefore, these preparations should be used only in exceptional or life-threatening bleeding episodes secondary to warfarin overdosage.
Purified Factor IX preparations should not be used because they cannot increase the levels of prothrombin, Factor VII and Factor X which are also depressed along with the levels of Factor IX as a result of warfarin treatment. Packed red blood cells may also be given if significant blood loss has occurred. Infusions of blood or plasma should be monitored carefully to avoid precipitating pulmonary edema in elderly patients or patients with heart disease.
The dosage and administration of warfarin sodium tablets, USP must be individualized for each patient according to the particular patients PT/INR response to the drug. The dosage should be adjusted based upon the patients PT/INR. (See Laboratory Control below for full discussion on INR).
Venous Thromboembolism (including pulmonary embolism): Available clinical evidence indicates that an INR of 2.0-3.0 is sufficient for prophylaxis and treatment of venous thromboembolism and minimizes the risk of hemorrhage associated with higher INRs. In patients, with risk factors for recurrent venous thromboembolism including venous insufficiency, inherited thrombophilia, idiopathic venous thromboembolism, and a history of thrombotic events, consideration should be given to longer term therapy (Schulman et al, 1995 and Schulman et al, 1997).
Atrial Fibrillation: Five recent clinical trials evaluated the effects of warfarin in patients with non-valvular atrial fibrillation (AF). Meta-analysis findings of these studies revealed that the effects of warfarin in reducing thromboembolic events including stroke were similar at either moderately high INR (2.0-4.5) or low INR (1.4-3.0). There was a significant reduction in minor bleeds at the low INR. 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 therapy in appropriate AF patients.
Post-Myocardial Infarction: In post myocardial infarction patients, warfarin sodium tablets, USP 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 the infarction. In patients thought to be at an increased risk of bleeding complications or on aspirin therapy, maintenance of warfarin sodium tablets, USP therapy at the lower end of this INR range is recommended.
Mechanical and Bioprosthetic Heart Valves: In patients with mechanical heart valve(s), long term prophylaxis with warfarin to an INR of 2.5-3.5 is recommended. In patients with bioprosthetic heart valve(s), based on limited data, the American College of Chest Physicians recommends warfarin 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 crystalline 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 tablets, USP (see PRECAUTIONS ). It is recommended that warfarin sodium tablets, USP therapy be initiated with a dose of 2 to 5 mg per day with dosage adjustments based on the results of PT/INR determinations.
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' 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 tablets, USP persists beyond 24 hours. If the patient forgets to take the prescribed dose of warfarin sodium tablets, USP at the scheduled time, the dose should be taken as soon as possible on the same day. The patient should not take the missed dose by doubling the daily dose to make up for missed doses, but should refer back to his or her physician.
Intravenous Route of Administration: Warfarin sodium for injection provides an alternative administration route for patients who cannot receive oral drugs. The IV dosage would be the same as those that would be used orally if the patient could take the drug by the oral route.
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 based on 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' judgment of the patient' reliability and response to warfarin sodium tablets, USP in order to maintain the individual within the therapeutic range. Acceptable intervals for PT/INR determinations are normally within the range of one to four weeks after a stable dosage has been determined. To ensure adequate control, it is recommended that additional PT tests are done when other warfarin products are interchanged with warfarin sodium tablets, USP, as well as whenever other medications are initiated, discontinued, or taken irregularly (see PRECAUTIONS ).
Different thromboplastin reagents vary substantially in their sensitivity to sodium warfarin-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: INR = (observed PT ratio) ISI 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-dependent 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 is shown in Table 3.
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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 tablets, USP to maintain the PT/INR at the low end of the therapeutic range may safely allow for continued anticoagulation. The operative site should be sufficiently limited and accessible to permit the effective use of local procedures for hemostasis. Under these conditions, dental and minor surgical procedures may be performed without undue risk of hemorrhage. Some dental or surgical procedures may necessitate the interruption of warfarin therapy. When discontinuing warfarin even for a short period of time, the benefits and risks should be strongly considered.
CONVERSION FROM HEPARIN THERAPY Since the anticoagulant effect of warfarin sodium tablets, USP is delayed, heparin is preferred initially for rapid anticoagulation. Conversion to warfarin sodium tablets, USP may begin concomitantly with heparin therapy or may be delayed 3 to 6 days. To ensure continuous anticoagulation, it is advisable to continue full dose heparin therapy and that warfarin sodium tablets, USP therapy be overlapped with heparin for 4 to 5 days, until warfarin sodium tablets, USP has produced the desired therapeutic response as determined by PT/INR. When warfarin sodium tablets, USP has produced the desired PT/INR or prothrombin activity, heparin may be discontinued.
Warfarin sodium tablets, USP may increase the aPTT test, even in the absence of heparin. During initial therapy with warfarin sodium tablets, USP, the interference with heparin anticoagulation is of minimal clinical significance.
As heparin may affect the PT/INR, patients receiving both heparin and warfarin sodium tablets, USP should have blood for PT/INR determination drawn at least:
Warfarin Sodium Tablets, USP: For oral use, single scored, imprinted numerically and packaged in bottles with potencies, colors and engravings as follows:
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Warfarin Sodium Tablets, USP are available in 1, 2, 2.5, 3, 4, 5, 6, 7.5 and 10 mg of warfarin sodium, USP. They are flat beveled capsule shaped tablets, scored on one side and engraved, as described in the above table, on the other side.
Protect from light. Store at controlled room temperature 15°-30°C (59°-86°F). Dispense in a tight, light-resistant container as defined in the USP.
Mfd. by:
Taro Pharmaceutical Industries Ltd., Haifa Bay, Israel 26110
Revised: August 1999
89714-0899