Warfarin Sodium 3 MG Oral Tablet
WARNINGS
The most serious risks associated with anticoagulant therapy with warfarin sodium are hemorrhage in any tissue or organ 12 (see BLACK BOX WARNING ) and, less frequently (<0.1%), necrosis and/or gangrene of skin and other tissues.
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 sodium tablets, 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).
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 tablets are administered concomitantly, refer below to CONVERSION FROM HEPARIN THERAPY for recommendations.
Increased caution should be observed when warfarin sodium tablets are administered in the presence of any predisposing condition where added risk of hemorrhage, necrosis, and/or gangrene is present.
Anticoagulation therapy with warfarin sodium tablets 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 tablets 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.
Warfarin sodium tablets 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.
13 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 Based on very limited published data, warfarin has not been detected in the breast milk of mothers treated with warfarin.
The same limited published data report that some breast-fed infants, whose mothers were treated with warfarin, had prolonged prothrombin times, although not as prolonged as those of the mothers.
The decision to breast-feed should be undertaken only after careful consideration of the available alternatives.
Women who are breast-feeding and anticoagulated with warfarin should be very carefully monitored so that recommended PT/INR values are not exceeded.
It is prudent to perform coagulation tests and to evaluate vitamin K status in infants before advising women taking warfarin to breast-feed.
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 concomitant anticoagulation therapy with heparin for 5 to 7 days during initiation of therapy with warfarin sodium tablets 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.
DRUG INTERACTIONS
Drug/Drug and Drug/Disease Interactions It is generally good practice to monitor the patient’s response with additional PT/INR determinations in the period immediately after discharge from the hospital, and whenever other medications, including botanicals, 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 tablets through pharmacodynamic or pharmacokinetic mechanisms.
Pharmacodynamic mechanisms for drug interactions with warfarin sodium tablets 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 sodium tablets 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 — diarrhea hyperthyroidism see CONTRAINDICATIONS elevated temperature poor nutritional state cancer hepatic disorders steatorrhea collagen vascular disease infectious hepatitis vitamin K deficiency congestive heart failure jaundice EXOGENOUS FACTORS: Potential drug interactions with warfarin sodium tablets are listed below by drug class and by specific drugs.
Classes of Drug also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations 5-lipoxygenase Inhibitor Antiplatelet Drugs/Effects Leukotriene Receptor Antagonist Adrenergic Stimulants, Central Antithyroid Drugs † Monoamine Oxidase Inhibitors Alcohol Abuse Reduction Beta-Adrenergic Blockers Narcotics, prolonged Preparations Cholelitholytic Agents Nonsteroidal Anti- Analgesics Diabetes Agents, Oral Inflammatory Agents Anesthetics, Inhalation Diuretics † Proton Pump Inhibitors Antiandrogen Fungal Medications, Psychostimulants Antiarrhythmics † Intravaginal, Systemic † Pyrazolones Antibiotics † Gastric Acidity and Peptic Salicylates Aminoglycosides (oral) Ulcer Agents † Selective Serotonin Cephalosporins, parenteral Gastrointestinal Reuptake Inhibitors Macrolides Prokinetic Agents Steroids, Adrenocortical † Miscellaneous Ulcerative Colitis Agents Steroids, Anabolic (17-Alkyl Penicillins, intravenous, Gout Treatment Agents Testosterone Derivatives) high dose Hemorrheologic Agents Thrombolytics Quinolones (fluoroquinolones) Hepatotoxic Drugs Thyroid Drugs Sulfonamides, long acting Hyperglycemic Agents Tuberculosis Agents † Tetracyclines Hypertensive Emergency Agents Uricosuric Agents Anticoagulants Hypnotics † Vaccines Anticonvulsants † Hypolipidemics † Vitamins † Antidepressants † Bile Acid-Binding Resins † Antimalarial Agents Fibric Acid Derivatives Antineoplastics † HMG-CoA Reductase Inhibitors † Antiparasitic/Antimicrobials Specific Drugs Reported acetaminophen fenoprofen paroxetine alcohol Increased and decreased PT/INR responses have been reported.
fluconazole penicillin G, intravenous allopurinol fluorouracil pentoxifylline aminosalicylic acid fluoxetine phenylbutazone amiodarone HCl flutamide phenytoin argatroban fluvastatin piperacillin aspirin fluvoxamine piroxicam atenolol gefitinib pravastatin atorvastatin gemfibrozil prednisone azithromycin glucagon propafenone bivalirudin halothane propoxyphene capecitabine heparin propranolol cefamandole ibuprofen propylthiouracil cefazolin ifosfamide quinidine cefoperazone indomethacin quinine cefotetan influenza virus vaccine rabeprazole cefoxitin itraconazole ranitidine ceftriaxone ketoprofen rofecoxib celecoxib ketorolac sertraline cerivastatin lansoprazole simvastatin chenodiol lepirudin stanozolol chloramphenicol levamisole streptokinase chloral hydrate levofloxacin sulfamethizole chlorpropamide levothyroxine sulfamethoxazole cholestyramine liothyronine sulfinpyrazone cimetidine lovastatin sulfisoxazole ciprofloxacin mefenamic acid sulindac cisapride methimazole tamoxifen clarithromycin methyldopa tetracycline clofibrate methylphenidate thyroid warfarin sodium overdose methylsalicylate ointment (topical) ticarcillin cyclophosphamide metronidazole ticlopidine danazol miconazole tissue plasminogen dextran (intravaginal, oral, systemic) activator (t-PA) dextrothyroxine moricizine hydrochloride tolbutamide diazoxide nalidixic acid tramadol diclofenac naproxen trimethoprim/sulfamethoxazole dicumarol neomycin urokinase diflunisal norfloxacin valdecoxib disulfiram ofloxacin valproate doxycycline olsalazine vitamin E erythromycin omeprazole zafirlukast esomeprazole oxandrolone zileuton ethacrynic acid oxaprozin ezetimibe oxymetholone fenofibrate pantoprazole The following factors, alone or in combination, may be responsible for DECREASED PT/INR response: ENDOGENOUS FACTORS: edema hypothyroidism hereditary coumarin resistance nephrotic syndrome hyperlipemia EXOGENOUS FACTORS: Potential drug interactions with warfarin sodium tablets are listed below by drug class and by specific drugs.
Classes of Drugs also: diet high in vitamin K unreliable PT/INR determinations Adrenal Cortical Steroid Inhibitors Antipsychotic Medications Hypolipidemics † Antacids Antithyroid Drugs † Bile Acid-Binding Resins † Antianxiety Agents Antiarrhythmics † Barbiturates Diuretics † HMG-CoA Reductase Inhibitors † Anticonvulsants † Enteral Nutritional Supplements Immunosuppressives Antidepressants † Fungal Medications, Systemic † Oral Contraceptives, Antihistamines Gastric Acidity and Peptic Ulcer Agents † Estrogen Containing Antineoplastics † Hypnotics † Selective Estrogen Receptor Modulators Steroids, Adrenocortical † Tuberculosis Agents † Vitamins † Specific Drugs Reported: alcohol Increased and decreased PT/INR responses have been reported.
warfarin sodium underdosage phenytoin aminoglutethimide cyclophosphamide pravastatin amobarbital dicloxacillin prednisone atorvastatin ethchlorvynol primidone azathioprine glutethimide propylthiouracil butabarbital griseofulvin raloxifene butalbital haloperidol ranitidine carbamazepine meprobamate rifampin chloral hydrate 6-mercaptopurine secobarbital chlordiazepoxide methimazole spironolactone chlorthalidone moricizine hydrochloride sucralfate cholestyramine nafcillin trazodone clozapine paraldehyde vitamin C (high dose) corticotropin pentobarbital vitamin K cortisone phenobarbital Because a patient may be exposed to a combination of the above factors, the net effect of warfarin sodium tablets 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.
OVERDOSAGE
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 sodium tablets therapy and if necessary, by administration of oral or parenteral vitamin K 1.
(Please see recommendations accompanying vitamin K 1 preparations prior to use.) 15, 16 Such use of vitamin K 1 reduces response to subsequent warfarin sodium tablets therapy.
Patients may return to a pretreatment thrombotic status following the rapid reversal of a prolonged PT/INR.
Resumption of warfarin sodium 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 sodium overdosage.
Purified Factor IX preparations should not be used because they cannot increase the levels of prothrombin, Factor VII and Factor X which are also depressed along with the levels of Factor IX as a result of warfarin sodium tablets 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.
DESCRIPTION
Warfarin sodium tablet (crystalline warfarin sodium) is an anticoagulant, which acts by inhibiting vitamin K-dependent coagulation factors.
Chemically, it is 3-(α-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.
Its molecular formula is C 19 H 15 NaO 4 , and its structural formula may be represented by the following: Crystalline warfarin sodium occurs as a white crystalline powder, odorless or practically odorless.
Each warfarin sodium tablet intended for oral administration contains warfarin sodium clathrates equivalent to 1 mg or 2 mg or 2.5 mg or 3 mg or 4 mg or 5 mg or 6 mg or 7.5 mg or 10 mg of warfarin sodium.
In addition each tablet contains the inactive ingredients hydroxypropyl cellulose, lactose monohydrate, magnesium stearate and pregelatinized starch.
Additionally each 1 mg tablet contains D&C red no.
6 barium lake, 2 mg tablet contains FD&C blue no.
2 aluminum lake and FD&C red no.
40 aluminum lake, 2.5 mg tablet contains D&C yellow no.
10 aluminum lake and FD&C blue no.
1 aluminum lake, 3 mg tablet contains FD&C yellow no.
6 aluminum lake, FD&C blue no.
2 aluminum lake and FD&C red no.
40 aluminum lake, 4 mg tablet contains FD&C blue no.
1 aluminum lake, 5 mg tablet contains FD&C yellow no.
6 aluminum lake, 6 mg tablet contains FD&C yellow no.
6 aluminum lake and FD&C blue no.
1 aluminum lake, 7.5 mg tablet contains D&C yellow no.
10 aluminum lake and FD&C yellow no.6 aluminum lake and 10 mg tablet is dye free.
Chemical Structure
HOW SUPPLIED
Warfarin Sodium Tablets, 1 mg are pink, oval, flat, beveled edge, uncoated tablets debossed with the logo of ‘WAR’, ‘1’ and bisect on one side and plain on other side and are supplied as follows: Warfarin Sodium Tablets, 2 mg are lavender, oval, flat, beveled edge, uncoated tablets debossed with the logo of ‘WAR’, ‘2’ and bisect on one side and plain on other side and are supplied as follows: Warfarin Sodium Tablets, 2.5 mg are green, oval, flat, beveled edge, uncoated tablets debossed with the logo of ‘WAR’, ‘2½’ and bisect on one side and plain on other side and are supplied as follows Warfarin Sodium Tablets, 3 mg are tan, oval, flat, beveled edge, uncoated tablets debossed with the logo of ‘WAR’, ‘3’ and bisect on one side and plain on other side and are supplied as follows: Warfarin Sodium Tablets, 4 mg are blue, oval, flat, beveled edge, uncoated tablets debossed with the logo of ‘WAR’, ‘4’ and bisect on one side and plain on other side and are supplied as follows: Warfarin Sodium Tablets, 5 mg are peach, oval, flat, beveled edge, uncoated tablets debossed with the logo of ‘WAR’, ‘5’ and bisect on one side and plain on other side and are supplied as follows Warfarin Sodium Tablets, 7.5 mg are yellow, oval, flat, beveled edge, uncoated tablets debossed with the logo of ‘WAR’, ‘7½’ and bisect on one side and plain on other side and are supplied as follows: Warfarin Sodium Tablets, 10 mg are white to off white, oval, flat, beveled edge, uncoated tablets debossed with the logo of ‘WAR’, ‘10’ and bisect on one side and plain on other side and are supplied as follows: Storage Store at 20° – 25°C (68° – 77°F) [see USP Controlled Room Temperature].
Protect from light.
Dispense in a tight, light-resistant container as defined in the USP.
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 sodium tablets are 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.
Lower initiation and maintenance doses of warfarin sodium tablets are recommended for elderly patients (see DOSAGE AND ADMINISTRATION ).
MECHANISM OF ACTION
Mechanism of Action Warfarin is thought to interfere with clotting factor synthesis by inhibition of the C1 subunit of the vitamin K epoxide reductase (VKORC1) enzyme complex, thereby reducing the regeneration of vitamin K 1 epoxide.
The degree of depression is dependent upon the dosage administered and, in part, by the patient’s VKORC1 genotype.
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 warfarin sodium tablets 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.
INDICATIONS AND USAGE
Warfarin sodium tablets are indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, and pulmonary embolism.
Warfarin sodium tablets are indicated for the prophylaxis and/or treatment of the thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement.
Warfarin sodium tablets are indicated to reduce the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic embolization after myocardial infarction.
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 tablets 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.
PREGNANCY
Use in Pregnancy Pregnancy Category X – see CONTRAINDICATIONS .
BOXED WARNING
WARNING: BLEEDING RISK Warfarin sodium can cause major or fatal bleeding.
Bleeding is more likely to occur during the starting period and with a higher dose (resulting in a higher INR).
Risk factors for bleeding include high intensity of anticoagulation (INR >4.0), age ≥65, highly variable INRs, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, serious heart disease, anemia, malignancy, trauma, renal insufficiency, concomitant drugs (see PRECAUTIONS ) and long duration of warfarin therapy.
Regular monitoring of INR should be performed on all treated patients.
Those at high risk of bleeding may benefit from more frequent INR monitoring, careful dose adjustment to desired INR, and a shorter duration of therapy.
Patients should be instructed about prevention measures to minimize risk of bleeding and to report immediately to physicians signs and symptoms of bleeding (see PRECAUTIONS: Information for Patients ).
INFORMATION FOR PATIENTS
The objective of anticoagulant therapy is to decrease the clotting ability of the blood so that thrombosis is prevented, while avoiding spontaneous bleeding.
Effective therapeutic levels with minimal complications are in part dependent upon cooperative and well-instructed patients who communicate effectively with their physician.
Patients should be advised: Strict adherence to prescribed dosage schedule is necessary.
Do not take or discontinue any other medication, including salicylates (e.g., aspirin and topical analgesics), other over-the-counter medications, and botanical (herbal) products except on advice of the physician.
Avoid alcohol consumption.
Do not take warfarin sodium tablets 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 sodium tablets are being taken.
If the prescribed dose of warfarin sodium tablets 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 tablets the next day to make up for missed doses.
The amount of vitamin K in food may affect therapy with warfarin sodium tablets.
Eat a normal, balanced diet maintaining a consistent amount of vitamin K.
Avoid drastic changes in dietary habits, such as eating large amounts of green leafy vegetables.
You should also avoid intake of cranberry juice or any other cranberry products.
Notify your health care provider if any of these products are part of your normal diet.
Contact physician to report any illness, such as diarrhea, infection or fever.
Notify physician immediately if any unusual bleeding or symptoms occur.
Signs and symptoms of bleeding include: pain, swelling or discomfort, prolonged bleeding from cuts, increased menstrual flow or vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or dark brown urine, red or tar black stools, headache, dizziness, or weakness.
If therapy with warfarin sodium tablets is discontinued, patients should be cautioned that the anticoagulant effects of warfarin sodium tablets may persist for about 2 to 5 days.
Patients should be informed that all warfarin sodium, USP, products represent the same medication, and should not be taken concomitantly, as overdosage may result.
A Medication Guide 14 should be available to patients when their prescriptions for warfarin sodium are issued.
Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity and mutagenicity studies have not been performed with warfarin sodium tablets.
The reproductive effects of warfarin sodium tablets have not been evaluated.
The use of warfarin during pregnancy has been associated with the development of fetal malformation in human (see CONTRAINDICATIONS ).
Use in Pregnancy Pregnancy Category X – see CONTRAINDICATIONS .
DOSAGE AND ADMINISTRATION
The dosage and administration of warfarin sodium tablets 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.
15, 16, 17, 18, 19 The best available information supports the following recommendations for dosing of warfarin sodium tablets.
Venous Thromboembolism (including deep venous thrombosis [DVT] and pulmonary embolism [PE]) For patients with a first episode of DVT or PE secondary to a transient (reversible) risk factor, treatment with warfarin for 3 months is recommended.
For patients with a first episode of idiopathic DVT or PE, warfarin is recommended for at least 6 to 12 months.
For patients with two or more episodes of documented DVT or PE, indefinite treatment with warfarin is suggested.
For patients with a first episode of DVT or PE who have documented antiphospholipid antibodies or who have two or more thrombophilic conditions, treatment for 12 months is recommended and indefinite therapy is suggested.
For patients with a first episode of DVT or PE who have documented deficiency of antithrombin, deficiency of Protein C or Protein S, or the Factor V Leiden or prothrombin 20210 gene mutation, homocystinemia, or high Factor VIII levels (>90 th percentile of normal), treatment for 6 to 12 months is recommended and indefinite therapy is suggested for idiopathic thrombosis.
The risk-benefit should be reassessed periodically in patients who receive indefinite anticoagulant treatment.
12, 20 The dose of warfarin should be adjusted to maintain a target INR of 2.5 (INR range, 2.0 to 3.0) for all treatment durations.
These recommendations are supported by the 7th ACCP guidelines.
15, 17, 21, 22 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.
There are no adequate and well-controlled studies in populations with atrial fibrillation and valvular heart disease.
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’ (7th ACCP) recommendation that an INR of 2.0-3.0 be used for warfarin therapy in appropriate AF patients.
17 Oral anticoagulation therapy with warfarin is recommended in patients with persistent or paroxysmal AF (PAF) (intermittent AF) at high risk of stroke (i.e., having any of the following features: prior ischemic stroke, transient ischemic attack, or systemic embolism, age >75 years, moderately or severely impaired left ventricular systolic function and/or congestive heart failure, history of hypertension, or diabetes mellitus).
In patients with persistent AF or PAF, age 65 to 75 years, in the absence of other risk factors, but who are at intermediate risk of stroke, antithrombotic therapy with either oral warfarin or aspirin, 325 mg/day, is recommended.
For patients with AF and mitral stenosis, anticoagulation with oral warfarin is recommended (7th ACCP).
For patients with AF and prosthetic heart valves, anticoagulation with oral warfarin should be used; the target INR may be increased and aspirin added depending on valve type and position, and on patient factors.
17 Post-Myocardial Infarction The results of the WARIS II study and 7th ACCP guidelines suggest that in most healthcare settings, moderate- and low-risk patients with a myocardial infarction should be treated with aspirin alone over oral vitamin-K antagonist (VKA) therapy plus aspirin.
In healthcare settings in which meticulous INR monitoring is standard and routinely accessible, for both high- and low-risk patients after myocardial infarction (MI), long-term (up to 4 years) high-intensity oral warfarin (target INR, 3.5; range, 3.0 to 4.0) without concomitant aspirin or moderate-intensity oral warfarin (target INR, 2.5; range, 2.0 to 3.0) with aspirin is recommended.
For high-risk patients with MI, including those with a large anterior MI, those with significant heart failure, those with intracardiac thrombus visible on echocardiography, and those with a history of a thromboembolic event, therapy with combined moderate-intensity (INR, 2.0 to 3.0) oral warfarin plus lowdose aspirin (≤100 mg/day) for 3 months after the MI is suggested.
23 Mechanical and Bioprosthetic Heart Valves For all patients with mechanical prosthetic heart valves, warfarin is recommended.
For patients with a St.
Jude Medical (St.
Paul, MN) bileaflet valve in the aortic position, a target INR of 2.5 (range, 2.0 to 3.0) is recommended.
For patients with tilting disk valves and bileaflet mechanical valves in the mitral position, the 7th ACCP recommends a target INR of 3.0 (range, 2.5 to 3.5).
For patients with caged ball or caged disk valves, a target INR of 3.0 (range, 2.5 to 3.5) in combination with aspirin, 75 to 100 mg/day is recommended.
For patients with bioprosthetic valves, warfarin therapy with a target INR of 2.5 (range, 2.0 to 3.0) is recommended for valves in the mitral position and is suggested for valves in the aortic position for the first 3 months after valve insertion.
15 Recurrent Systemic Embolism and Other Indications Oral anticoagulation therapy has not been evaluated by properly designed clinical trials in patients with valvular disease associated with atrial fibrillation, patients with mitral stenosis, and patients with recurrent systemic embolism of unknown etiology.
A moderate dose regimen (INR 2.0 to 3.0) is recommended for these patients.
17 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 tablets 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.
It is recommended that warfarin sodium tablets therapy be initiated with a dose of 2 to 5 mg per day with dosage adjustments based on the results of PT/INR determinations.
17, 18 The lower initiation doses should be considered for patients with certain genetic variations in CYP2C9 and VKORC1 enzymes as well as for elderly and/or debilitated patients and patients with potential to exhibit greater than expected PT/INR responses to warfarin sodium tablets (see CLINICAL PHARMACOLOGY and PRECAUTIONS ).
Maintenance Most patients are satisfactorily maintained at a dose of 2 to 10 mg daily.
Flexibility of dosage is provided by breaking scored tablets in half.
The individual dose and interval should be gauged by the patient’s prothrombin response.
Acquired or inherited warfarin resistance is rare, but should be suspected if large daily doses of warfarin sodium tablets are required to maintain a patient’s PT/INR within a normal therapeutic range.
Lower maintenance doses are recommended for elderly and/or debilitated patients and patients with a potential to exhibit greater than expected PT/INR response to warfarin sodium tablets (see PRECAUTIONS ).
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.
14, 15, 17, 18, 21, 22 Missed Dose The anticoagulant effect of warfarin sodium tablets persists beyond 24 hours.
If the patient forgets to take the prescribed dose of warfarin sodium tablets 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.
LABORATORY CONTROL The PT reflects the depression of vitamin K dependent Factors VII, X and II.
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.
24 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 judgment of the patient’s reliability and response to warfarin sodium tablets 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 be 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 ).
Safety and efficacy of warfarin therapy can be improved by increasing the quality of laboratory control.
Reports suggest that in usual care monitoring, patients are in therapeutic range only 33%-64% of the time.
Time in therapeutic range is significantly greater (56%-93%) in patients managed by anticoagulation clinics, among self-testing and self-monitoring patients, and in patients managed with the help of computer programs.
25 Self-testing patients had fewer bleeding events than patients in usual care.
25 TREATMENT DURING DENTISTRY AND SURGERY The management of patients who undergo dental and surgical procedures requires close liaison between attending physicians, surgeons and dentists.
15, 19 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 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 sodium tablets therapy.
When discontinuing warfarin sodium tablets 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 is delayed, heparin is preferred initially for rapid anticoagulation.
Conversion to warfarin sodium tablets 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 therapy be overlapped with heparin for 4 to 5 days, until warfarin sodium tablets have produced the desired therapeutic response as determined by PT/INR.
When warfarin sodium tablets have produced the desired PT/INR or prothrombin activity, heparin may be discontinued.
Warfarin sodium tablets may increase the activated partial thromboplastin time (aPTT) test, even in the absence of heparin.
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.
During initial therapy with warfarin sodium tablets, 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 should have blood for PT/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.