Action And Clinical Pharmacology: Warfarin 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 to 6 hours, IX – 24 hours, and X – 48 to 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. 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 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 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 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.
The administration of warfarin via the i.v. 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 may not be achieved until 72-96 hours after dosing, indicating that the administration of i.v. warfarin should not provide any increased biological effect or earlier onset of action.
There are no differences in the apparent volume of distribution after i.v. and oral administration of single doses of warfarin solution. Warfarin distributes into a relatively small apparent volume of distribution of about 0.14 L/kg. A distribution phase lasting 6 to 12 hours is distinguishable after rapid i.v. or oral administration of an aqueous solution.
Indications And Clinical Uses: For the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, atrial fibrillation with embolization, and as an adjunct in the prophylaxis of systemic embolism after myocardial infarction, including stroke, reinfarction and death.
The following are some of the more common clinical disorders which may be associated with or predispose patients to the above indications: thrombophlebitis, congestive heart failure, surgical procedure or trauma associated with a high risk of thromboembolism, myocardial infarction, cerebral embolism.
It may also be useful as an adjunct in the treatment of transient cerebral ischemic attacks due to intravascular clotting.
Contra-Indications: Anticoagulation is contraindicated in any localized or general physical condition or personal circumstances in which the hazard of hemorrhage might be greater than the potential clinical benefits of anticoagulation, such as:
Pregnancy: Warfarin passes through the placental barrier and may cause fatal hemorrhage to the fetus in utero. Women of childbearing potential must take precautions not to become pregnant while on warfarin therapy. Furthermore, there have been reports of birth malformations in children born to mothers who have been treated with warfarin during pregnancy.
Embryopathy characterized by nasal hypoplasia with or without stippled epiphyses (chondrodysplasia punctata) has been reported in pregnant women exposed to warfarin during the first trimester. CNS abnormalities also have been reported, including dorsal midline dysplasia characterized by agenesis of the corpus callosum, Dandy-Walker malformation, and midline cerebellar atrophy. Ventral midline dysplasia, characterized by optic atrophy, and eye abnormalities have been observed. Mental retardation, blindness, and other CNS abnormalities have been reported in association with second and third trimester exposure. Although rare, teratogenic reports following in utero exposure to warfarin include urinary tract anomalies such as single kidney, asplenia, anencephaly, spina bifida, cranial nerve palsy, hydrocephalus, cardiac defects and congenital heart disease, polydactyly, deformities of toes, diaphragmatic hernia, 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 the light of those risks.
Hemorrhagic tendencies or blood dyscrasias.
Recent or contemplated surgery of: CNS, eye, traumatic surgery resulting in large open surfaces.
Bleeding tendencies associated with active ulceration or overt bleeding of gastrointestinal, genitourinary or respiratory tracts; cerebrovascular hemorrhage; aneurysms – cerebral, dissecting aorta; pericarditis and pericardial effusions; bacterial endocarditis.
Threatened abortion, eclampsia and pre-eclampsia.
Inadequate laboratory facilities.
Unsupervised patients with senility, alcoholism, or psychosis or other lack of patient cooperation.
Spinal puncture and other diagnostic or therapeutic procedures with potential for uncontrollable bleeding.
Miscellaneous: major regional, lumbar block anesthesia and malignant hypertension.
Manufacturers’ Warnings In Clinical States: The most serious risks associated with anticoagulant therapy with warfarin are hemorrhage in any tissue or organ and, less frequently (
Warfarin is a potent drug with a half-life of 2.5 days; therefore, its effects may become more pronounced as daily maintenance doses overlap. It cannot be emphasized too strongly that treatment of each patient is a highly individualized matter. 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 times (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 Dosage, Conversion from Heparin Therapy for recommendations.
Caution should be observed when warfarin is administered in any situation or in the presence of any predisposing condition where added risk of hemorrhage or necrosis is present.
Anticoagulation therapy with warfarin may enhance the release of atheromatous plaque emboli, thereby increasing the risk of complications from systemic cholesterol microembolization, including the “purple toe syndrome”. Discontinuation of warfarin therapy is recommended when such phenomena are observed. While the “purple toe syndrome” is reported to be reversible, other complications of microembolization may not be reversible.
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 to 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.
A severe elevation (>50 seconds) in activated partial thromboplastin time (aPTT) with a PT ratio/INR in the desired range has been identified as an indication of increased risk of postoperative hemorrhage. This has been noted in patients undergoing elective hip surgery receiving warfarin alone.
Administration of anticoagulants in the following conditions will be based upon clinical judgment in which the risks of anticoagulant therapy are weighed against the risk of thrombosis or embolization in untreated cases. The following may be associated with these increased risks:
Lactation : Warfarin appears in the milk of nursing mothers in an inactive form. Infants nursed by warfarin treated mothers had no change in PT. Effects in premature infants have not been evaluated.
Severe to moderate hepatic or renal insufficiency.
Infectious diseases or disturbances of intestinal flora-sprue, antibiotic therapy.
Trauma which may result in internal bleeding.
Surgery or trauma resulting in large exposed raw surfaces.
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 become more responsive to warfarin, thereby requiring more frequent laboratory monitoring, and reduced doses of warfarin.
Concurrent use of anticoagulants with streptokinase or urokinase is not recommended and may be hazardous. (Please note recommendations accompanying these preparations.)
Precautions: Periodic determination of PT ratio/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 ratio/INR determinations in the period immediately after discharge from the hospital, and whenever other medications are initiated, discontinued or taken irregularly. However, other factors may also affect the anticoagulant response and the tables are provided for your reference only.
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.
Because a patient may be exposed to a combination of listed factors, the net effect of warfarin on PT ratio/INR responses may be unpredictable. More frequent PT ratio/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 ratio/INR monitoring is advisable. Coumarins may also affect the action of other drugs. Hypoglycemic agents (chlorpropamide and tolbutamide) and anticonvulsants (phenytoin and phenobarbital) may accumulate in the body as a result of interference with either their metabolism or excretion.
It has been reported that concomitant administration of warfarin and ticlopidine may be associated with cholestatic hepatitis.
Special Risk Patients: Warfarin is a narrow therapeutic range (index) drug, and caution should be observed when 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.
I.M. injections of concomitant medications should be confined to the upper extremities which permits easy access for manual compression, inspections for bleeding and use of pressure bandages.
Close monitoring of patients receiving nonsteroidal anti-inflammatory agents (NSAIDs) is recommended to be certain that no change in anticoagulation dosage is required. In addition to specific drug interactions that might affect prothrombin time, NSAIDs can inhibit platelet aggregation, and can cause gastrointestinal bleeding, peptic ulceration and/or perforation.
Acquired or inherited warfarin resistance should be suspected if large daily doses of warfarin are required to maintain a patient’s PT ratio/INR within a normal therapeutic range.
Pregnancy: See Contraindications.
Children: Safety and effectiveness in children below 18 years of age have not been established in randomized, controlled clinical trials. However, the use of warfarin in pediatric patients has been documented for the prevention and treatment of thromboembolic events. Difficulty achieving and maintaining therapeutic PT ratio/INR ranges in the pediatric patient has been reported. More frequent PT ratio/INR determinations are recommended because of possible changing warfarin requirements.
The Following Factors, Alone or in Combination, May Be Responsible for Increased PT Ratio or 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 are listed below by drug class and by specific drugs. adrenergic stimulants, central alcohol abuse reduction preparations analgesics anesthetics, inhalation antiarrhythmics* antibiotics* aminoglycosides (oral) cephalosporins, parenteral macrolides penicillins, i.v., 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 diabetes agents, oral diuretics* fungal medications, systemic* gastric acidity and peptic ulcer agents* gastrointestinal, ulcerative colitis agents gout treatment agents hemorrheologic agents hepatotoxic drugs hyperglycemic agents hypertensive emergency agents hypnotics* hypolipidemics* MAO inhibitors narcotics, prolonged nonsteroidal anti-inflammatory agents psychostimulants pyrazolones salicylates steroids, adrenocortical* steroids, anabolic (17-alkyl testosterone derivatives) thrombolytics thyroid drugs tuberculosis agents* uricosuric agents vaccines vitamins*
Specific Drugs Reported acetaminophen alcohol* allopurinol aminosalicylic acid amiodarone HCl ASA cefamandole cefazolin cefoperazone cefotetan cefoxitin ceftriaxone chenodiol chloramphenicol chloral hydrate* chlorpropamide cholestyramine* cimetidine ciprofloxacin clarithromycin clofibrate cyclophosphamide* danazol dextran dextrothyroxine diazoxide diclofenac dicumarol diflunisal disulfiram doxycycline erythromycin ethacrynic acid fenoprofen fluconazole fluorouracil glucagon halothane heparin ibuprofen ifosfamide indomethacin influenza virus vaccine itraconazole ketoprofen ketorolac levamisole levothyroxine liothyronine lovastatin mefenamic acid methimazole* methyldopa methylphenidate methylsalicylate ointment (topical) metronidazole miconazole moricizine HCl* nalidixic acid naproxen neomycin norfloxacin ofloxacin olsalazine omeprazole oxaprozin oxymetholone paroxetine penicillin G, i.v. pentoxifylline phenylbutazone phenytoin* piperacillin piroxicam prednisone* propafenone propoxyphene propranolol propylthiouracil* quinidine quinine ranitidine* sertraline simvastatin stanozolol streptokinase sulfamethizole sulfamethoxazole sulfinpyrazone sulfisoxazole sulindac tamoxifen tetracycline thyroid ticarcillin ticlopidine tissue plasminogen activator (t-PA) tolbutamide trimethoprim/sulfamethoxazole urokinase valproate vitamin E warfarin overdose.
Also: Other medications affecting blood elements which may modify hemostasis dietary deficiencies; prolonged hot weather; unreliable PT determinations. *Increased and decreased PT ratio/INR responses have been reported.
Factors Alone or in Combination, Which May Be Responsible for Decreased PT Ratio or INR Response
Endogenous Factors: edema hereditary coumarin resistance hyperlipemia hypothyroidism nephrotic syndrome.
Exogenous Factors: Potential drug interactions with warfarin are listed below by drug class and by specific drugs. adrenal cortical steroid inhibitors antacids antianxiety agents antiarrhythmics* antibiotics* anticonvulsants* antidepressants* antihistamines 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* aminoglutethimide amobarbital azathioprine butabarbital butalbital carbamazepine chloral hydrate* chlordiazepoxide chlorthalidone cholestyramine* corticotropin cortisonecyclophosphamide* dicloxacillin ethchlorvynol glutethimide griseofulvin haloperidol meprobamate methimazole* moricizine HCl* nafcillin paraldehyde pentobarbitalphenobarbital phenytoin* prednisone* primidone propylthiouracil* ranitidine* rifampin secobarbital spironolactone sucralfate trazodone vitamin C (high dose) vitamin K warfarin underdosage
Also: diet high in vitamin K unreliable PT determinations *Increased and decreased PT ratio/INR responses have been reported.
Adverse Reactions: Potential adverse reactions to warfarin may include:
Fatal or nonfatal hemorrhage from any tissue or organ. This is a consequence of the anticoagulant effect. The signs, and 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, muscle 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 ratio/INR (see Overdose: Symptoms and Treatment).
Bleeding which occurs when the PT ratio/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 eruptions, urticaria, abdominal pain including cramping, asthenia, nausea, vomiting, diarrhea, headache, pruritus, alopecia, and paresthesia.
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.
Symptoms And Treatment Of Overdose: 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 K1. (Please see recommendations accompanying vitamin K1 preparations prior to use.)
Such use of vitamin K1 reduces responses to subsequent warfarin therapy. Patients may return to a pretreatment thrombotic status following the rapid reversal of a prolonged PT. Resumption of warfarin administration reverses the effect of vitamin K1, and a therapeutic PT can again be obtained by careful dosage adjustment. If rapid anticoagulation is indicated, heparin may be preferable for initial therapy.
If minor bleeding progresses to major bleeding, give 5 to 25 mg (rarely up to 50 mg) parenteral vitamin K1. In emergency situations of severe hemorrhage, clotting factors can be returned to normal by administering 200 to 500 mL of whole blood or fresh frozen plasma, or by giving commercial Factor IX complex.
A risk of hepatitis and other viral diseases is associated with the use of these blood products; Factor IX complex is also associated with an increased risk of thrombosis. Therefore, these preparations should be used only in exceptional or life-threatening bleeding episodes secondary to warfarin overdosage.
Purified Factor IX preparations should not be used because they cannot increase the levels of prothrombin, Factor VII and Factor X, which are also depressed along with the levels of Factor IX as a result of warfarin treatment. Packed red blood cells may also be given if significant blood loss has occurred. Infusions of blood or plasma should be monitored carefully to avoid precipitating pulmonary edema in elderly patients or patients with heart disease.
Dosage And Administration: Administration: The administration and dosage of warfarin must be individualized according to the patient’s responsiveness to the drug. The dosage should be adjusted according to results of the patient’s PT ratio/INR. Measurement of warfarin induced effects on PT can vary substantially due to the sensitivity of different thromboplastin reagents.
Early clinical studies of oral anticoagulants, which formed the basis for recommended therapeutic ranges of 1.5 to 2.5 times control PT, used sensitive human brain thromboplastin. When using the less sensitive rabbit brain thromboplastins commonly employed in PT assays today, adjustments must be made to the targeted PT range that reflect this decrease in sensitivity. Available clinical evidence indicates that an INR of 2.0 to 3.0, is sufficient for prophylaxis and treatment of venous thromoboembolism and minimizes the risk of hemorrhage associated with higher INRs. Five recent clincial trials evaluated the effects of warfarin in patients with nonvalvular atrial fibrillation (AF). 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 to 4.5) or low INR (1.4 to 3.0). There was a significant reduction in minor bleeds at the low INR. Although clinical studies have used a wide range of warfarin dosing, a more recent study suggests that in patients with atrial fibrillation, anticoagulant prophylaxis is effective at INRs of 2.0 to 3.0. The study also shows that the risk of thromboembolic stroke may increase substantially at INRs less than 2.0. INR value should not exceed 4.0, to reduce the risk of anticoagulant-related bleeding. Similar data from clinical studies in valvular atrial fibrillation patients are not available. The trials in nonvalvular atrial fibrillation support The American College of Chest Physicians'(ACCP) recommendation that an INR of 2.0 to 3.0 be used for long-term warfarin therapy in appropriate AF patients. 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 ratio of greater than 4.0 appears to provide no additional therapeutic benefit in most patients and is associated with a higher risk of bleeding. In AF patients undergoing elective cardioversion, anticoagulant therapy should be given for 3 weeks before cardioversion and continued until normal sinus rhythm has been maintained for 4 weeks.
Two well-controlled studies in postmyocardial infarction patients demonstrated substantial benefit of long-term oral anticoagulation in reducing the risk of death, recurrent myocardial infarction, and thromboembolic events, such as stroke. Both studies targeted an INR range of 2.8 to 4.8 for evaluating efficacy and safety. Clinical evidence from these two studies suggests that an INR range of 2.0 to 4.0 significantly reduced the risk of thromboembolic events and that INR values greater than 4.0 are associated with an increased risk of bleeding. In postmyocardial patients, warfarin therapy should be initiated early and dosage should be adjusted to maintain an INR of 2.5 to 3.5 long-term. In patients thought to be at increased risk of bleeding complications or on ASA therapy, maintenance of warfarin therapy at the lower end of this INR range is recommended.
The proceedings and recommendations of the 1992 National Conference on Antithrombotic Therapy 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.
To define the appropriate therapeutic regimen it is important to be familiar with the sensitivity of the thromboplastin reagent used in the laboratory and its relationship to the International Reference Preparation (IRP), a sensitive thromboplastin prepared from human brain.
A system of standardizing the PT in oral anticoagulant control was introduced by the World Health Organization in 1983. It is based upon the determination of an International Normalized Ratio (INR) which provides a common basis for communications of PT results and interpretations of therapeutic ranges. The INR 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 IRP, which has an International Sensitivity Index (ISI) of 1.0, were used to perform the test. The INR can be calculated as: INR = (observed PT ratio)ic2ISIic0 observed PT ratio = (Patient PT/Control PT) where the ISI is the correction factor in the equation that relates 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.
Initial Dosage: The dosing of warfarin must be individualized according to the patient’s response to the drug as indicated by the INR and/or PT ratio. It is recommended that warfarin therapy be initiated with a dose of 2 to 5 mg/day with dosage adjustments based on the results of INR and/or PT ratio determinations. Low initiation doses are recommended for elderly and/or debilitated patients and patients with potential for increased responsiveness to warfarin (see Precautions). 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.
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.
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 persists beyond 24 hours. If the patient forgets to take the prescribed dose of warfarin 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 this or her physician.
I.V. Route of Administration: Warfarin 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 for injection should be administered as a slow bolus injection over 1 to 2 minutes into a peripheral vein. It is not recommended for i.m. administration. The vial should be reconstituted with 2.7 mL of sterile Water for Injection and inspected for particulate matter and discoloration immediately prior to use. Do not use if either particulate matter and/or discoloration is noted. After reconstitution, warfarin 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 INR reflects the depression of vitamin K dependent Factors VII, X and II. The INR should be determined daily after the administration of the initial dose until INR results stabilize in the therapeutic range. Intervals between subsequent INR determinations should be based upon the patient’s INR response and the physician’s judgment of the patient’s reliability. For example, INR may be monitored 2 or 3 times weekly for 1 to 2 weeks, then less often, depending on the stability of the INR results. If the INR response remains stable, the frequency of testing may be reduced with intervals as long as every 4 to 6 weeks for appropriate patients.
To ensure adequate control, it is recommended that additional PT tests are done when other warfarin products are interchanged with Coumadin and also if other medications are coadministered with warfarin (see Precautions).
In switching to another warfarin product, particular emphasis needs to be placed on INR control. INR outside of the therapeutic range may result in serious clinical consequences: lack of efficacy leading to thromboembolic stroke or myocardial infarction, if INR values are low, and intracranial bleeding if they are high.
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 ratio/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 to maintain the PT ratio/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 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 is delayed, heparin is preferred initially for rapid anticoagulation. Conversion to warfarin may begin concomitantly with heparin therapy or may be delayed 3 to 6 days. To ensure continuous anticoagulation, it is advisable to continue full dose heparin therapy and that warfarin therapy be overlapped with heparin for 4 to 5 days, until warfarin has produced the desired therapeutic response as determined by PT ratio/INR. When warfarin has produced the desired PT ratio/INR or prothrombin activity, heparin may be discontinued.
Warfarin may increase the aPTT test. During initial therapy with warfarin, the interference with heparin anticoagulation is of minimal clinical significance.
As heparin may affect the PT, patients receiving both heparin and warfarin should have blood drawn for PT ratio/INR determination, at least: 5 hours after the last i.v. bolus dose of heparin; or 4 hours after cessation of a continuous i.v. infusion of heparin; or 24 hours after last s.c. heparin injection.
Reconstituted Solutions: Available for i.v. use only. Not recommended for i.m. administration. Reconstitute with 2.7 mL of sterile Water for Injection to yield 2 mg/mL. After reconstitution, store at controlled room temperature (15 to 30°C) and use within 4 hours. Do not refrigerate. Discard any unused solution. The reconstituted solution should be inspected visually for discoloration, haziness, particulate matter and leakage prior to administration.
Availability And Storage: Injection: Each vial contains: warfarin sodium 5.4 mg. Nonmedicinal ingredients: mannitol, sodium chloride, sodium hydroxide (as needed for pH adjustment from 8.1 to 8.3), sodium phosphate, dibasic, heptahydrate and sodium phosphate monobasic, monohydrate. Single use vials, packages of 6. Protect from light. Store in carton until contents have been used. Store at controlled room temperature (15 to 30°C). After reconstitution, store at controlled room temperature (15 to 30°C) and use within 4 hours. Do not refrigerate.
Tablets: 1 mg: Each pink, single scored tablet with on one side and DuPont on the other, contains: crystalline warfarin sodium 1 mg. Nonmedicinal ingredients: D&C Red #6, lactose anhydrous, magnesium stearate and pregelatinized tapioca starch. Bottles of 100 and 250.
2 mg: Each lavender, single scored tablet with on one side and DuPont on the other, contains: crystalline warfarin sodium 2 mg. Nonmedicinal ingredients: FD&C Blue #2 and FD&C Red #40, lactose anhydrous, magnesium stearate and pregelatinized tapioca starch. Bottles of 100 and 250.
2.5 mg: Each green, single scored tablet with on one side and DuPont on the other, contains crystalline warfarin sodium 2.5 mg. Nonmedicinal ingredients: FD&C Blue #1, D&C Yellow #10, lactose anhydrous, magnesium stearate and pregelatinized tapioca starch. Bottles of 100 and 250.
4 mg: Each blue, single scored tablet with on one side and DuPont on the other, contains: crystalline warfarin sodium 4 mg. Nonmedicinal ingredients: FD&C Blue #1 Lake, lactose anhydrous, magnesium stearate and pregelatinized tapioca starch. Bottles of 100 and 250.
5 mg: Each peach, single scored tablet with on one side and DuPont on the other, contains: crystalline warfarin sodium 5 mg. Nonmedicinal ingredients: FD&C Yellow #6, lactose anhydrous, magnesium stearate and pregelatinized tapioca starch. Bottles of 100 and 250.
10 mg: Each white, single scored tablet with on one side and DuPont on the other, contains: crystalline warfarin sodium 10 mg. Nonmedicinal ingredients: lactose anhydrous, magnesium stearate and pregelatinized tapioca starch. Dye-free. Bottles of 100.
Protect from light. Store in carton until contents have been used. Store at controlled room temperature (15 to 30°C). Dispense in a tight, light-resistant container as defined in the USP. (Shown in Product Recognition Section)
COUMADIN® DuPont Pharma Warfarin Sodium Anticoagulant
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