DESCRIPTION
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 - and -enantiomers. Warfarin sodium is an isopropanol clathrate. The crystallization of warfarin sodium virtually eliminates trace impurities present in amorphous warfarin. Its structural formula may be represented as follows: RS
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.
Each tablet, for oral administration, contains 1 mg, 2 mg, 2½ mg, 3 mg, 4 mg, 5 mg, 6 mg, 7½ mg or 10 mg warfarin sodium. In addition, each tablet contains the following inactive ingredients: anhydrous lactose, hypromellose 2208 (3cPs), magnesium stearate, and pregelatinized starch.
The 1 mg also contains D&C red no. 6 barium lake.
The 2 mg also contains FD&C blue no. 2 aluminum lake, and FD&C red no. 40 aluminum lake.
The 2½ mg also contains D&C yellow no. 10 aluminum lake, and FD&C blue no. 1 aluminum lake.
The 3 mg also contains FD&C blue no. 2 aluminum lake, FD&C red no. 40 aluminum lake, and FD&C yellow no. 6 aluminum lake.
The 4 mg also contains FD&C blue no. 1 aluminum lake.
The 5 mg also contains FD&C yellow no. 6 aluminum lake.
The 6 mg also contains FD&C blue no. 1 aluminum lake, and FD&C yellow no. 6 aluminum lake.
The 7½ mg also contains D&C yellow no. 10 aluminum lake, and FD&C yellow no. 6 aluminum lake.
The 10 mg does not contain any dyes.
CLINICAL PHARMACOLOGY
Warfarin sodium and other coumarin anticoagulants act by inhibiting the synthesis of vitamin K dependent clotting factors, which include Factors II, VII, IX and X, and the anticoagulant proteins C and S. Half-lives of these clotting factors are as follows: Factor II - 60 hours, VII - 4 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 effect is a sequential depression of Factor VII, Protein C, Factor IX, Protein S, and Factor 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 γ-carboxyglutamic acid residues in the proteins which are essential for biological activity. in vivo
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 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%. 1
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 may become more pronounced as effects of daily maintenance doses overlap. Anticoagulants have no direct effect on an established thrombus, nor do they reverse ischemic tissue damage. However, once a thrombus has occurred, the goal of anticoagulant treatment is to prevent further extension of the formed clot and prevent secondary thromboembolic complications which may result in serious and possibly fatal sequelae.
Pharmacokinetics
Warfarin sodium is a racemic mixture of the - and -enantiomers. The -enantiomer exhibits 2 to 5 times more anticoagulant activity than the -enantiomer in humans, but generally has a more rapid clearance. RSSR
Absorption
Warfarin sodium is essentially completely absorbed after oral administration with peak concentration generally attained within the first 4 hours.
Distribution
There are no differences in the apparent volumes of distribution after intravenous and oral administration of single doses of warfarin 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 , Lactation). Approximately 99% of the drug is bound to plasma proteins. WARNINGS
Metabolism
The elimination of warfarin is almost entirely by metabolism. Warfarin sodium is stereoselectively metabolized by hepatic microsomal enzymes (cytochrome P-450) to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolites (warfarin 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 anticoagulant activity of warfarin. in vivo
The -enantiomer of warfarin is mainly metabolized to 7-hydroxywarfarin by CYP2C9, a polymorphic enzyme. The variant alleles CYP2C9*2 and CYP2C9*3 result in decreased CYP2C9 enzymatic 7-hydroxylation of S-warfarin. The frequencies of these alleles in Caucasians are approximately 11% and 7% for CYP2C9*2 and CYP2C9*3, respectively. Patients with one or more of these variant CYP2C9 alleles have decreased S-warfarin clearance (Table 1). Sin vitro12
Table 1: Relationship Between S-Warfarin Clearance and CYP2C9 Genotype in Caucasian Patients
|
|
|
CYP2C9 Genotype |
N |
Mean (SD)
S-Warfarin Clearance/Lean Body Weight (mL/min/kg)
* |
|
*1/*1 |
118 |
0.065 (0.025) † |
|
*1/*2 or *1/*3 |
59 |
0.041 (0.021) † |
|
*2/*2, *2/*3, or *3/*3 |
11 |
0.020 (0.011) † |
|
Total |
188 |
|
Other CYP2C9 alleles associated with reduced enzymatic activity occur at lower frequencies, including *5, *6, and *11 alleles in populations of African ancestry and *5, *9, and *11 alleles in Caucasians.
Excretion
The terminal half-life of warfarin after a single dose is approximately 1 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.
Pharmacogenomics
A meta-analysis of 9 qualified studies including 2775 patients (99% Caucasian) was performed to examine the clinical outcomes associated with CYP2C9 gene variants in warfarin-treated patients. In this meta-analysis, 3 studies assessed bleeding risks and 8 studies assessed daily dose requirements. The analysis suggested an increased bleeding risk for patients carrying either the CYP2C9*2 or CYP2C9*3 alleles. Patients carrying at least one copy of the CYP2C9*2 allele required a mean daily warfarin dose that was 17% less than the mean daily dose for patients homozygous for the CYP2C9*1 allele. For patients carrying at least one copy of the CYP2C9*3 allele, the mean daily warfarin dose was 37% less than the mean daily dose for patients homozygous for the CYP2C9*1 allele. 3
In an observational study, the risk of achieving INR >3 during the first 3 weeks of warfarin therapy was determined in 219 Swedish patients retrospectively grouped by CYP2C9 genotype. The relative risk of overanticoagulation as measured by INR >3 during the first 2 weeks of therapy was approximately doubled for those patients classified as *2 or *3 compared to patients who were homozygous for the *1 allele. 4
Warfarin reduces the regeneration of vitamin K from vitamin K epoxide in the vitamin K cycle, through inhibition of vitamin K epoxide reductase (VKOR), a multiprotein enzyme
complex. Certain single nucleotide polymorphisms in the VKORC1 gene (especially the -1639G>A allele) have been associated with lower dose requirements for warfarin. In 201 Caucasian patients treated with stable warfarin doses, genetic variations in the VKORC1 gene were associated with lower warfarin doses. In this study, about 30% of the variance in warfarin dose could be attributed to variations in the VKORC1 gene alone; about 40% of the variance in warfarin dose could be attributed to variations in VKORC1 and CYP2C9 genes combined. About 55% of the variability in warfarin dose could be explained by the combination of VKORC1 and CYP2C9 genotypes, age, height, body weight, interacting drugs, and indication for warfarin therapy in Caucasian patients. Similar observations have been reported in Asian patients. 556,7
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.
Asians
Asian patients may require lower initiation and maintenance doses of warfarin. One non-controlled study conducted in 151 Chinese outpatients reported a mean daily warfarin requirement of 3.3 ± 1.4 mg to achieve an INR of 2 to 2.5. These patients were stabilized on warfarin for various indications. Patient age was the most important determinant of warfarin requirement in Chinese patients with a progressively lower warfarin requirement with increasing age.
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.
The administration of warfarin sodium via the intravenous (IV) route should provide the patient with the same concentration of an equal oral dose, but maximum plasma concentration will be reached earlier. However, the full anticoagulant effect of a dose of warfarin may not be achieved until 72 to 96 hours after dosing, indicating that the administration of IV warfarin sodium should not provide any increased biological effect or earlier onset of action.
INDICATIONS AND USAGE
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.
CONTRAINDICATIONS
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 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 . Furthermore, there have been reports of birth malformations in children born to mothers who have been treated with warfarin during pregnancy. in utero
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 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. in utero
Spontaneous abortion and stillbirth 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 eva luated and the indications critically reviewed with the patient. If the patient becomes pregnant while taking this drug, she should be apprised of the potential risks to the fetus, and the possibility of termination of the pregnancy should be discussed in light of those risks.
Hemorrhagic tendencies or blood dyscrasias.
(1) central nervous system; (2) eye; (3) traumatic surgery resulting in large open surfaces. Recent or contemplated surgery of:
(1) gastrointestinal, genitourinary or respiratory tracts; (2) cerebrovascular hemorrhage; (3) aneurysms-cerebral, dissecting aorta; (4) pericarditis and pericardial effusions; (5) bacterial endocarditis. Bleeding tendencies associated with active ulceration or overt bleeding of:
eclampsia and preeclampsia. Threatened abortion,
Inadequate laboratory facilities.
alcoholism, or psychosis or other lack of patient cooperation. Unsupervised patients with senility,
and other diagnostic or therapeutic procedures with potential for uncontrollable bleeding. Spinal puncture
Miscellaneous
Major regional, lumbar block anesthesia, malignant hypertension and known hypersensitivity to warfarin or to any other components of this product.
WARNINGS
The most serious risks associated with anticoagulant therapy with warfarin sodium are hemorrhage in any tissue or organ (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. 12
It cannot be emphasized too strongly that treatment of each patient is a highly individualized matter. Warfarin sodium, a narrow therapeutic range (index) drug, may be affected by factors such as other drugs and dietary vitamin K. Dosage should be controlled by periodic determinations of prothrombin time (PT)/International Normalized Ratio (INR). Determinations of whole blood clotting and bleeding times are not effective measures for control of therapy. Heparin prolongs the one-stage PT. When heparin and warfarin sodium are administered concomitantly, refer below to Conversion From Heparin Therapy for recommendations.
Increased caution should be observed when warfarin sodium is administered in the presence of any predisposing condition where added risk of hemorrhage, necrosis, and/or gangrene is present.
Anticoagulation therapy with warfarin sodium may enhance the release of atheromatous plaque emboli, thereby increasing the risk of complications from systemic cholesterol microembolization, including the “purple toes syndrome.” Discontinuation of warfarin sodium therapy is recommended when such phenomena are observed.
Systemic atheroemboli and cholesterol microemboli can present with a variety of signs and symptoms including purple toes syndrome, livedo reticularis, rash, gangrene, abrupt and intense pain in the leg, foot, or toes, foot ulcers, myalgia, penile gangrene, abdominal pain, flank or back pain, hematuria, renal insufficiency, hypertension, cerebral ischemia, spinal cord infarction, pancreatitis, symptoms 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.
Warfarin sodium 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 eva luate vitamin K status in infants before advising women taking warfarin to breast-feed. Effects in premature infants have not been eva luated.
Severe to moderate hepatic or renal insufficiency.
sprue, antibiotic therapy. Infectious diseases or disturbances of intestinal flora:
which may result in internal bleeding. Trauma
resulting in large exposed raw surfaces. Surgery or trauma
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 eva luated as a risk factor for tissue necrosis. The risk associated with these conditions, both for recurrent thrombosis and for adverse reactions, is difficult to eva luate 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 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.
PRECAUTIONS
See DOSAGE AND ADMINISTRATION, Numerous factors, alone or in combination including changes in diet, medications, botanicals, and genetic variations in the CYP2C9 and VKORC1 enzymes see CLINICAL PHARMACOLOGY, may influence the response of the patient to warfarin. Periodic determination of PT/INR is essential. (Laboratory Control.)(Pharmacogenomics)
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 through pharmacodynamic or pharmacokinetic mechanisms. Pharmacodynamic mechanisms for drug interactions with warfarin sodium are synergism (impaired hemostasis, reduced clotting factor synthesis), competitive antagonism (vitamin K), and altered physiologic control loop for vitamin K metabolism (hereditary resistance). Pharmacokinetic mechanisms for drug interactions with warfarin sodium are mainly enzyme induction, enzyme inhibition, and reduced plasma protein binding. It is important to note that some drugs may interact by more than one mechanism.
The following factors, alone or in combination, may be responsible for INCREASED PT/INR response:
Endogenous Factors:
|
blood dyscrasias-see CONTRAINDICATIONS |
hepatic disorders: |
|
|
infectious hepatitis |
|
cancer |
jaundice |
|
collagen vascular disease |
hyperthyroidism |
|
congestive heart failure |
poor nutritional state |
|
diarrhea |
steatorrhea |
|
elevated temperature |
vitamin K deficiency |
Exogenous Factors:
Potential drug interactions with warfarin sodium are listed below by drug class and by specific drugs.
Classes of Drugs
|
5-lipoxygenase Inhibitor |
Antiplatelet Drugs/Effects |
Leukotriene Receptor Antagonist |
|
Adrenergic Stimulants, Central |
Antithyroid Drugs* |
Monoamine Oxidase Inhibitors |
|
Alcohol Abuse Reduction Preparations |
Beta-Adrenergic Blockers |
Narcotics, prolonged |
|
Analgesics |
Cholelitholytic Agents |
Nonsteroidal Anti-Inflammatory Agents |
|
Anesthetics, Inhalation |
Diabetes Agents, Oral |
Proton Pump Inhibitors |
|
Antiandrogen |
Diuretics* |
Psychostimulants |
|
Antiarrhythmics* |
Fungal Medications, Intravaginal, Systemic* |
Pyrazolones |
|
Antibiotics* |
Gastric Acidity and Peptic Ulcer Agents* |
Salicylates |
|
Aminoglycosides (oral) |
Gastrointestinal |
Selective Serotonin Reuptake Inhibitors |
|
Cephalosporins, parenteral |
Prokinetic Agents |
Steroids, Adrenocortical* |
|
Macrolides |
Ulcerative Colitis Agents |
Steroids, Anabolic (17-Alkyl Testosterone Derivatives) |
|
Miscellaneous |
Gout Treatment Agents |
Thrombolytics |
|
Penicillins, intravenous, high dose |
Hemorrheologic Agents |
Thyroid Drugs |
|
Quinolones (fluoroquinolones) |
Hepatotoxic Drugs |
Tuberculosis Agents* |
|
Sulfonamides, long acting |
Hyperglycemic Agents |
Uricosuric Agents |
|
Tetracyclines |
Hypertensive Emergency Agents |
Vaccines |
|
Anticoagulants |
Hypnotics* |
Vitamins* |
|
Anticonvulsants* |
Hypolipidemics* |
|
|
Antidepressants* |
Bile Acid-Binding Resins* |
|
|
Antimalarial Agents |
Fibric Acid Derivatives |
|
|
Antineoplastics* |
HMG-CoA Reductase Inhibitors* |
|
|
Antiparasitic/Antimicrobials |
|
|
Specific Drugs Reported
|
acetaminophen |
fenoprofen |
oxymetholone |
|
alcohol* |
fluconazole |
pantoprazole |
|
allopurinol |
fluorouracil |
paroxetine |
|
aminosalicylic acid |
fluoxetine |
penicillin G, intravenous |
|
amiodarone HCl |
flutamide |
pentoxifylline |
|
argatroban |
fluvastatin |
phenylbutazone |
|
aspirin |
fluvoxamine |
phenytoin* |
|
atenolol |
gefitinib |
piperacillin |
|
atorvastatin* |
gemfibrozil |
piroxicam |
|
azithromycin |
glucagon |
pravastatin* |
|
bivalirudin |
halothane |
prednisone* |
|
capecitabine |
heparin |
propafenone |
|
cefamandole |
ibuprofen |
propoxyphene |
|
cefazolin |
ifosfamide |
propranolol |
|
cefoperazone |
indomethacin |
propylthiouracil* |
|
cefotetan |
influenza virus vaccine |
quinidine |
|
cefoxitin |
itraconazole |
quinine |
|
ceftriaxone |
ketoprofen |
rabeprazole |
|
celecoxib |
ketorolac |
ranitidine* |
|
cerivastatin |
lansoprazole |
rofecoxib |
|
chenodiol |
lepirudin |
sertraline |
|
chloramphenicol |
levamisole |
simvastatin |
|
chloral hydrate* |
levofloxacin |
stanozolol |
|
chlorpropamide |
levothyroxine |
streptokinase |
|
cholestyramine* |
liothyronine |
sulfamethizole |
|
cimetidine |
lovastatin |
sulfamethoxazole |
|
ciprofloxacin |
mefenamic acid |
sulfinpyrazone |
|
cisapride |
methimazole* |
sulfisoxazole |
|
clarithromycin |
methyldopa |
sulindac |
|
clofibrate |
methylphenidate |
tamoxifen |
|
cyclophosphamide* |
methylsalicylate ointment (topical) |
tetracycline |
|
danazol |
metronidazole |
thyroid |
|
dextran |
miconazole (intravaginal, oral, systemic) |
ticarcillin |
|
dextrothyroxine |
moricizine hydrochloride* |
ticlopidine |
|
diazoxide |
nalidixic acid |
tissue plasminogen activator (t-PA) |
|
diclofenac |
naproxen |
tolbutamide |
|
dicumarol |
neomycin |
tramadol |
|
diflunisal |
norfloxacin |
trimethoprim/sulfamethoxazole |
|
disulfiram |
ofloxacin |
urokinase |
|
doxycycline |
olsalazine |
valdecoxib |
|
erythromycin |
omeprazole |
valproate |
|
esomeprazole |
oxandrolone |
vitamin E |
|
ethacrynic acid |
oxaprozin |
warfarin sodium overdose |
|
ezetimibe |
|
zafirlukast |
|
fenofibrate |
|
zileuton |
also: other medications affecting blood elements which may modify hemostasis
dietary deficiencies
prolonged hot weather
unreliable PT/INR determinations
*Increased and decreased PT/INR responses have been reported.
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 are listed below by drug class and by specific drugs.
Classes of Drugs
|
Adrenal Cortical Steroid Inhibitors |
Antipsychotic Medications |
Hypolipidemics* |
|
Antacids |
Antithyroid Drugs* |
Bile Acid-Binding Resins* |
|
Antianxiety Agents |
Barbiturates |
HMG-CoA Reductase Inhibitors* |
|
Antiarrhythmics* |
Diuretics* |
Immunosuppressives |
|
Antibiotics* |
Enteral Nutritional Supplements |
Oral Contraceptives, Estrogen Containing |
|
Anticonvulsants* |
Fungal Medications, Systemic* |
Selective Estrogen Receptor Modulators |
|
Antidepressants* |
Gastric Acidity and Peptic Ulcer Agents* |
Steroids, Adrenocortical* |
|
Antihistamines |
Hypnotics* |
Tuberculosis Agents* |
|
Antineoplastics* |
|
Vitamins* |
Specific Drugs Reported
|
alcohol* |
cyclophosphamide* |
phenytoin* |
|
aminoglutethimide |
dicloxacillin |
pravastatin* |
|
amobarbital |
ethchlorvynol |
prednisone* |
|
atorvastatin* |
glutethimide |
primidone |
|
azathioprine |
griseofulvin |
propylthiouracil* |
|
butabarbital |
haloperidol |
raloxifene |
|
butalbital |
meprobamate |
ranitidine* |
|
carbamazepine |
6-mercaptopurine |
rifampin |
|
chloral hydrate* |
methimazole* |
secobarbital |
|
chlordiazepoxide |
moricizine hydrochloride* |
spironolactone |
|
chlorthalidone |
nafcillin |
sucralfate |
|
cholestyramine* |
paraldehyde |
trazodone |
|
clozapine |
pentobarbital |
vitamin C (high dose) |
|
corticotropin |
phenobarbital |
vitamin K |
|
cortisone |
|
warfarin sodium underdosage |
also: diet high in vitamin K
unreliable PT/INR determinations
* Increased and decreased PT/INR responses have been reported.
Because a patient may be exposed to a combination of the above factors, the net effect of warfarin sodium 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.
Botanical (Herbal) Medicines
Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with warfarin sodium. Few adequate, well-controlled studies exist eva luating the potential for metabolic and/or pharmacologic interactions between botanicals and warfarin sodium. Due to a lack of manufacturing standardization with botanical medicinal preparations, the amount of active ingredients may vary. This could further confound the ability to assess potential interactions and effects on anticoagulation. It is good practice to monitor the patient&r |
