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Pronunciation |
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(WAR
far
in) |

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U.S. Brand
Names |
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Coumadin® |

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Generic
Available |
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Yes: Tablet |

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Canadian Brand
Names |
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Warfilone® |

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Synonyms |
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Warfarin Sodium |

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Pharmacological Index |
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Anticoagulant, Coumarin Derivative |

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Use |
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Prophylaxis and treatment of venous thrombosis, pulmonary embolism and
thromboembolic disorders; atrial fibrillation with risk of embolism and as an
adjunct in the prophylaxis of systemic embolism after myocardial infarction
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Pregnancy Risk
Factor |
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D |

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Pregnancy/Breast-Feeding
Implications |
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Clinical effects on the fetus: Oral anticoagulants cross the placenta and
produce fetal abnormalities. Warfarin should not be used during pregnancy
because of significant risks. Adjusted-dose heparin can be given safely
throughout pregnancy in patients with venous thromboembolism.
Breast-feeding/lactation: Warfarin does not pass into breast milk and can be
given to nursing mothers |

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Contraindications |
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Hypersensitivity to warfarin or any component of the product; pregnancy;
hemorrhagic tendencies; hemophilia; thrombocytopenia purpura; leukemia; recent
or potential surgery of the eye or CNS; major regional lumbar block anesthesia
or surgery resulting in large, open surfaces; patients bleeding from the GI,
respiratory, or GU tract; threatened abortion; aneurysm; ascorbic acid
deficiency; history of bleeding diathesis; prostatectomy; continuous tube
drainage of the small intestine; polyarthritis; diverticulitis; emaciation;
malnutrition; cerebrovascular hemorrhage; eclampsia/pre-eclampsia; blood
dyscrasias; severe uncontrolled or malignant hypertension; severe hepatic
disease; pericarditis or pericardial effusion; subacute bacterial endocarditis;
visceral carcinoma; following spinal puncture and other diagnostic or
therapeutic procedures with potential for significant bleeding; history of
warfarin-induced necrosis; an unreliable, noncompliant patient; alcoholism;
patient who has a history of falls or is a significant fall
risk |

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Warnings/Precautions |
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Cautious use in severe renal disease, although has been used. Hemorrhage is
the most serious risk. Have patient report any signs or symptoms of bleeding or
any falls or accidents immediately. Patient must also report any new or
discontinued medications, herbal or alternative products used, significant
changes in smoking or eating habits. Necrosis or gangrene of the skin and other
tissues can rarely occur due to early hypercoagulability.
"Purple toes syndrome," due to cholesterol microembolization, may rarely occur
(often after several weeks of therapy). Women may be at risk of developing
ovarian hemorrhage at the time of ovulation. Use with caution in traumas,
infection (antibiotics and fever may alter affects), renal insufficiency,
prolonged dietary insufficiencies (vitamin K deficiency), moderate-severe
hypertension, polycythemia vera, vasculitis, open wound, active TB, history of
PUD, anaphylactic disorders, indwelling catheters, severe diabetes, and
menstruating and postpartum women. Use with caution in protein C deficiency. The
elderly may be more sensitive. Use care in selection of patients appropriate for
this treatment. Ensure patient cooperation especially from the alcoholic,
illicit drug user, demented, or psychotic patient. |

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Adverse
Reactions |
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As with all anticoagulants, bleeding is the major adverse effect of warfarin.
Hemorrhage may occur at virtually any site. Risk is dependent on multiple
variables, including the intensity of anticoagulation and patient
susceptibility.
"Purple toes syndrome," caused by cholesterol microembolization, also occurs
rarely. Typically, this occurs after several weeks of therapy, and may present
as a dark, purplish, mottled discoloration of the plantar and lateral surfaces.
Other manifestations of cholesterol microembolization may include rash, livedo
reticularis, rash, gangrene, abrupt and intense pain in lower extremities,
abdominal, flank, or back pain, hematuria, renal insufficiency, hypertension,
cerebral ischemia, spinal cord infarction, or other symptom of vascular
compromise.
Additional adverse effects are often related to idiosyncratic reactions, and
the frequency cannot be accurately estimated.
Cardiovascular: Vasculitis, edema, hemorrhagic shock
Central nervous system: Fever, lethargy, malaise, asthenia, pain, headache,
dizziness, stroke
Dermatologic: Rash, dermatitis, bullous eruptions, urticaria, pruritus,
alopecia
Gastrointestinal: Anorexia, nausea, vomiting, stomach cramps, abdominal pain,
diarrhea, flatulence, gastrointestinal bleeding, taste disturbance, mouth ulcers
Genitourinary: Priapism, hematuria
Hematologic: Hemorrhage, leukopenia, unrecognized bleeding sites (eg, colon
cancer) may be uncovered by anticoagulation, retroperitoneal hematoma,
agranulocytosis
Hepatic: Increased transaminases, hepatic injury, jaundice,
Neuromuscular & skeletal: Paresthesia, osteoporosis
Respiratory: Hemoptysis, epistaxis, pulmonary hemorrhage, tracheobronchial
calcification
Miscellaneous: Hypersensitivity/allergic reactions |

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Overdosage/Toxicology |
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Symptoms of overdose include internal or external hemorrhage and hematuria.
Avoid emesis and lavage to avoid possible trauma and incidental bleeding. When
an overdose occurs, the drug should be immediately discontinued and vitamin
K1 (phytonadione) may be administered, up to 25 mg I.V. for adults.
When hemorrhage occurs, fresh frozen plasma transfusions can help control
bleeding by replacing clotting factors. In urgent bleeding, prothrombin complex
concentrates may be needed.
Management of elevated INR:
INR >3 and less than or equal to 6: If no bleeding or need for
rapid reversal (ie, no need for surgery), omit next few warfarin doses and
restart at lower dose when INR less than or equal to 3.0
INR >6 and <10.0: If no bleeding but in need of rapid reversal
for surgery, stop warfarin and give phytonadione 0.5-1 mg I.V.; repeat 0.5 mg
phytonadione I.V. if INR >3 after 24 hours; restart warfarin at a lower dose;
oral vitamin K (1-2.5mg) can be given in place of parenteral phytonadione when a
more gradual reversal is acceptable
INR >10.0 and <20.0: If no bleeding, stop warfarin and give
phytonadione 3-5 mg I.V.; check INR every 6-12 hours; repeat phytonadione if
needed; reassess need and dose of warfarin
INR >20.0: If serious bleeding or warfarin overdose, stop
warfarin; give phytonadione 10 mg I.V.; check INR every 6 hours, if needed,
repeat phytonadione every 12 hours and give plasma transfusion or factor
concentrate; consider giving heparin if warfarin still indicated
Symptoms of overdose include internal or external hemorrhage and hematuria.
Avoid emesis and lavage to avoid possible trauma and incidental bleeding. When
an overdose occurs, the drug should be immediately discontinued and vitamin
K1 (phytonadione) may be administered, up to 25 mg I.V. for adults.
When hemorrhage occurs, fresh frozen plasma transfusions can help control
bleeding by replacing clotting factors. In urgent bleeding, prothrombin complex
concentrates may be needed. |

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Drug
Interactions |
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CYP1A2 enzyme substrate (minor), CYP2C8, 2C9, 2C18, 2C19, and 3A3/4 enzyme
substrate; CYP2C9 enzyme inhibitor
Induction of enzymes: Barbiturates, carbamazepine, glutethimide,
griseofulvin, nafcillin, phenytoin, rifampin
Increased procoagulant factors: Estrogens, oral contraceptives, vitamin K
(including nutritional supplements)
Decreased drug absorption: Aluminum hydroxide, cholestyramine*,
colestipol*
Other: Ethchlorvynol, griseofulvin, spironolactone**, sucralfate
*Cholestyramine and colestipol may increase the anticoagulant effect by
binding vitamin K in the gut; yet, the decreased drug absorption appears to be
of more concern.
**Diuretic-induced hemoconcentration with subsequent concentration of
clotting factors has been reported to decrease the effects of oral
anticoagulants.
Increased bleeding tendency: (Use of these agents with oral
anticoagulants may increase the chances of hemorrhage.)
Inhibit platelet aggregation: Cephalosporins, dipyridamole, indomethacin,
oxyphenbutazone, penicillin (parenteral), phenylbutazone, salicylates,
sulfinpyrazone
Inhibit procoagulant factors: Antimetabolites, quinidine, quinine,
salicylates
Ulcerogenic drugs: Adrenal corticosteroids, indomethacin, oxyphenbutazone,
phenylbutazone, potassium products, salicylates
Enhanced anticoagulant effects:
Decrease Vitamin K: Oral antibiotics can increase or decrease INR. Check INR
3 days after patient begins antibiotics to see the INR value and adjust the
warfarin dose accordingly.
Displace anticoagulant: Chloral hydrate, clofibrate, diazoxide, ethacrynic
acid, miconazole, nalidixic acid, phenylbutazone, salicylates, sulfonamides,
sulfonylureas, triclofos
Inhibit Metabolism: Alcohol (acute ingestion)*, Allopurinol, amiodarone,
chloramphenicol, chlorpropamide, cimetidine, co-trimoxazole, disulfiram,
metronidazole, phenylbutazone, phenytoin, propoxyphene, sulfinpyrazone,
sulfonamides, tolbutamide
Other: Acetaminophen, anabolic steroids, clofibrate, danazol, erythromycin,
gemfibrozil, glucagon, influenza vaccine, ketoconazole, propranolol, ranitidine,
sulindac, thyroid drugs, capecitabine, celecoxib, rofecoxib
*The hypoprothrombinemic effect of oral anticoagulants has been reported to
be both increased and decreased during chronic and excessive alcohol ingestion.
Data are insufficient to predict the direction of this interaction in alcoholic
patients. |

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Stability |
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Protect from light; injection is stable for 4 hours at room temperature after
reconstitution with 2.7 mL of sterile water |

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Mechanism of
Action |
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Interferes with hepatic synthesis of vitamin K-dependent coagulation factors
(II, VII, IX, X) |

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Pharmacodynamics/Kinetics |
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Onset of anticoagulation effect: Oral: Within 36-72 hours
Peak effect: Within 5-7 days
Absorption: Oral: Rapid
Metabolism: In the liver
Half-life: 42 hours, highly variable among individuals |

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Usual Dosage |
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Oral:
Infants and Children: 0.05-0.34 mg/kg/day; infants <12 months of age may
require doses at or near the high end of this range; consistent anticoagulation
may be difficult to maintain in children <5 years of age
Adults: 5-15 mg/day for 2-5 days, then adjust dose according to results of
prothrombin time; usual maintenance dose ranges from 2-10 mg/day
I.V. (administer as a slow bolus injection): 2-5 mg/day
Dosing adjustment/comments in hepatic disease: Monitor effect at
usual doses; the response to oral anticoagulants may be markedly enhanced in
obstructive jaundice (due to reduced vitamin K absorption) and also in hepatitis
and cirrhosis (due to decreased production of vitamin K-dependent clotting
factors); prothrombin index should be closely monitored |

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Dietary
Considerations |
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Alcohol: Chronic use of alcohol inhibits warfarin metabolism; avoid or limit
use
Food:
Vitamin K: Foods high in vitamin K (eg, beef liver, pork liver, green tea and
leafy green vegetables) inhibit anticoagulant effect. Do not change dietary
habits once stabilized on warfarin therapy; a balanced diet with a consistent
intake of vitamin K is essential; avoid large amounts of alfalfa, asparagus,
broccoli, Brussels sprouts, cabbage, cauliflower, green teas, kale, lettuce,
spinach, turnip greens, watercress. It is recommended that the diet contain a
CONSISTENT vitamin K content of 70-140 mcg/day. Check with physician before
changing diet.
Vitamin E: May increase warfarin effect; do not change dietary habits or
vitamin supplements once stabilized on warfarin therapy |

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Monitoring
Parameters |
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Prothrombin time, hematocrit, INR |

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Reference Range |
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Therapeutic: 2-5 mg/mL (SI: 6.5-16.2
mmol/L)
Prothrombin time should be
11/2
to 2 times the control or INR should be
2 to 3 times
based upon indication
Normal prothrombin time: 10-13 seconds
INR ranges based upon indication:
Atrial fibrillation: 2.0-3.0
Venous thromboembolism (DVT, PE): 2.0-3.0
TIA and stroke: 2.0-3.0
Bioprosthetic heart valve: 2.0-3.0
Acute myocardial infarction with risk factors*: 2.5-3.5
Mechanical heart valve (bileaflet, tilting disk): 2.5-3.5
Mechanical heart valve (caged ball, caged disk): 3.0-4.0
*Anterior Q-wave infarction, severe left-ventricular dysfunction, mural
thrombus on 2D echo, atrial fibrillation, history of systemic or pulmonary
embolism, congestive heart failure
Warfarin levels are not used for monitoring degree of anticoagulation. They
may be useful if a patient with unexplained coagulopathy is using the drug
surreptitiously or if it is unclear whether clinical resistance is due to true
drug resistance or lack of drug intake.
Normal prothrombin time (PT): 10.9-12.9 seconds. Healthy premature newborns
have prolonged coagulation test screening results (eg, PT, APTT, TT) which
return to normal adult values at approximately 6 months of age. Healthy
prematures, however, do not develop spontaneous hemorrhage or thrombotic
complications because of a balance between procoagulants and inhibitors
The World Health Organization (WHO), in cooperation with other
regulatory-advisory bodies, has developed system of standardizing the reporting
of PT values through the determination of the International Normalized Ratio
(INR). The INR involves the standardization of the PT by the generation of two
pieces of information: the PT ratio and the International Sensitivity Index
(ISI)
Therapeutic ranges are now available or being developed to assist practicing
physicians in their treatment of patients with a wide variety of thrombotic
disorders |

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Test
Interactions |
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Warfarin
PTT |

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Cardiovascular
Considerations |
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Warfarin is used for anticoagulation in a broad spectrum of cardiovascular
diseases, including atrial fibrillation, venous thromboses, refractory
myocardial ischemia, and in patients with prosthetic heart valves. It is
important that patients be closely monitored and that the INR be maintained in
the range considered optimal for the therapeutic objective.
Warfarin is teratogenic and therefore, should not be used in pregnancy. The
advent of low molecular weight heparins have provided an important alternative
to warfarin therapy, particularly in pregnant women with prosthetic heart
valves. Administration of low molecular weight heparins in predetermined doses
at home has obviated the need for hospitalization with intravenous heparin
therapy for these patients.
It is important that INR be closely monitored for several reasons. These
include the problem of dietary changes, changing warfarin efficacy. Furthermore,
warfarin interacts with a very wide spectrum of prescription and
over-the-counter medications. Any change in a patient's medication profile
should be carefully monitored and potential effects on increasing or attenuating
warfarin effectiveness should be addressed. It is important to advise patients
on warfarin to seek prompt medical evaluation if they develop very severe
headache or backache or should they experience significant trauma to rule out
the possibility of significant concealed bleeding. |

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Mental Health: Effects
on Mental Status |
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None reported |

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Mental Health:
Effects on Psychiatric
Treatment |
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May cause leukopenia; use caution with clozapine and carbamazepine;
barbiturates and carbamazepine may decrease the anticoagulant effect of
warfarin; chloral hydrate, alcohol, disulfiram, and SSRIs may enhance the
anticoagulant effect |

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Dental Health: Local
Anesthetic/Vasoconstrictor
Precautions |
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No information available to require special precautions |

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Dental Health:
Effects on Dental Treatment |
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Signs of warfarin overdose may first appear as bleeding from gingival tissue;
consultation with prescribing physician is advisable prior to surgery to
determine temporary dose reduction or withdrawal of
medication |

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Patient
Information |
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Take exactly as directed; if dose is missed, take as soon as possible. Do not
double doses. Do not take any medication your prescriber is not aware of and
follow diet and activity as recommended by prescriber. You may have a tendency
to bleed easily while taking this drug; brush teeth with soft brush, floss with
waxed floss, use electric razor, and avoid scissors or sharp knives and
potentially harmful activities. You may experience nausea or vomiting (small
frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help).
May discolor urine or stool. Report skin rash or irritation, unusual fever,
persistent nausea or GI upset, unusual bleeding or bruising (bleeding gums,
nosebleed, blood in urine, dark stool, bloody emesis), pain in joints or back,
swelling or pain at injection site. |

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Nursing
Implications |
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Should not be given in close proximity to other drugs because absorption may
be decreased. Administer warfarin at least 1-2 hours prior to, or 6 hours after,
cholestyramine or sucralfate, because cholestyramine or sucralfate may bind
warfarin and decrease its total absorption; avoid all I.M.
injections. |

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Dosage Forms |
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Powder for injection, as sodium, lyophilized: 2 mg, 5 mg
Tablet, as sodium: 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7.5 mg, 10 mg
|

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References |
|
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