Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3707
| Predicate | Object |
|---|---|
| rdf:type | |
| rdfs:label |
COUMADIN (Tablet)
|
| dailymed-instance:dosage |
The dosage and administration of COUMADIN 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.The
best available information supports the following recommendations for dosing
of COUMADIN.<br/>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 (>90th 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.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.<br/>Atrial Fibrillation: Five 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. 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 oralwarfarin should be used; the target INR may be increased and aspirin added
depending on valve type and position, and on patient factors.<br/>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 low-dose aspirin (���100 mg/day) for 3 months after the MI is suggested.<br/>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 witha 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.<br/>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. 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.<br/>Initial Dosage: The dosing of COUMADIN 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 COUMADIN therapy be initiated with a dose of 2 to 5
mg per day with dosage adjustments based on the results of PT/INR determinations.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 COUMADIN .<br/>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 COUMADIN 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 COUMADIN .<br/>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.<br/>Missed Dose: The anticoagulant effect of COUMADIN persists beyond 24 hours.
If the patient forgets to take the prescribed dose of COUMADIN 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.<br/>Intravenous Route of Administration: COUMADIN for Injection provides an alternate administration route
for patients who cannot receive oral drugs. The IV dosages would be the same
as those that would be used orally if the patient could take the drug by the
oral route. COUMADIN for Injection should be administered as a slow bolus
injection over 1 to 2 minutes into a peripheral vein. It is not recommended
for intramuscular 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, COUMADIN 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.<br/>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.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 COUMADIN in order to maintain the individual within the therapeutic
range. Acceptable intervals for PT/INR determinations are normally
within the range of 1 to 4 weeks after a stable dosage has been determined. To
ensure adequate control, it is recommended that additional PT tests be done
when other warfarin productsare interchanged with warfarin sodium tablets,
USP, as well as whenever other medications are initiated, discontinued, or
taken irregularly . 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.Self-testing
patients had fewer bleeding events than patients in usual care.<br/>Treatment During Dentistry and Surgery: The management of patients who undergo dental and surgical procedures
requires close liaison between attending physicians, surgeons and dentists.PT/INR
determination is recommended just prior to any dental or surgical procedure.
In patients undergoing minimal invasive procedures who must be anticoagulated
prior to, during, or immediately following these procedures, adjusting the
dosage of COUMADIN 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 COUMADIN therapy.
When discontinuing COUMADIN even for a short period of time, the benefits
and risks should be strongly considered.<br/>Conversion From Heparin Therapy: Since the anticoagulant effect of COUMADIN is delayed, heparin
is preferred initially for rapid anticoagulation. Conversion to COUMADIN 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 COUMADIN therapy be overlapped with heparin for 4 to 5 days,
until COUMADIN has produced the desired therapeutic response as determined
by PT/INR. When COUMADIN has produced the desired PT/INR or prothrombin activity,
heparin may be discontinued. COUMADIN 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 COUMADIN, the interference with heparin
anticoagulation is of minimal clinical significance. As heparin may affect the PT/INR, patients receiving both heparin
and COUMADIN should have blood for PT/INR determination drawn at least:
|
| dailymed-instance:descripti... |
COUMADIN (crystalline warfarin sodium) is an anticoagulant which
acts by inhibiting vitamin K-dependent coagulation factors. Chemically, it
is 3-(��-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 empirical formula is CHNaO, and its structural formula may be represented by the following: Crystalline warfarin sodium occurs as a white, odorless, crystalline
powder, is discolored by light and is very soluble in water; freely soluble
in alcohol; very slightly soluble in chloroform and in ether. COUMADIN Tablets for oral use also contain: COUMADIN for Injection is supplied as a sterile, lyophilized powder,
which, after reconstitution with 2.7 mL sterile Water for Injection, contains:
|
| dailymed-instance:clinicalP... |
COUMADIN and other coumarin anticoagulants act by inhibiting the
synthesis of vitamin K dependent clotting factors, which include Factors II,
VII, IX and X, and the anticoagulant proteins C and S. Half-lives of these
clotting factors are as follows: Factor II - 60 hours, VII - 4-6 hours, IX
- 24 hours, and X - 48-72 hours. The half-lives of proteins C and S are approximately
8 hours and 30 hours, respectively. The resultant in vivo effect
is a sequential depression of 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��-carboxyglutamic acid residues in the
proteins which are essential for biological activity.<br/>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 Kepoxide.
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 COUMADIN 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.<br/>Pharmacokinetics: COUMADIN is a racemic mixture of the R- and S-enantiomers.
The S-enantiomer exhibits 2-5 times more
anticoagulant activity than the R-enantiomer in humans, but
generally has a more rapid clearance.<br/>Absorption: COUMADIN is essentially completely absorbed after oral administrationwith peak concentration generally attained within the first 4 hours.<br/>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 similarto each other
and to that of the racemate. Concentrations in fetal plasma approach the maternal
values, but warfarin has not been found in human milk (see WARNINGS:
Lactation). Approximately 99% of the drug is bound to plasma
proteins.<br/>Metabolism: The elimination of warfarin is almost entirely by metabolism. COUMADIN
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. Themetabolites of warfarin that
have been identified include dehydrowarfarin, two diastereoisomer alcohols,
4���-, 6-, 7-, 8- and 10-hydroxywarfarin. The cytochrome P-450 isozymes involved
in the metabolism of warfarin include 2C9, 2C19, 2C8, 2C18, 1A2, and 3A4.
2C9 is likely to be the principal form of human liver P-450 which modulates
the in vivo anticoagulant activity of warfarin. The S-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 in vitro 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). 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.<br/>Excretion: The terminal half-life of warfarin after a single dose is approximately
one week; however, the effective half-life ranges from 20 to 60 hours, with
a mean of about 40 hours. The clearance of R-warfarin is generally half that
of S-warfarin, thus as the volumes of distribution are similar, the half-life
of R-warfarin is longer than that of S-warfarin. The half-life of R-warfarin
ranges from 37 to 89 hours, while that of S-warfarin ranges from 21 to 43
hours. Studies with radiolabeled drug have demonstrated that up to 92% of
the orally administered dose is recovered in urine. Very little warfarin is
excreted unchanged in urine. Urinaryexcretion is in the form of metabolites.<br/>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.<br/>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.<br/>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.<br/>Hepatic Dysfunction: Hepatic dysfunction can potentiate the response to warfarin through
impaired synthesis of clotting factors and decreased metabolism of warfarin. The administration of COUMADIN 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 72-96 hours after dosing,
indicating that the administration of IV COUMADIN should not provide any increased
biological effect or earlier onset of action.
|
| dailymed-instance:activeIng... | |
| dailymed-instance:contraind... |
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:<br/>Pregnancy: COUMADIN is contraindicated in women who are or may become pregnant
because the drug passes through the placental barrier and may cause fatal
hemorrhage to the fetus in utero. Furthermore, there have
been reports of birth malformations in children born to mothers who have been
treated with warfarin during pregnancy. Embryopathy characterized by nasal hypoplasia with or without stippled
epiphyses (chondrodysplasia punctata) has been reported in pregnant women
exposed to warfarin during the first trimester. Central nervous system abnormalities
also have been reported, including dorsal midline dysplasia characterized
by agenesis of the corpus callosum, Dandy-Walker malformation, and midline
cerebellar atrophy. Ventral midline dysplasia, characterized by optic atrophy,
and eye abnormalities have been observed. Mental retardation, blindness, and
other central nervous system abnormalities have been reported in association
with second and third trimester exposure. Although rare, teratogenic reports
following in utero exposure to warfarin include urinary tract
anomalies such as single kidney, asplenia, anencephaly, spina bifida, cranial
nerve palsy, hydrocephalus, cardiac defects and congenital heart disease,
polydactyly, deformities of toes, diaphragmatic hernia, corneal leukoma, cleft
palate, cleft lip, schizencephaly, and microcephaly. Spontaneous abortion and 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 evaluated and the indications critically reviewed
with the patient. If the patient becomes pregnant while taking this drug,
she should be apprised of the potential risks to the fetus, and the possibility
of termination of the pregnancy should be discussed in light of those risks. Hemorrhagic tendencies or blood dyscrasias. Recent or contemplated surgery of: (1) central nervous
system; (2) eye; (3) traumatic surgery resulting in large open surfaces. Bleeding tendencies associated with active ulceration or
overt bleeding of: (1) gastrointestinal, genitourinary
or respiratory tracts; (2) cerebrovascular hemorrhage; (3) aneurysms-cerebral,
dissecting aorta; (4) pericarditis and pericardial effusions; (5) bacterial
endocarditis. Threatened abortion, eclampsia and preeclampsia. Inadequate laboratory facilities. Unsupervised patients with senility, alcoholism, 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,
malignant hypertension and known hypersensitivity to warfarin or to any other
components of this product.
|
| dailymed-instance:supply |
Tablets: For oral use, single scored with one face imprinted numerically
with 1, 2, 2-1/2, 3, 4, 5, 6, 7-1/2 or 10 superimposed and inscribed with���COUMADIN���and with the opposite face plain. COUMADIN is available in bottles
and Hospital Unit-Dose Blister Packages with potencies and colors as follows: Protect from light. Store at controlled room temperature (59��-86��F,
15��-30��C). Dispense in a tight, light-resistant container as defined in the
USP. Hospital Unit-Dose Blister Packages are to be stored in carton
until contents have been used.<br/>Injection: Available for intravenous use only. Not recommended for intramuscular
administration. Reconstitute with 2.7 mL of sterile Water for Injection to
yield 2 mg/mL. Net contents 5.4 mg lyophilized powder. Maximum yield 2.5 mL. Protect from light. Keep vial in box until used. Store at controlled
room temperature (59��-86��F, 15��-30��C). After reconstitution, store at controlled room temperature (59��-86��F,
15��-30��C) and use within 4 hours. Do not refrigerate. Discard any unused solution.
|
| dailymed-instance:boxedWarn... |
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 , 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 measuresto minimize risk of bleeding
and to report immediately to physicians signs and symptoms of bleeding .
|
| dailymed-instance:activeMoi... | |
| dailymed-instance:inactiveI... | |
| dailymed-instance:precautio... |
Periodic determination of PT/INR is essential. Numerous
factors, alone or in combination including changes in diet, medications, botanicals,
and genetic variations in the CYP2C9 and VKORC1 enzymes (see CLINICAL
PHARMACOLOGY: Pharmacogenomics)
may influence the response of the patient to warfarin.<br/>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 COUMADIN through pharmacodynamic
or pharmacokinetic mechanisms. Pharmacodynamic mechanisms for drug interactions
with COUMADIN 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 COUMADIN 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: EXOGENOUS FACTORS: Potential drug interactions with COUMADIN are listed below
by drug class and by specific drugs. The following factors, alone or in combination, may be responsible
for DECREASED PT/INR response: ENDOGENOUS FACTORS: EXOGENOUS FACTORS: Potential drug interactions with COUMADIN (Warfarin Sodium)
are listed below by drug class and by specific drugs. Because a patient may be exposed to a combination of the above
factors, the net effect of COUMADIN 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.<br/>Botanical (Herbal) Medicines: Caution should be exercised when botanical medicines (botanicals)
are taken concomitantly with COUMADIN. Few adequate, well-controlled studies
exist evaluating the potential for metabolic and/or pharmacologic interactions
between botanicals and COUMADIN. 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'sresponse with additional PT/INR determinations when initiating or discontinuing
botanicals. Specific botanicals reported to affect COUMADIN therapy include
the following: Some botanicals may cause bleeding events when taken alone (e.g.,
garlic and Ginkgo biloba) and may have anticoagulant, antiplatelet, and/or
fibrinolytic properties. These effects would be expected to be additive to
the anticoagulant effects of COUMADIN. Conversely, other botanicals may have
coagulant properties when taken alone or may decrease the effects of COUMADIN. Some botanicals that may affect coagulation are listed below for
reference; however, this list should not be considered all-inclusive. Many
botanicals have several common names and scientific names. The most widely
recognized common botanical names are listed.<br/>Effect on Other Drugs: 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.<br/>Considerations for Increased Bleeding Risk: COUMADIN is a narrow therapeutic range (index) drug, and additional
caution should be observed when warfarin sodium is administered to certain
patients. Reported 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 ,
and long duration of warfarin therapy. Identification of risk factors for
bleeding and certain genetic variations in CYP2C9 and VKORC1 in a patient
may increase the need for more frequent INR monitoring and the use of lower
warfarin doses . Bleeding is more likely
to occur during the starting period and with a higher dose of COUMADIN (resulting
in ahigher INR). Intramuscular (I.M.) injections of concomitant medications should
be confined to the upper extremities which permits easy access for manual
compression, inspections for bleeding and use of pressure bandages. Caution should be observed when COUMADIN (or warfarin) is administered
concomitantly with nonsteroidal anti-inflammatory drugs (NSAIDs), including
aspirin, to be certain that no change in anticoagulation dosage is required.
In addition to specific drug interactions that might affect PT/INR, NSAIDs,
including aspirin, can inhibit platelet aggregation, and can cause gastrointestinal
bleeding, peptic ulceration and/or perforation.<br/>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 COUMADIN during pregnancy and do not
become pregnant while taking it .
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 COUMADIN is being taken. If theprescribed dose of COUMADIN 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 COUMADIN the next day to make up for missed doses. The amount of vitamin
K in food may affect therapy with COUMADIN. 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 healthcare
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
COUMADIN is discontinued, patients should be cautioned that the anticoagulant
effects of COUMADIN 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 Guideshould be available to patients
when their prescriptions for warfarin sodium are issued.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity and mutagenicity studies have not been performed
with COUMADIN. The reproductive effects of COUMADIN have not been evaluated.
The use of warfarin during pregnancy has been associated with the development
of fetal malformations in humans .<br/>Use in Pregnancy:<br/>Pregnancy Category X: See CONTRAINDICATIONS.<br/>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 COUMADIN in pediatric patients is well-documented for the prevention
and treatment of thromboembolic events. Difficulty achieving and maintainingtherapeutic PT/INR ranges in the pediatric patient has been reported. More
frequent PT/INR determinations are recommended because of possible changing
warfarin requirements.<br/>Geriatric Use: Patients 60 years or older appear to exhibit greater than expected
PT/INR response to the anticoagulant effects of warfarin . COUMADIN is contraindicated
in any unsupervised patient with senility. Caution should be observed with
administration of warfarin sodium to elderly patients in any situation or
physical condition where added risk of hemorrhage is present. Lower initiation
and maintenance doses of COUMADIN are recommended for elderly patients .
|
| dailymed-instance:overdosag... |
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.<br/>Treatment: Excessive anticoagulation, with or without bleeding, may be controlled
by discontinuing COUMADIN therapy and if necessary, by administration of oral
or parenteral vitamin K. (Please see recommendations
accompanying vitamin Kpreparations prior to use.) Such use of vitamin Kreduces response
to subsequent COUMADIN therapy. Patients may return to a pretreatment thrombotic
status following the rapid reversal of a prolonged PT/INR. Resumption of COUMADIN
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. 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 COUMADIN
(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 COUMADIN
treatment. Packed red blood cells may also be given if significant blood loss
has occurred. Infusions of blood or plasma should be monitoredcarefully to
avoid precipitating pulmonary edema in elderly patients or patients with heart
disease.
|
| dailymed-instance:genericMe... |
WARFARIN SODIUM
|
| dailymed-instance:fullName |
COUMADIN (Tablet)
|
| dailymed-instance:adverseRe... |
Potential adverse reactions to COUMADIN may include: Rare events of tracheal or tracheobronchial calcification have
been reported in association with long-term warfarin therapy. The clinical
significance of this event is unknown. Priapism has been associated with anticoagulant administration;
however, a causal relationship has not been established.
|
| dailymed-instance:warning |
The most serious risks associated with anticoagulant therapy with
warfarin sodium are hemorrhage in any tissue or organand, 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. COUMADIN (Warfarin Sodium), a narrow therapeuticrange (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 COUMADIN are administered
concomitantly, refer below to Conversion From Heparin Therapy for
recommendations. Increased caution should be observed when COUMADIN is administered
in the presence of any predisposing condition where added risk of hemorrhage,
necrosis, and/or gangrene is present. Anticoagulation therapy with COUMADIN 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 COUMADIN 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 sequelaeof 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. COUMADIN 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. 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 COUMADIN 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.
|
| dailymed-instance:indicatio... |
COUMADIN is indicated for the prophylaxis and/or treatment of venous
thrombosis and its extension, and pulmonary embolism. COUMADIN is indicated for the prophylaxis and/or treatment of the
thromboembolic complications associated with atrial fibrillation and/or cardiac
valve replacement. COUMADIN is indicated to reduce the risk of death, recurrent myocardial
infarction, and thromboembolic events such as stroke or systemic embolization
after myocardial infarction.
|
| dailymed-instance:represent... | |
| dailymed-instance:routeOfAd... | |
| dailymed-instance:name |
COUMADIN
|