WARFARIN SOD
DESCRIPTION:
WARF (crystalline warfarin sodium), is an anticoagulant which acts by
inhibiting vitamin K- dependent coagulation factors. Chemically, it is 3-(alpha-
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 C19H15NaO4.
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.
ACTIONS/CLINICAL PHARMACOLOGY:
WARF 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
Factors VII, IX, 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 gamma- carboxyglutamic acid residues in the
proteins which are essential for biological activity. Warfarin is thought to
interfere with clotting factor synthesis by inhibition of the regeneration of
vitamin K1 epoxide. The degree of depression is dependent upon the dosage
administered. Therapeutic doses of warfarin decrease the total amount of the
active form of each vitamin K dependent clotting factor made by the liver by
approximately 30% to 50%.
An anticoagulation effect generally occurs within 24 hours after drug
administration. However, peak anticoagulant effect may be delayed 72 to 96
hours. The duration of action of a single dose of racemic warfarin is 2 to 5
days. The effects of WARF 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: WARF 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.
ABSORPTION: WARF 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
WARNINGS--Lactation). Approximately 99% of the drug is bound to plasma proteins.
METABOLISM: The elimination of warfarin is almost entirely by metabolism.
WARF 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 In Vivo anticoagulant activity of warfarin.
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. Urinary excretion is in the form of metabolites.
ELDERLY: There are no significant age-related differences in the
pharmacokinetics of racemic warfarin. Limited information suggests that there is
no difference in the clearance of S-warfarin in elderly versus young subjects.
However, there may be a slight decrease in the clearance of R- warfarin in the
elderly compared to the young. Older patients (60 years or older) appear to
exhibit greater than expected PT/INR response to the anticoagulant effects of
warfarin. As patient age increases, less warfarin is required to produce a
therapeutic level of anticoagulation. The cause of this response to warfarin is
not known.
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 WARF via the intravenous (I.V.) route should provide
the patient with the same concentration of an equal oral dose, but maximum
plasma concentration will be reached earlier. However, the full anticoagulant
effect of a dose of warfarin may not be achieved until 72-96 hours after dosing,
indicating that the administration of I.V. WARF should not provide any
increased biological effect or earlier onset of action.
CLINICAL STUDIES:
CLINICAL TRIALS
ATRIAL FIBRILLATION (AF): In five prospective randomized controlled clinical
trials involving 3711 patients with nonrheumatic AF, warfarin significantly
reduced the risk of systemic thromboembolism including stroke (See Table 1). The
risk reduction ranged from 60% to 86% in all except one trial (CAFA: 45%) which
stopped early due to published positive results from two of these trials. The
incidence of major bleeding in these trials ranged from 0.6 to 2.7% (See Table
1). 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. Similar data from clinical
studies in valvular atrial fibrillation patients are not available.
TABLE 1
CLINICAL STUDIES OF WARFARIN IN NON-RHEUMATIC AF PATIENTS*
---------------------------------------------------------------------------------------------------------------------------------------------------
Study N PT INR Thromboembolism % Major Bleeding
Ratio
Warfarin- Control %Risk P-value Warfarin Control
Treated Patients Reduction Treated Patients
Patients Patients
-----------------------------------------------------------------------------------------------------------------------------------------------------
AFASAK 335 336 1.5- 2.8- 60 0.027 0.6 0.0
2.0 4.2
SPAF 210 211 1.3- 2.0- 67 0.01 1.9 1.9
1.8 4.5
BAATAF 212 208 1.2- 1.5- 86 <0.05 0.9 0.5
1.5 2.7
CAFA 187 191 1.3- 2.0- 45 0.25 2.7 0.5
1.6 3.0
SPINAF 260 265 1.2- 1.4- 79 0.001 2.3 1.5
1.5 2.8
--------------------------------------------------------------------------------------------------------------------------------------------------------
* All study results of warfarin vs. control are based on intention-to-treat
analysis and include ischemic stroke and systemic thromboembolism,
excluding hemorrhage and transient ischemic attacks.
MYOCARDIAL INFARCTION: WARIS (The Warfarin Re- Infarction Study) was a double-
blind, randomized study of 1214 patients 2 to 4 weeks post- infarction treated
with warfarin to a target INR of 2.8 to 4.8. (But note that a lower INR was
achieved and increased bleeding was associated with INR's above 4.0; see Dosage
and Administration.) The primary endpoint was a combination of total mortality
and recurrent infarction. A secondary endpoint of cerebrovascular events was
assessed. Mean follow- up of the patients was 37 months. The results for each
endpoint separately, including an analysis of vascular death, are provided in
the following table:
TABLE 2
% Risk
Warfarin Placebo Reduction
Event (N=607) (N=607) RR (95%CI) (p-value)
------------------------------------------------------------------------------------------------------------------------------------------
Total Patient Years of 2018 1944
Follow-up
-----------------------------------------------------------------------------------------------------------------------------------------
Total Mortality 94 (4.7/100 py) 123 (6.3/100 0.76 (0.60, 24 (p=0.030)
py) 0.97)
Vascular Death 82 (4.1/100 py) 105 (5.4/100 0.78 (0.60, 22 (p=0.068)
py) 1.02)
-----------------------------------------------------------------------------------------------------------------------------------------
Recurrent MI 82 (4.1/100 py) 124 (6.4/100 0.66 (0.51, 34 (p=0.001)
py) 0.85)
-----------------------------------------------------------------------------------------------------------------------------------------
Cerebrovascular Event 20 44 (2.3/100 py) 0.46 54 (p=0.002)
(1.0/100 py) (0.28, 0.75)
--------------------------------------------------------------------------------------------------------------------------------------------
RR=Relative risk; Risk reduction=(I-RR); CI=Confidence interval; MI=Myocardial
infarction; py=patient years
MECHANICAL AND BIOPROSTHETIC HEART VALVES: In a prospective, randomized, open
label, positive- controlled study (Mok et al, 1985) in 254 patients, the
thromboembolic-free interval was found to be significantly greater in patients
with mechanical prosthetic heart valves treated with warfarin alone compared
with dipyridamole- aspirin (p<0.005) and pentoxifylline-aspirin (p<0.05) treated
patients. Rates of thromboembolic events in these groups were 2.2, 8.6, and
7.9/100 patient years, respectively. Major bleeding rates were 2.5, 0.0, and
0.9/100 patient years, respectively.
In a prospective, open label, clinical trial (Saour et al, 1990) comparing
moderate (INR 2.65) vs. high intensity (INR 9.0) warfarin therapies in 258
patients with mechanical prosthetic heart valves, thromboembolism occurred with
similar frequency in the two groups (4.0 and 3.7 events/100 patient years,
respectively). Major bleeding was more common in the high intensity group (2.1
events/100 patient years) vs 0.95 events/100 patient years in the moderate
intensity group.
In a randomized trial (Turpie et al, 1988) in 210 patients comparing two
intensities of warfarin therapy (INR 2.0-2.25 vs. INR 2.5-4.0) for a three month
period following tissue heart value replacement, thromboembolism occurred with
similar frequency in the two groups (major embolic events 2.0% vs. 1.9%,
respectively and minor embolic events 10.8% vs. 10.2%, respectively). Major
bleeding complications were more frequent with the higher intensity (major
hemorrhages 4.6%) vs. none in the lower intensity.
INDICATIONS AND USAGE:
WARF (Warfarin Sodium) is indicated for the prophylaxis and/or treatment of
venous thrombosis and its extension, and pulmonary embolism.
WARF is indicated for the prophylaxis and/or treatment of the thromboembolic
complications associated with atrial fibrillation and/or cardiac valve
replacement.
WARF is 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: WARF 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 still birth are known to occur and a higher risk of
fetal mortality is associated with the use of warfarin. Low birth weight and
growth retardation have also been reported.
Women of childbearing potential who are candidates for anticoagulant therapy
should be carefully evaluated and the indications critically reviewed with the
patient. If the patient becomes pregnant while taking this drug, she should be
apprised of the potential risks to the fetus, and the possibility of termination
of the pregnancy should be discussed in 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 and 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 sodium
warfarin are hemorrhage in any tissue or organ and, less frequently (<0.1%),
necrosis and/or gangrene of skin and other tissues. The risk of hemorrhage is
related to the level of intensity and the duration of anticoagulant therapy.
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. WARF, 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) or other suitable coagulation tests. Determinations of
whole blood clotting and bleeding times are not effective measures for control
of therapy. Heparin prolongs the one-stage PT. When heparin and WARF are
administered concomitantly, refer below to CONVERSION FROM HEPARIN THERAPY for
recommendations.
Caution should be observed when WARF is administered in any situation or in
the presence of any predisposing condition where added risk of hemorrhage or
necrosis is present.
Anticoagulation therapy with WARF 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 WARF therapy is recommended when such phenomena are
observed.
Systemic atheroemboli and cholesterol microemboli can present with a variety of
signs and symptoms including purple toes syndrome, livedo reticularis, rash,
gangrene, abrupt and intense pain in the leg, foot, or toes, foot ulcers,
myalgia, penile gangrene, abdominal pain, flank or back pain, hematuria, renal
insufficiency, hypertension, cerebral ischemia, spinal cord infarction,
pancreatitis, symptoms simulating polyarteritis, or any other sequelae of
vascular compromise due to embolic occlusion. The most commonly involved
visceral organs are the kidneys followed by the pancreas, spleen, and liver.
Some cases have progressed to necrosis or death.
Purple toes syndrome is a complication of oral anticoagulation characterized by
a dark, purplish or mottled color of the toes, usually occurring between 3-10
weeks, or later, after the initiation of therapy with warfarin or related
compounds. Major features of this syndrome include purple color of plantar
surfaces and sides of the toes that blanches on moderate pressure and fades with
elevation of the legs; pain and tenderness of the toes; waxing and waning of the
color over time. While the purple toes syndrome is reported to be reversible,
some cases progress to gangrene or necrosis which may require debridement of the
affected area, or may lead to amputation.
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.
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: WARF appears in the milk of nursing mothers in an inactive form.
Infants nursed by WARF treated mothers had no change in prothrombin times
(PTs). 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 WARF may
minimize the incidence of tissue necrosis. Warfarin therapy should be
discontinued when warfarin is suspected to be the cause of developing necrosis
and heparin therapy may be considered for anticoagulation.
MISCELLANEOUS: polycythemia vera, vasculitis, and severe diabetes.
Minor and severe allergic/hypersensitivity reactions and anaphylactic reactions
have been reported.
In patients with acquired or inherited warfarin resistance, decreased
therapeutic responses to WARF have been reported. Exaggerated therapeutic
responses have been reported in other patients.
Patients with congestive heart failure may exhibit greater than expected PT/INR
response to WARF, thereby requiring more frequent laboratory monitoring, and
reduced doses of WARF.
Concurrent use of anticoagulants with streptokinase or urokinase is not
recommended and may be hazardous. (Please note recommendations accompanying
these preparations.)
PRECAUTIONS:
PERIODIC DETERMINATION OF PT/INR OR OTHER SUITABLE COAGULATION TEST IS
ESSENTIAL.
NUMEROUS FACTORS, ALONE OR IN COMBINATION, INCLUDING TRAVEL, CHANGES IN DIET,
ENVIRONMENT, PHYSICAL STATE AND MEDICATION MAY INFLUENCE RESPONSE OF THE PATIENT
TO ANTICOAGULANTS. IT IS GENERALLY GOOD PRACTICE TO MONITOR THE PATIENT'S
RESPONSE WITH ADDITIONAL PT/INR DETERMINATIONS IN THE PERIOD IMMEDIATELY AFTER
DISCHARGE FROM THE HOSPITAL, AND WHENEVER OTHER MEDICATIONS 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 WARF THROUGH PHARMACODYNAMIC OR PHARMACOKINETIC
MECHANISMS. PHARMACODYNAMIC MECHANISMS FOR DRUG INTERACTIONS WITH WARF 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 WARF 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
cancer
collagen vascular disease
congestive heart failure
diarrhea
elevated temperature
hepatic disorders
infectious hepatitis
jaundice
hyperthyroidism
poor nutritional state
steatorrhea
vitamin K deficiency
EXOGENOUS FACTORS:
POTENTIAL DRUG INTERACTIONS WITH WARF ARE LISTED BELOW BY DRUG CLASS AND BY
SPECIFIC DRUGS.
CLASSES OF DRUGS
Adrenergic Stimulants, Central
Alcohol Abuse Reduction Preparations
Analgesics
Anesthetics, Inhalation
Antiarrhythmics*
Antibiotics*
Aminoglycosides (oral)
Cephalosporins, parenteral
Macrolides
Miscellaneous
Penicillins, intravenous, high dose
Quinolones (fluoroquinolones)
Sulfonamides, long acting
Tetracyclines
Anticoagulants
Anticonvulsants*
Antidepressants*
Antimalarial Agents
Antineoplastics*
Antiparasitic/Antimicrobials
Antiplatelet Drugs/Effects
Antithyroid Drugs*
Beta-Adrenergic Blockers
Bromelains
Cholelitholytic Agents
Diabetes Agents, Oral
Diuretics*
Fungal Medications, Systemic*
Gastric Acidity and Peptic Ulcer Agents*
Gastrointestinal, Ulcerative Colitis Agents
Gout Treatment Agents
Hemorrheologic Agents
Hepatotoxic Drugs
Hyperglycemic Agents
Hypertensive Emergency Agents
Hypnotics*
Hypolipidemics*
Monoamine Oxidase Inhibitors
Narcotics, prolonged
Nonsteroidal Anti-Inflammatory Agents
Psychostimulants
Pyrazolones
Salicylates
Selective Serotonin Reuptake Inhibitors
Steroids, Adrenocortical*
Steroids, Anabolic (17-Alkyl Testosterone Derivatives)
Thrombolytics
Thyroid Drugs
Tuberculosis Agents*
Uricosuric Agents
Vaccines
Vitamins*
SPECIFIC DRUGS REPORTED
acetaminophen
alcohol*
allopurinol
aminosalicylic acid
amiodarone HCl
aspirin
azithromycin
cefamandole
cefazolin
cefoperazone
cefotetan
cefoxitin
ceftriaxone
chenodiol
chloramphenicol
chloral hydrate*
chlorpropamide
cholestyramine*
cimetidine
ciprofloxacin
clarithromycin
clofibrate
WARF overdose
cyclophosphamide*
danazol
dextran
dextrothyroxine
diazoxide
diclofenac
dicumarol
diflunisal
disulfiram
doxycycline
erythromycin
ethacrynic acid
fenoprofen
fluconazole
fluorouracil
fluoxetine
fluvoxamine
glucagon
halothane
heparin
ibuprofen
ifosfamide
indomethacin
influenza virus vaccine
itraconazole
ketoprofen
ketorolac
levamisole
levothyroxine
liothyronine
lovastatin
mefenamic acid
methimazole*
methyldopa
methylphenidate
methylsalicylate ointment (topical)
metronidazole
miconazole
moricizine hydrochloride*
nalidixic acid
naproxen
neomycin
norfloxacin
ofloxacin
olsalazine
omeprazole
oxaprozin
oxymetholone
paroxetine
penicillin G, intravenous
pentoxifylline
phenylbutazone
phenytoin*
piperacillin
piroxicam
prednisone*
propafenone
propoxyphene
propranolol
propylthiouracil*
quinidine
quinine
ranitidine*
sertraline
simvastatin
stanozolol
streptokinase
sulfamethizole
sulfamethoxazole
sulfinpyrazone
sulfisoxazole
sulindac
tamoxifen
tetracycline
thyroid
ticarcillin
ticlopidine
tissue plasminogen activator (t-PA)
tolbutamide
trimethoprim/sulfamethoxazole
urokinase
valproate
vitamin E
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
hereditary coumarin resistance
hyperlipemia
hypothyroidism
nephrotic syndrome
EXOGENOUS FACTORS:
POTENTIAL DRUG INTERACTIONS WITH WARF ARE LISTED BELOW BY DRUG CLASS AND BY
SPECIFIC DRUGS.
CLASSES OF DRUGS
Adrenal Cortical Steroid Inhibitors
Antacids
Antianxiety Agents
Antiarrhythmics*
Antibiotics*
Anticonvulsants*
Antidepressants*
Antihistamines
Antineoplastics*
Antipsychotic Medications
Antithyroid Drugs*
Barbiturates
Diuretics*
Enteral Nutritional Supplements
Fungal Medications, Systemic*
Gastric Acidity and Peptic Ulcer
Agents*
Hypnotics*
Hypolipidemics*
Immunosuppressives
Oral Contraceptives, Estrogen Containing
Steroids, Adrenocortical*
Tuberculosis Agents*
Vitamins*
SPECIFIC DRUGS REPORTED
alcohol*
aminoglutethimide
amobarbital
azathioprine
butabarbital
butalbital
carbamazepine
chloral hydrate*
chlordiazepoxide
chlorthalidone
cholestyramine*
corticotropin
cortisone
WARF underdosage
cyclophosphamide*
dicloxacillin
ethchlorvynol
glutethimide
griseofulvin
haloperidol
meprobamate
6-mercaptopurine
methimazole*
moricizine hydrochloride*
nafcillin
paraldehyde
pentobarbital
phenobarbital
phenytoin*
prednisone*
primidone
propylthiouracil*
ranitidine*
rifampin
secobarbital
spironolactone
sucralfate
trazodone
vitamin C (high dose)
vitamin K
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 WARF 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.
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.
SPECIAL RISK PATIENTS: WARF is a narrow therapeutic range (index) drug, and
caution should be observed when warfarin sodium is administered to certain
patients such as the elderly or debilitated or when administered in any
situation or physical condition where added risk of hemorrhage is present.
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 WARF (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.
Acquired or inherited warfarin resistance should be suspected if large daily
doses of WARF are required to maintain a patient's PT/INR within a normal
therapeutic range.
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) and other over-the-counter medications except on advice
of the physician. Avoid alcohol consumption. Do not take WARF during
pregnancy and do not become pregnant while taking it (see CONTRAINDICATIONS).
Avoid any activity or sport that may result in traumatic injury. Prothrombin
time tests and regular visits to physician or clinic are needed to monitor
therapy. Carry identification stating that WARF is being taken. If the
prescribed dose of WARF 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
WARF the next day to make up for missed doses. The amount of vitamin K in
food may affect therapy with WARF. 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. 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 WARF is discontinued,
patients should be cautioned that the anticoagulant effects of WARF may
persist for about 2 to 5 days.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY: Carcinogenicity and
mutagenicity studies have not been performed with WARF. The reproductive
effects of WARF have not been evaluated.
USE IN PREGNANCY: Pregnancy Category X--See CONTRAINDICATIONS.
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 WARF in pediatric patients is well-documented for the
prevention and treatment of thromboembolic events. Difficulty achieving and
maintaining therapeutic PT/INR ranges in the pediatric patient has been
reported. More frequent PT/INR determinations are recommended because of
possible changing warfarin requirements.
DRUG INTERACTIONS:
POTENTIAL DRUG INTERACTIONS WITH WARF ARE LISTED BELOW BY DRUG CLASS AND BY
SPECIFIC DRUGS.
CLASSES OF DRUGS
Adrenergic Stimulants, Central
Alcohol Abuse Reduction Preparations
Analgesics
Anesthetics, Inhalation
Antiarrhythmics*
Antibiotics*
Aminoglycosides (oral)
Cephalosporins, parenteral
Macrolides
Miscellaneous
Penicillins, intravenous, high dose
Quinolones (fluoroquinolones)
Sulfonamides, long acting
Tetracyclines
Anticoagulants
Anticonvulsants*
Antidepressants*
Antimalarial Agents
Antineoplastics*
Antiparasitic/Antimicrobials
Antiplatelet Drugs/Effects
Antithyroid Drugs*
Beta-Adrenergic Blockers
Bromelains
Cholelitholytic Agents
Diabetes Agents, Oral
Diuretics*
Fungal Medications, Systemic*
Gastric Acidity and Peptic Ulcer Agents*
Gastrointestinal, Ulcerative Colitis Agents
Gout Treatment Agents
Hemorrheologic Agents
Hepatotoxic Drugs
Hyperglycemic Agents
Hypertensive Emergency Agents
Hypnotics*
Hypolipidemics*
Monoamine Oxidase Inhibitors
Narcotics, prolonged
Nonsteroidal Anti-Inflammatory Agents
Psychostimulants
Pyrazolones
Salicylates
Steroids, Adrenocortical*
Steroids, Anabolic (17-Alkyl Testosterone Derivatives)
Thrombolytics
Thyroid Drugs
Tuberculosis Agents*
Uricosuric Agents
Vaccines
Vitamins*
SPECIFIC DRUGS REPORTED
acetaminophen
alcohol*
allopurinol
aminosalicylic acid
amiodarone HCl
aspirin
cefamandole
cefazolin
cefoperazone
cefotetan
cefoxitin
ceftriaxone
chenodiol
chloramphenicol
chloral hydrate*
chlorpropamide
cholestyramine*
cimetidine
ciprofloxacin
clarithromycin
clofibrate
WARF overdose
cyclophosphamide*
danazol
dextran
dextrothyroxine
diazoxide
diclofenac
dicumarol
diflunisal
disulfiram
doxycycline
erythromycin
ethacrynic acid
fenoprofen
fluconazole
fluorouracil
glucagon
halothane
heparin
ibuprofen
ifosfamide
indomethacin
influenza virus vaccine
itraconazole
ketoprofen
ketorolac
levamisole
levothyroxine
liothyronine
lovastatin
mefenamic acid
methimazole*
methyldopa
methylphenidate
methylsalicylate ointment (topical)
metronidazole
miconazole
moricizine hydrochloride*
nalidixic acid
naproxen
neomycin
norfloxacin
ofloxacin
olsalazine
omeprazole
oxaprozin
oxymetholone
paroxetine
penicillin G, intravenous
pentoxifylline
phenylbutazone
phenytoin*
piperacillin
piroxicam
prednisone*
propafenone
propoxyphene
propranolol
propylthiouracil*
quinidine
quinine
ranitidine*
sertraline
simvastatin
stanozolol
streptokinase
sulfamethizole
sulfamethoxazole
sulfinpyrazone
sulfisoxazole
sulindac
tamoxifen
tetracycline
thyroid
ticarcillin
ticlopidine
tissue plasminogen activator (t-PA)
tolbutamide
trimethoprim/sulfamethoxazole
urokinase
valproate
vitamin E
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
hereditary coumarin resistance
hyperlipemia
hypothyroidism
nephrotic syndrome
EXOGENOUS FACTORS:
POTENTIAL DRUG INTERACTIONS WITH WARF ARE LISTED BELOW BY DRUG CLASS AND BY
SPECIFIC DRUGS.
CLASSES OF DRUGS
Adrenal Cortical Steroid Inhibitors
Antacids
Antianxiety Agents
Antiarrhythmics*
Antibiotics*
Anticonvulsants*
Antidepressants*
Antihistamines
Antineoplastics*
Antipsychotic Medications
Antithyroid Drugs*
Barbiturates
Diuretics*
Enteral Nutritional Supplements
Fungal Medications, Systemic*
Gastric Acidity and Peptic Ulcer
Agents*
Hypnotics*
Hypolipidemics*
Immunosuppressives
Oral Contraceptives, Estrogen Containing
Steroids, Adrenocortical*
Tuberculosis Agents*
Vitamins*
SPECIFIC DRUGS REPORTED
alcohol*
aminoglutethimide
amobarbital
azathioprine
butabarbital
butalbital
carbamazepine
chloral hydrate*
chlordiazepoxide
chlorthalidone
cholestyramine*
corticotropin
cortisone
WARF underdosage
cyclophosphamide*
dicloxacillin
ethchlorvynol
glutethimide
griseofulvin
haloperidol
meprobamate
methimazole*
moricizine hydrochloride*
nafcillin
paraldehyde
pentobarbital
phenobarbital
phenytoin*
prednisone*
primidone
propylthiouracil*
ranitidine*
rifampin
secobarbital
spironolactone
sucralfate
trazodone
vitamin C (high dose)
vitamin K
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 WARF 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.
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.
ADVERSE REACTIONS:
Potential adverse reactions to WARF may include:
-- Fatal or nonfatal hemorrhage from any tissue or organ. This is a consequence
of the anticoagulant effect. The signs, symptoms, and severity will vary
according to the location and degree or extent of the bleeding. Hemorrhagic
complications may present as paralysis; paresthesia; headache, chest, abdomen,
joint, muscle or other pain; dizziness; shortness of breath, difficult breathing
or swallowing; unexplained swelling; weakness; hypotension; or unexplained
shock. Therefore, the possibility of hemorrhage should be considered in
evaluating the condition of any anticoagulated patient with complaints which do
not indicate an obvious diagnosis. Bleeding during anticoagulant therapy does
not always correlate with PT/INR. (See OVERDOSAGE--Treatment.)
-- Bleeding which occurs when the PT/INR is within the therapeutic range
warrants diagnostic investigation since it may unmask a previously unsuspected
lesion, e.g., tumor, ulcer, etc.
-- Necrosis of skin and other tissues. (See WARNINGS.)
-- Adverse reactions reported infrequently include: hypersensitivity/allergic
reactions, systemic cholesterol microembolization, purple toes syndrome,
hepatitis, cholestatic hepatic injury, jaundice, elevated liver enzymes,
vasculitis, edema, fever, rash, dermatitis, including bullous eruptions,
urticaria, abdominal pain including cramping, flatulence/bloating, fatigue,
lethargy, malaise, asthenia, nausea, vomiting, diarrhea, pain, headache,
dizziness, taste perversion, pruritus, alopecia, cold intolerance, and
paresthesia including feeling cold and chills.
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.
OVERDOSAGE:
SIGNS AND SYMPTOMS: Suspected or overt abnormal bleeding (e.g., appearance of
blood in stools or urine, hematuria, excessive menstrual bleeding, melena,
petechiae, excessive bruising or persistent oozing from superficial injuries)
are early manifestations of anticoagulation beyond a safe and satisfactory
level.
TREATMENT: Excessive anticoagulation, with or without bleeding, may be
controlled by discontinuing WARF therapy and if necessary, by administration
of oral or parenteral vitamin K1. (Please see recommendations accompanying
vitamin K1 preparations prior to use.)
Such use of vitamin K1 reduces response to subsequent WARF therapy. Patients
may return to a pretreatment thrombotic status following the rapid reversal of a
prolonged PT/INR. Resumption of WARF 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 K1. 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 WARF 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 WARF treatment. Packed red
blood cells may also be given if significant blood loss has occurred. Infusions
of blood or plasma should be monitored carefully to avoid precipitating
pulmonary edema in elderly patients or patients with heart disease.
DOSAGE AND ADMINISTRATION:
The dosage and administration of WARF 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. (See LABORATORY
CONTROL below for full discussion on INR.)
VENOUS THROMBOEMBOLISM (INCLUDING PULMONARY EMBOLISM): Available clinical
evidence indicates that an INR of 2.0-3.0 is sufficient for prophylaxis and
treatment of venous thromboembolism and minimizes the risk of hemorrhage
associated with higher INRs.
ATRIAL FIBRILLATION: Five recent clinical trials evaluated the effects of
warfarin in patients with non-valvular atrial fibrillation (AF). Meta- analysis
findings of these studies revealed that the effects of warfarin in reducing
thromboembolic events including stroke were similar at either moderately high
INR (2.0-4.5) or low INR (1.4-3.0). There was a significant reduction in minor
bleeds at the low INR. 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' (ACCP)
recommendation that an INR of 2.0-3.0 be used for long term warfarin therapy in
appropriate AF patients.
POST-MYOCARDIAL INFARCTION: In post myocardial infarction patients, WARF
therapy should be initiated early (2-4 weeks post-infarction) and dosage should
be adjusted to maintain an INR of 2.5-3.5 long-term. The recommendation is based
on the results of the WARIS study in which treatment was initiated 2 to 4 weeks
after the infarction. In patients thought to be at an increased risk of bleeding
complications or on aspirin therapy, maintenance of WARF therapy at the
lower end of this INR range is recommended.
MECHANICAL AND BIOPROSTHETIC HEART VALVES: In patients with mechanical heart
valve(s), long term prophylaxis with warfarin to an INR of 2.5-3.5 is
recommended. In patients with bioprosthetic heart valve(s), based on limited
data, the American College of Chest Physicians recommends warfarin therapy to an
INR of 2.0-3.0 for 12 weeks after valve insertion. In patients with additional
risk factors such as atrial fibrillation or prior thromboembolism, consideration
should be given for longer term therapy.
RECURRENT SYSTEMIC EMBOLISM: In cases where the risk of thromboembolism is
great, such as in patients with recurrent systemic embolism, a higher INR may be
required.
AN INR OF GREATER THAN 4.0 APPEARS TO PROVIDE NO ADDITIONAL THERAPEUTIC BENEFIT
IN MOST PATIENTS AND IS ASSOCIATED WITH A HIGHER RISK OF BLEEDING.
INITIAL DOSAGE: The dosing of WARF 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. Low initiation doses are recommended for elderly and/or debilitated
patients and patients with potential to exhibit greater than expected PT/INR
response to WARF (see PRECAUTIONS). It is recommended that WARF therapy
be initiated with a dose of 2 to 5 mg per day with dosage adjustments based on
the results of PT/INR determinations.
MAINTENANCE: Most patients are satisfactorily maintained at a dose of 2 to 10
mg daily. Flexibility of dosage is provided by breaking scored tablets in half.
The individual dose and interval should be gauged by the patient's prothrombin
response.
DURATION OF THERAPY: The duration of therapy in each patient should be
individualized. In general, anticoagulant therapy should be continued until the
danger of thrombosis and embolism has passed.
MISSED DOSE: The anticoagulant effect of WARF persists beyond 24 hours. If
the patient forgets to take the prescribed dose of WARF 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.
INTRAVENOUS ROUTE OF ADMINISTRATION: WARF for Injection provides an
alternate administration route for patients who cannot receive oral drugs. The
I.V. dosages would be the same as those that would be used orally if the patient
could take the drug by the oral route. WARF 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,
WARF for Injection is chemically and physically stable for 4 hours at room
temperature. It does not contain any antimicrobial preservative and, thus, care
must be taken to assure the sterility of the prepared solution. The vial is not
recommended for multiple use and unused solution should be discarded.
LABORATORY CONTROL The PT reflects the depression of vitamin K dependent
Factors VII, X and II. There are several modifications of the one-stage PT and
the physician should become familiar with the specific method used in his
laboratory. The degree of anticoagulation indicated by any range of PTs may be
altered by the type of thromboplastin used; the appropriate therapeutic range
must be based on the experience of each laboratory. 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 WARF in order to maintain the individual within
the therapeutic range. Acceptable intervals for PT/INR determinations are
normally within the range of one to four weeks after a stable dosage has been
determined. To ensure adequate control, it is recommended that additional PT
tests are done when other warfarin products are interchanged with WARF and
also if other medications are coadministered with WARF (see PRECAUTIONS).
Different thromboplastin reagents vary substantially in their sensitivity to
sodium warfarin-induced effects on PT. To define the appropriate therapeutic
regimen it is important to be familiar with the sensitivity of the
thromboplastin reagent used in the laboratory and its relationship to the
International Reference Preparation (IRP), a sensitive thromboplastin reagent
prepared from human brain.
A system of standardizing the PT in oral anticoagulant control was introduced by
the World Health Organization in 1983. It is based upon the determination of an
International Normalized Ratio (INR) which provides a common basis for
communication of PT results and interpretations of therapeutic ranges. The INR
system of reporting is based on a logarithmic relationship between the PT ratios
of the test and reference preparation. The INR is the PT ratio that would be
obtained if the International Reference Preparation (IRP), which has an ISI of
1.0, were used to perform the test. Early clinical studies of oral
anticoagulants, which formed the basis for recommended therapeutic ranges of 1.5
to 2.5 times control mean normal PT, used sensitive human brain thromboplastin.
When using the less sensitive rabbit brain thromboplastins commonly employed in
PT assays today, adjustments must be made to the targeted PT range that reflect
this decrease in sensitivity.
The INR can be calculated as:
INR = (observed PT ratio) ISI
where the ISI (International Sensitivity Index) is the correction factor in the
equation that relates the PT ratio of the local reagent to the reference
preparation and is a measure of the sensitivity of a given thromboplastin to
reduction of vitamin K-dependent coagulation factors; the lower the ISI, the
more "sensitive" the reagent and the closer the derived INR will be to the
observed PT ratio.(REF. 1)
The proceedings and recommendations of the 1992 National Conference on
Antithrombotic Therapy(REF. 2-4) review and evaluate issues related to oral
anticoagulant therapy and the sensitivity of thromboplastin reagents and provide
additional guidelines for defining the appropriate therapeutic regimen.
The conversion of the INR to PT ratios for the less-intense (INR 2.0-3.0) and
more intense (INR 2.5-3.5) therapeutic range recommended by the ACCP for
thromboplastins over a range of ISI values is shown in Table 3.(REF. 5)
TABLE 3
RELATIONSHIP BETWEEN INR AND PT RATIOS
FOR THROMBOPLASTINS WITH DIFFERENT ISI VALUES (SENSITIVITIES)
---------------------------------------------------------------------------------------------------------------------------------------------
PT RATIOS
---------------------------------------------------------------------------------------------------------------------------------------------
ISI ISI ISI ISI ISI
1.0 1.4 1.8 2.3 2.8
---------------------------------------------------------------------------------------------------------------------------------------------
INR=2.0-3.0 2.0-3.0 1.6-2.2 1.5-1.8 1.4-1.6 1.3-1.5
---------------------------------------------------------------------------------------------------------------------------------------------
INR=2.5-3.5 2.5-3.5 1.9-2.4 1.7-2.0 1.5-1.7 1.4-1.6
---------------------------------------------------------------------------------------------------------------------------------------------
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 WARF 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 WARF therapy. When discontinuing WARF even for a short
period of time, the benefits and risks should be strongly considered.
CONVERSION FROM HEPARIN THERAPY Since the anticoagulant effect of WARF is
delayed, heparin is preferred initially for rapid anticoagulation. Conversion to
WARF 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 WARF therapy be overlapped with heparin for 4
to 5 days, until WARF has produced the desired therapeutic response as
determined by PT/INR. When WARF has produced the desired PT/INR or
prothrombin activity, heparin may be discontinued.
WARF may increase the aPTT test, even in the absence of heparin. During
initial therapy with WARF, the interference with heparin anticoagulation is
of minimal clinical significance.
As heparin may affect the PT/INR, patients receiving both heparin and WARF
should have blood for PT/INR determination drawn at least:
-- 5 hours after the last IV bolus dose of heparin, or
-- 4 hours after cessation of a continuous IV infusion of heparin, or
-- 24 hours after the last subcutaneous heparin injection.
************************************************************************