WARFARIN
CASRN: 81-81-2
Human Health Effects:
Human Toxicity Excerpts:
BASING ESTIMATES OF TOXICITY TO MAN ON VALUES FOR SINGLE LETHAL DOSES FOR ANIMALS, IT
HAS BEEN SUGGESTED THAT AN ADULT MAN WOULD HAVE TO EAT 1.5 LB WARFARIN CONC (0.5%) OR
ABOUT 30 LB OF STRONG RAT BAIT (0.025%) TO RESULT IN FATALITY. ON OTHER HAND, DAILY
INGESTION FOR 6 DAYS OF ... 1 TO 2 MG/KG HAS PRODUCED SEVERE ILLNESS IN AN ATTEMPTED
SUICIDE. ... SYMPTOMS OF POISONING, WHICH BEGIN AFTER A FEW DAYS OR WEEKS OF REPEATED
INGESTION, INCLUDE EPISTAXIS, BLEEDING GUMS, PALLOR, AND SOMETIMES PETECHIAL RASH LEADING
TO HEMATOMAS AROUND JOINTS AND ON BUTTOCKS ... BLOOD IN URINE AND FECES ... PARALYSIS DUE
TO CEREBRAL HEMORRHAGE, AND FINALLY ... HEMORRHAGIC SHOCK AND DEATH.
IN RARE INSTANCES IT HAS PRODUCED HEMORRHAGES IN THE RETINA.
... POISONING HAS BEEN ATTRIBUTED TO EXTENSIVE, PROLONGED SKIN CONTACT IN PROCESS OF
PREPARING & DISTRIBUTING BAITS. ... THE HANDS OF 23-YR-OLD FARMER WERE WET WITH THE
/0.5% SODIUM SALT/ SOLN EACH OF THE 10 TIMES HE MADE BAIT /BY POURING SOLN OVER DRIED
BREAD/ DURING A 24-DAY PERIOD, & HE DID NOT WASH HIS HANDS UNTIL SEVERAL HR AFTER EACH
APPLICATION. TWO DAYS AFTER LAST CONTACT WITH RODENTICIDE, GROSS HEMATURIA APPEARED. NEXT
DAY HEMATOMATA WERE NOTICED ON ARMS & LEGS; THERE WAS DULL PAIN IN BOTH GROINS.
HEMATURIA SUBSIDED AFTER 3 DAYS OF REST BUT RECURRED ALONG WITH NOSE BLEEDING WHEN THE MAN
RETURNED TO WORK. WHEN ADMITTED TO HOSPITAL, PROTHROMBIN, CLOTTING, & BLEEDING TIMES
WERE ABNORMALLY LONG & ANEMIA WAS SEVERE (HEMOGLOBIN, 8.1%; RED CELL COUNT 2.9
MILLION/CU MM). PATIENT RESPONDED PROMPTLY TO TREATMENT WITH VITAMIN K1. /WARFARIN SODIUM/
IN AUGUST, 1981, PEDIATRIC HOSPITALS IN HO CHI MINH CITY (FORMERLY SAIGON), VIETNAM,
BEGAN TO REPORT CASES OF A HEMORRHAGIC SYNDROME IN INFANTS. THE CAUSE OF THIS PHENOMENON
WAS IDENTIFIED AS TALCUM POWDER CONTAMINATED WITH THE ANTICOAGULANT WARFARIN. ANALYSIS OF
TALCUM POWDERS REVEALED WARFARIN IN CONCENTRATIONS BETWEEN 1.7% AND 6.5%. 741 CASES WERE
DETECTED AND 177 PATIENTS DIED. THE ACCIDENT DEMONSTRATES THE SIGNIFICANT TRANSCUTANEOUS
UPTAKE OF THE ANTICOAGULANT.
IT ... HAS BECOME EVIDENT THAT WARFARIN ... IS TERATOGENIC IN MAN. ... MOST ... CASES
HAVE INVOLVED NASAL HYPOPLASIA RANGING FROM BARELY RECOGNIZABLE TO VERY SEVERE. MANY OF
THE BABIES HAD CHONDRODYSPLASIA PUNCTATA, AND THIS DEFECT OF CARTILAGE DEVELOPMENT MAY BE
THE BASIS NOT ONLY OF NASAL DEFORMITY BUT ALSO OF DEFECTS OF THE BONES, SUCH AS
MENINGOCELE, AND DEFORMITIES OF THE LIMBS, AND A HIGH ARCHED PALATE SEEN MUCH MORE RARELY
IN BABIES OF WOMEN TREATED WITH WARFARIN DURING THE FIRST TRIMESTER. OTHER TERATOGENIC
EFFECTS REPORTED IN ONE OR MORE CASES INCLUDE MICROPHTHALMIA, BLINDNESS, HYDROCEPHALUS,
PERSISTENT TRUNCUS ARTERIOSUS, AND MENTAL RETARDATION.
Since ... /a 1968 report of/ nasal hypoplasia in the offspring of a woman treated with
warfarin during pregnancy an assoc has been made between the use of coumarin deriv &
Conradi syndrome which consists of nasal hypoplasia with calcific strippling of the
secondary epiphyses. The dose given to the mother was ... 2.5 to 10 mg per day during 1st
trimester. One patient received coumadin during only 1st 8 weeks & another took
phenindione. Nasal obstruction complicated the neonatal course of these infants who were
of low birth wt. Three of the children were reported to be blind but their long term
development is still unknown. Eleven ... /other/ cases ... /are reported on warfarin
therapy during pregnancy & its association with multiple congenital anomalies &
phenotypic chondrodysplasia punctata/. ... /A summary of/ clinical data ... cites 5
offspring with CNS problems incl hydrocephalus /resulting from warfarin therapy/. The
pathology of a human fetus exposed to warfarin has been reported. /Warfarin Sodium/
/In/ two cases ... in which coagulation tests were performed in two infants who were
breast-fed by mothers receiving sodium warfarin, no effects were noted. Therefore, it was
recommended that mother receiving warfarin sodium be allowed to breast-feed their normal
full-term infants. /Warfarin sodium/
Cases of warfarin-induced skin necrosis /have been reported/. A 53 year old man
experienced two episodes of skin necrosis on his left flank and buttock, following the
initiation of warfarin therapy for thrombophlebitis. The lesion formed multiple
hemorrhagic bullae that ruptured, and an eschar formed that did not heal and eventually
required skin grafting.
Skin vasculitis with bilateral breast involvement occurred in a 52 year old female
following the administration of warfarin 21 mg over 3 days. At the time of appearance of
the initial lesion, the prothrombin time was 45 sec with a control of 13 sec. Following
discontinuation of warfarin and administration of vitamin K, lesions gradually disappeared
over a period of a week.
A 57 year old man presented with apparently spontaneous lower extremity deep vein
thrombosis and pulmonary embolism. He was treated in conventional fashion with intravenous
heparin and oral warfarin. After 4 daily doses of warfarin the prothrombin and
proconvertin (P+P) time was within therapeutic range, and heparin was stopped. Over the
next six hours complete defibrination occurred, associated with severe bleeding
complications. Functional protein C measured after normalization of routine coagulation
tests averaged 40% of normal, and was only 3.5% of normal immediately prior to the episode
of defibrination. We conclude that the very low functional protein C levels seen
immediately prior to defibrination were caused by a combination of pre-existent protein C
deficiency and warfarin therapy, and directly predisposed to defibrination once heparin
was stopped, despite "therapeutic" warfarin anticoagulation. Exacerbation of
intravascular coagulation should be considered a potential prothrombotic effect of
warfarin therapy in protein C deficient individuals.
A 25 year old man with Klinefelter's syndrome and recurrent thrombophlebitis, for which
he had been receiving long-term warfarin sodium therapy, had bilateral ecchymoses on the
hips coincident with serologically confirmed Epstein-Barr virus-caused mononucleosis.
Biopsy specimens taken from the hip lesions showed microscopic findings consistent with a
diagnosis of warfarin necrosis. Direct immunofluorescence microscopy disclosed vessel-wall
deposition of IgM and heavy upper-dermal deposition of IgG. Electron microscopy disclosed
nonspecific endothelial cell blebs that projected into the vessel lumen. The temporal
association of mononucleosis with the onset of warfarin necrosis suggests that the viral
illness may have precipitated an immunologic endothelial surface reaction, leading to
thrombosis and secondary hemorrhage with infarction.
An inception cohort of 565 patients starting outpatient therapy with warfarin on
discharge from a university hospital was assembled to determine the relation of bleeding
to prothrombin times and important remediable lesions. Detailed records of outpatient
prothrombin times were obtained for 103 of 130 case subjects with major or minor bleeding
and for 117 control patients without bleeding. A nested case control design was used to
evaluate the association of bleeding with temporally related prothrombin times; odds
ratios were estimated using multivariate logistic regression analysis to control for known
predictors of major bleeding. The relation of bleeding to important remediable lesions was
determined in all 130 cases of bleeding. Results showed that for each 1.0 increase in the
prothrombin time to control ratio, the odds ratio for major bleeding during the wk after a
prothrombin time measurement increased 80%; the odds ratio for minor bleeding increased
50%. These odds ratios were lower during the first mo of therapy and higher thereafter.
Bleeding was related to important remediable lesions in 49 of 130 cases (38%), but these
lesions were unknown before bleeding in only 22 cases (17%). The mean prothrombin time
rose sharply at the time of bleeding in patients without important remediable lesions, but
not in patients with lesions. New, previously unknown lesions (including 9 malignancies)
were discovered in 20 of 59 case subjects (34%) with GI bleeding or hematuria, but in only
2 of 71 case subjects (3%) with other bleeding (p < 0.001).
Risk of major hemorrhage (resulting in death or hospitalization) or minor hemorrhage
(all other cases) was studied in medical records of 2029 patients who had been given
warfarin any time between December 1970 through December 1980 at the Northern California
Kaiser-Permanente Medical Care Program. Almost 7% of patients had a major hemorrhage on
warfarin and an additional 23.7% had at least 1 minor bleeding episode. Age, female sex,
and congestive heart failure were associated with small incr in the risk of major
hemorrhage but not with the risk of minor bleeding. A prothrombin time ratio greater than
2.5 was associated with a fourteen-fold incr in the risk of a major hemorrhage (95% CI
5.1, 42.7), but major hemorrhages occurred in patients on warfarin at all measured values
of the prothrombin time ratio.
A woman aged 20 yr developed a deep venous thrombosis in the 7th mo of her first
pregnancy. She was treated with heparin during the pregnancy and with warfarin after
delivery. It was intended to continue the anticoagulant therapy for 1 yr. Unfortunately,
she conceived during this period and used warfarin for the first 14-wk gestation. She
failed to recognize her new pregnancy and did not contact her physician until 12 hr before
the beginning of labor. Vaginal delivery was uncomplicated but the infant did not breathe
and, inspite of attempts at resuscitation, died after 35 min. The infant appeared to be
mature, weighed 3660 g and was 48 cm long. Autopsy revealed almost total agenesis of the
left diaphragm and hypoplasia of both lungs.
A farmer who had skin exposure of a 0.5% solution of warfarin over a period of 24 days
... developed gross hematuria two days following the last contact with the solution. He
developed spontaneous hematomas on the arms and legs. Within four days, other effects were
noted, such as epistaxis, hemorrhages of the palate and mouth, and bleeding from the lower
lip. After appropriate treatment, normal blood finds occurred.
In Korea, a family of 14 persons lived for a period of 15 days on a diet consisting
almost entirely of corn (maize) meal containing warfarin. The first symptoms appeared 7-10
days after the eating of warfarin was begun. Massive bruises or hematoma developed at the
knee and elbow joints and on the buttocks in all cases. Extensive gum and nasal hemorrhage
usually appeared about a day later, and by day 15 blood loss was extensive.
A 32 yr old man was murdered by feeding him warfarin for 13 days. On the fourth day
after intake started, the victim began having severe nosebleeds. Later, he bled from the
mouth. Two days before death, he complained of pain in his limbs. His symptoms became
worse and he died of circulatory failure on day 15.
Plasma levels of warfarin were 6.8 and 11.2 ppm 4 and 7 hr, respectively, after the
ingestion of 500 mg of warfarin sodium in a suicide attempt. Plasma levels declined
thereafter, and the half-time for disappearance was calculated as 46 hr. Part of the dose
was removed by gastric lavage soon after ingestion. This and other appropriate treatment
prevented any increase in bleeding tendency.
Administration of warfarin during pregnancy is a cause of birth defects and abortion. A
syndrome characterized by nasal hypoplasia and stippled epiphyseal calcifications that
resemble chondrodysplasia punctata may result from maternal ingestion of warfarin during
the first trimester. Central nervous system abnormalities have been reported following
exposure during the second and third trimesters. Fetal or neonatal hemorrhage and
intrauterine death may occur, even when maternal PT values are in the therapeutic range.
Bleeding is the major toxicity of oral anticoagulant drugs. Especially serious episodes
involve sites where irreversible damage may result from compression of vital structures
(e.g., intracranial. pericardial, nerve sheath, or spinal cord) or from massive internal
blood loss that may not be diagnosed rapidly (e.g., gastrointestinal, intraperitoneal,
retroperitoneal). /Oral Anticoagulants/
A reversible, sometimes painful, blue-tinged discoloration of the plantar surfaces and
sides of the toes that blanches with pressure and fades with elevation of the legs (purple
toe syndrome) may develop 3 to 8 weeks after initiation of therapy with coumarin
anticoagulants. Other infrequent reactions include alopecia, urticaria, dermatitis, fever,
nausea, diarrhea, abdominal cramps, and anorexia. /Oral Anticoagulants/
Vascular lesions may ... be more prominent with warfarin than with its congeners. A
single large dose produces no untoward signs or symptoms until clinical evidence of
hemorrhage, which is usually apparent on the second, third, or fourth day, but a
significant change in the blood prothrombin level can be detected within 24 hours. After a
single intravenous injection of the sodium salt (about 1 mg/kg), the maximal response in
man is usually reached in 48 hours, and recovery is essentially complete by the fifth day.
The fairly long plasma half-life (7 days in one would-be suicide) is due at least in part
to intensive enterohepatic recycling.
Anticoagulant therapy with heparin and sodium warfarin in 74 patients with gynecologic
malignancy and venous thromboembolism were evaluated as to hemorrhagic complication,
recurrent thrombosis, and completion of prescribed course of therapy. Clinically
significant bleeding complications occurred in 25 patients ... 29 patients did not
complete the course of therapy because of the bleeding complications or death within 3
months. Venous thromboembolism recurred in 11 patients.
Drug Warnings:
DOSAGE REQUIREMENTS VARY GREATLY AMONG INDIVIDUAL PATIENTS & DOSAGE MUST BE
CAREFULLY INDIVIDUALIZED BASED ON CLINICAL AND & LABORATORY FINDINGS IN ORDER TO
OBTAIN OPTIMUM THERAPEUTIC EFFECTS WITHOUT INCURRING HEMORRHAGE. ... SOME CLINICIANS
ADVISE AGAINST ADMINISTRATION OF "LOADING DOSE" /BECAUSE OF HEMORRHAGING/ &
... RECOMMEND INITIAL DOSAGE 0F 10-15 MG DAILY UNTIL DESIRED PROTHROMBIN TIME IS REACHED.
/POTASSIUM AND SODIUM WARFARIN/
Patients in congestive heart failure who are given oral anticoagulants ... have an
augmented hypoprothrombinemic response; this lessens as myocardial function improves. ...
Hypermetabolic states, such as fever & hyperthyroidism, increase the responsiveness to
oral anticoagulants, whereas myxedematous patients require larger doses ... There is also
a positive correlation between patient age & degree of response to oral
anticoagulants; this effect is independent of body wt, & the pharmacokinetics of
warfarin is unaltered. ... During pregnancy a state of decreased responsiveness to oral
anticoagulants results from increased activity of factors VII, VIII, IX & X. However,
this affects only the mother, & the fetus is highly susceptible to oral anticoagulants
because ... /they/ cross the placenta freely & the fetus has limited capacity to
synthesize clotting factors. ... Uremia ... significantly increases ... the fraction of
drug in plasma that is free & the clearance of warfarin from the circulation.
When given during 1st trimester (esp 6th-9th wk) of pregnancy, warfarin is assoc with
embryopathy ... Only about 1/3 of infants exposed during this period are normal & live
born. Other abnormalities, incl CNS & eye defects (eg, blindness), are thought to
result from longer exposure, probably during the 2nd & 3rd trimesters.
Panwarfin 7.5-mg tablets contain ... tartrazine (FD&C yellow no 5) which may cause
allergic reactions incl bronchial asthma in susceptible individuals. Although incidence of
tartrazine sensitivity is low, it frequently occurs in patients who are sensitive to
aspirin. /Panwarfin/
UNTIL FURTHER ... DATA CAN BE ACCUMULATED & EVALUATED, IT WOULD BE ADVISABLE TO
MONITOR FREQUENTLY BLOOD GLUCOSE LEVELS AND PROTHROMBIN TIMES DURING COMBINED USE OF
CHLORPROPAMIDE AND WARFARIN.
Coumarin- and indandione-derivative anticoagulants cross the placenta and are not
recommended during pregnancy. Congenital malformations and other adverse effects on fetal
development including severe nasal hypoplasia, stippling of bones, optic atrophy,
microcephaly, and growth and mental retardation have been reported in infants born to
mother taking these agents during pregnancy. This is especially critical during the first
trimester. However, many clinicians recommend that these agents not be used at all during
pregnancy because facial anomalies in the infant have occurred following maternal use in
the third trimester. Also, fetal or neonatal hemorrhage, fetal death in utero, and
increased risk of maternal hemorrhage during the second and third trimesters have been
reported. However, other clinicians state that these agents may be used for brief periods
in the second and third trimesters. /Anticoagulants/
If a coumarin or indandione derivative is used during the third trimester, it should be
discontinued after the 37th week of gestation, and heparin substituted if maternal
anticoagulation is required, to reduce the risk of fetal hemorrhage during labor and of
neonatal hemorrhage following delivery. Anticoagulants also increase the risk of maternal
hemorrhage during or following delivery. /Anticoagulants/
Anticoagulants may increase the risk of maternal hemorrhage if administered in the
postpartum period. /Anticoagulants/
Infants, especially neonates, may be more susceptible to the effects of anticoagulants
because of vitamin K deficiency. /Anticoagulants/
Geriatric patients may be more susceptible to the effects of anticoagulants, resulting
in increased risk of hemorrhage, possible because of the presence of advanced vascular
disease resulting in altered homeostatic mechanisms, hepatic function impairment resulting
in decreased procoagulant factor synthesis or anticoagulant metabolism, or renal function
impairment. Lower maintenance doses than those usually recommended for adults may be
required for these patients. /Anticoagulants/
Anticoagulant therapy increases the risk of localized hemorrhage during and following
oral surgical procedures. Consultation with the prescribing physician may be advisable
prior to oral surgery, to determine whether a temporary dosage reduction or withdrawal of
anticoagulant therapy is feasible. Also, local measures to minimize bleeding should be
used at the time of surgery. /Anticoagulants/
The occurrence of gastrointestinal hemorrhage during anticoagulant therapy, especially
if the prothrombin time is within the therapeutic range, may indicate the presence of an
underlying occult lesion such as a tumor or ulcer. /Anticoagulants/
Adrenal hemorrhage resulting in acute adrenal insufficiency has been reported to occur
rarely during anticoagulant therapy. Diagnosis may be difficult because the initial
symptoms (abdominal pain, apprehension, diarrhea, dizziness or fainting, headache, loss of
appetite, nausea or vomiting, and weakness) are nonspecific and variable. If acute adrenal
insufficiency is suspected, anticoagulant therapy must be discontinued and high-dose
adrenocorticoid therapy (preferably with hydrocortisone, since other glucocorticoid may
not provide sufficient sodium retention) instituted immediately. Delay of treatment while
laboratory confirmation of the diagnosis is awaited may prove fatal for the patient. It
has been proposed that abdominal computerized axial tomographic (CAT) scanning may be of
use in diagnosing this condition more rapidly. /Anticoagulants/
Contraindications to oral anticoagulants include pre-existing or coexisting
abnormalities of blood coagulation, active bleeding, recent or imminent surgery of the
central nervous system or eye, diagnostic or therapeutic procedures with potential for
uncontrollable bleeding including lumbar puncture, malignant hypertension, peptic
ulceration, pregnancy, threatened abortion, intrauterine device, cerebrovascular
hemorrhage, and bacterial endocarditis. Relative contraindications include
thrombocytopenia, pericarditis, pericardial effusions, and unreliability of the patient or
of patient supervision. /Oral anticoagulants/
Most commonly, oral anticoagulant-induced bleeding is minor and consists of bruising,
hematuria, epistoxis, conjunctival hemorrhage, minor gastrointestinal bleeding, bleeding
from wounds and sites of trauma, and vaginal bleeding. More serious major or fatal
bleeding is most commonly gastrointestinal, intracranial, vaginal, retroperitoneal, or
related to a wound or site of trauma, although a large variety of other sites of bleeding
have been reported. Intracranial bleeding occurs most frequently in patients receiving
oral anticoagulants for cerebrovascular disease and most commonly presents as a subdural
hematoma, often unassociated with head trauma. Fatal gastrointestinal bleeding is most
commonly from a peptic ulcer, although any gastrointestinal lesion may be a potential
source of major bleeding. Overall, a bleeding lesion can be identified in about two thirds
of cases of oral anticoagulants-related hemorrhage. /Oral anticoagulants/
Overall, the bleeding rate of oral anticoagulant therapy is influenced by several
factors: the intensity of anticoagulation, either intentionally or inadvertent; the
underlying clinical disorder for which anticoagulant therapy is used with bleeding
occurring most frequently in ischemic cerebrovascular disease and venous thromboembolism;
and, with bleeding occurring most commonly in the elderly; the presence of adverse drug
interactions or comorbid factors such as clinical states potentiating warfarin action,
pre-existing hemorrhagic diathesis, malignancy, recent surgery, trauma, or pre-existing
potential bleeding sites (e.g., surgical wound, peptic ulcer, recent cerebral hemorrhage,
carcinoma of colon); the simultaneous use of aspirin (but not of dipyridamote); and
patient reliability (e.g., increased bleeding in alcoholics not due to ethanol-warfarin
drug interaction but rather to unreliability of drug intake). /Oral anticoagulants/
IT IS INADVISABLE TO CARRY OUT LONG-TERM THERAPY IN CHRONIC ALCOHOLIC, IN INDIVIDUAL
WHO MAY REQUIRE INTENSIVE SALICYLATE THERAPY, OR IN CASES OF MALIGNANT HYPERTENSION &
ACTIVE TUBERCULOSIS. ORAL ANTICOAGULANT THERAPY DURING PREGNANCY CARRIES SIGNIFICANT
HEMORRHAGIC RISK FOR FETUS. /ORAL ANTICOAGULANTS/
... CONTRAINDICATED IN HEMORRHAGIC TENDENCIES, BLOOD DYSCRASIAS, ULCERATIVE LESIONS OF
GI TRACT, DIVERTICULITIS, COLITIS, SUBACUTE BACTERIAL ENDOCARDITIS, THREATENED ABORTION,
RECENT OPERATIONS ON BRAIN OR SPINAL CORD. REGIONAL & LUMBAR-BLOCK ANESTHESIA, VITAMIN
K DEFICIENCY ... HEPATIC OR RENAL DISEASE. /ORAL ANTICOAGULANTS/
IT IS IMPERATIVE THAT SUITABLE LAB FACILITIES BE AVAIL FOR ACCURATE CONTROL OF THERAPY
WITH COUMARIN DRUGS. IN ADDN, SUITABLE PREPN OF VITAMIN K SHOULD BE AVAIL, AS WELL AS
WHOLE FRESH BLOOD OR PLASMA FOR EMERGENCY TRANSFUSION. /ORAL ANTICOAGULANTS/
PULMONARY INTERSTITIAL HEMORRHAGE...MAY BE CONFUSED CLINICALLY WITH PULMONARY EMBOLISM.
... IT IS GENERALLY AGREED THAT ANY HEPATIC DAMAGE OCCURRING IN PT WITHOUT PREEXISTING
LIVER DISEASE IS PURELY SECONDARY TO LOCAL HEMORRHAGE IN LIVER OR HYPOXIA FROM HEMORRHAGIC
ANEMIA. /ORAL ANTICOAGULANTS/
Anticoagulant therapy must always be monitored by determination of one-stage
prothrombin times, & the patient must be observed carefully for development of
bleeding. Bleeding often occurs even when the prothrombin time is within the expected
therapeutic range. /Anticoagulants/
If a patient shows any sign of bleeding, the next dose of anticoagulant should be
withheld and the plasma thromboplastin measured. If bleeding is minor or self-limited,
therapy may be continued after adjusting the dosage and/or correcting the reason for the
altered response. /Oral Anticoagulants/
Given the variability in half-lives of the drugs and proteins involved, careful
monitoring for evidence of bleeding or thrombosis and frequent measurements of the plasma
thromboplastin are essential. /Oral Anticoagulants/
Prior to initiation of therapy, laboratory tests are used in conjunction with the
patient's history and physical examination to uncover hemostatic defects that might make
the use of oral anticoagulant drugs more dangerous (congenital coagulation factor
deficiency, thrombocytopenia, hepatic or renal insufficiency, vascular abnormalities,
etc.). Thereafter, the plasma thromboplastin is used to monitor efficacy and compliance.
Therapeutic ranges for various clinical indications have been established empirically and
reflect dosages that reduce the morbidity from thromboembolic disease while increasing as
little as possible the risk of serious hemorrhage. /Oral Anticoagulants/
Infants, especially neonates, may be more susceptible to the effects of anticoagulants
because of vitamin K deficiency. /Anticoagulants/
Records of 565 patients starting outpatient therapy with warfarin upon discharge from a
university hospital were reviewed to determine the incidence of major bleeding and to
identify predictive factors known at the start of therapy. Follow-up information was
obtained for 562 patients (99.5%). Bleeding was classified as major or minor using
explicit criteria. The cumulative incidence of bleeding was estimated by means of survival
analysis. Independent risk factors for major bleeding were identified using Cox regression
analysis in 375 randomly chosen patients; they were tested in the remaining 187 patients.
Results showed that major bleeding occurred in 65 patients (12%) and was fatal in 10
patients (2%). The cumulative incidences of major bleeding at 1, 12 and 48 mo were 3%, 11%
and 22%, respectively. The monthly risk of major bleeding decreased over time, from 3%
during the first mo of outpatient therapy to 0.3% per mo after the first year of therapy.
Five independent risk factors that predicted major bleeding in the testing group were: age
65 yr or greater; history of stroke; history of GI bleeding; a serious comorbid condition
(recent myocardial infarction, renal insufficiency, or severe anemia); and atrial
fibrillation. The cumulative incidence of major bleeding at 48 mo was 2% in 57 low risk
patients, 17% in 110 middle risk patients, and 63% in 20 high risk patients.
There is evidence that treatment with coumarin drugs during pregnancy causes nasal
hypoplasia and stippled epiphyses (chondrodysplasia punctata) in the fetus, and when taken
late in pregnancy may cause optic atrophy and microcephaly. /Coumarin drugs/
Medical Surveillance:
A complete history and physical examination: The purpose is to detect preexisting
conditions that might place the exposed employee at increased risk, and to establish a
baseline for future health monitoring. Persons with a history of blood disorders with
bleeding tendencies would be expected to be at increased risk from exposure. Examination
of the blood should be stressed.
Populations at Special Risk:
Persons with a history of blood disorders with bleeding tendencies, would be expected
to be at increased risk from exposure.
Not only has hereditary resistance of people to warfarin been observed ... but
exceptional susceptibility, also presumably on an hereditary basis, has been reported.
There is evidence that treatment with coumarin drugs during pregnancy causes nasal
hypoplasia and stippled epiphyses (chondrodysplasia punctata) in the fetus, and when taken
late in pregnancy may cause optic atrophy and microcephaly. /Coumarin drugs/
Geriatric patients may be more susceptible to the effects of anticoagulants, resulting
in increased risk of hemorrhage, possible because of the presence of advanced vascular
disease resulting in altered homeostatic mechanisms, hepatic function impairment resulting
in decreased procoagulant factor synthesis or anticoagulant metabolism, or renal function
impairment. Lower maintenance doses that those usually recommended for adults may be
required for these patients. /Anticoagulants/
Infants, especially neonates, may be more susceptible to the effects of anticoagulants
because of vitamin K deficiency. /Anticoagulants/
Probable Routes of Human Exposure:
Warfarin ... /is/ readily avail to general public. Baits are not always secure from ...
children. ... Warfarin & other rodenticides may be hidden in meat or sausage &
purposely left in yards to poison animals maliciously.
Use of warfarin as drug offers greater dosage &, therefore greater opportunity for
side effects than pest control operators encounter.
Emergency Medical Treatment:
Emergency Medical Treatment:
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of Micromedex' copyrights and is strictly prohibited. The following Overview, *** WARFARIN ***, is relevant for this HSDB record chemical. |
| Life Support: |
o This overview assumes that basic life support measures
have been instituted.
|
| Clinical Effects: |
SUMMARY OF EXPOSURE
0.2.1.1 ACUTE EXPOSURE
o Onset: The primary effect of warfarin overdose is
prolongation of prothrombin time, and subsequent risk
of hemorrhage. The onset of prolonged PT correlates
with the half-life of factor VII, usually appears
within 24 hours of ingestion, and peaks between 36 to
72 hours.
o Signs/symptoms: Clinical manifestations begin a few
days or weeks after ingestion, and include nose bleed,
bleeding gums, pallor, hematomas around joints and on
buttocks, and blood in urine and feces. Other symptoms
can include back pain, bleeding lips, mucous membrane
hemorrhage, abdominal pain, vomiting, and petechial
rash. Later, paralysis due to cerebral hemorrhage, and
finally hemorrhagic shock and death may occur.
o Risk factors: Persons with a history of blood
disorders with bleeding tendencies would be expected to
be at increased risk from exposure. Hereditary
resistance of people to warfarin, as well as suspected
hereditary susceptibility, has been reported.
o Warfarin is poisonous by ingestion, inhalation, and the
intravenous route. It is moderately toxic by skin
contact, subcutaneous, and intraperitoneal routes.
o Warfarin sodium is a synthetic vitamin K antagonist
used as a rodenticide and in anticoagulation therapy.
It may be absorbed following ingestion, inhalation, or
dermal contact.
o Toxicity to the fetus has been reported; it is
recommended that warfarin not be used in either early
pregnancy or after the 32nd week of pregnancy.
CARDIOVASCULAR
0.2.5.1 ACUTE EXPOSURE
o Hypotension and cardiac tamponade have been reported
following warfarin therapy.
RESPIRATORY
0.2.6.1 ACUTE EXPOSURE
o Upper airway bleeding may result in pain, dysphonia,
dysphagia, dyspnea and inability to clear secretions.
o Alveolar hemorrhage is an uncommon occurrence,
resulting in dyspnea, chest tightness, and anemia.
o A hemothorax was reported following warfarin therapy to
treat ischemic cardiomyopathy.
0.2.6.2 CHRONIC EXPOSURE
o Warfarin sodium can be absorbed by inhalation and cause
systemic poisoning.
NEUROLOGIC
0.2.7.1 ACUTE EXPOSURE
o Intracranial hemorrhage and hematomyelia may occur
following warfarin therapy.
GASTROINTESTINAL
0.2.8.1 ACUTE EXPOSURE
o Abdominal pain, vomiting, gastrointestinal bleeding,
hemoptysis, and bloody or melenotic stools may occur.
0.2.8.2 CHRONIC EXPOSURE
o Spontaneous rupture of the spleen has been described in
a patient over anticoagulated with warfarin sodium.
HEPATIC
0.2.9.1 ACUTE EXPOSURE
o Hepatitis and hepatic hematomas have been reported
following oral coumarin anticoagulant use.
GENITOURINARY
0.2.10.2 CHRONIC EXPOSURE
o Bleeding complications have been reported, including
vaginal bleeding, rupture of ovarian cysts with
intraperitoneal hemorrhage, hematuria, hematospermia.
HEMATOLOGIC
0.2.13.1 ACUTE EXPOSURE
o Bleeding is the most common sign. It may manifest as
epistaxis, hemoptysis, hematuria, hematospermia,
subconjunctival hemorrhage, gingival bleeding,
gastrointestinal bleeding, bloody or melenotic stools,
vaginal bleeding, bruising, or abdominal and back pain.
0.2.13.2 CHRONIC EXPOSURE
o Hemorrhage leading to death, hospitalization, or
transfusion is reported in patients on long-term
anticoagulant therapy.
DERMATOLOGIC
0.2.14.1 ACUTE EXPOSURE
o Skin necrosis, rash, alopecia, and "purple toe"
syndrome may occur.
o Dermal necrosis has been reported with therapeutic
warfarin sodium administration for as little as 72
hours. The lesions may be ecchymotic, mottled, or
erythematous.
o Warfarin may be absorbed through the skin and cause
systemic poisoning.
MUSCULOSKELETAL
0.2.15.1 ACUTE EXPOSURE
o Acute compartment syndrome and carpal tunnel syndrome
have been reported following therapeutic use of
warfarin.
REPRODUCTIVE HAZARDS
o The use of warfarin during pregnancy has been associated
with teratogenic effects.
o Fetal intraventricular hemorrhage has been reported
following maternal ingestion of warfarin.
o Craniofacial, musculoskeletal, skin, eye,
gastrointestinal, and cardiovascular developmental
abnormalities have been observed in the offspring of
women administered warfarin sodium during pregnancy.
o Intrauterine fetal demise, intrauterine growth
retardation, and hemorrhagic disease of the newborn have
been reported following administration of warfarin
sodium to pregnant women.
CARCINOGENICITY
0.2.21.2 HUMAN OVERVIEW
o At the time of this review, no data were available to
assess the carcinogenic potential of this agent.
GENOTOXICITY
o Warfarin sodium induced mutations and DNA inhibition in
mouse leukocytes.
OTHER
0.2.23.1 ACUTE EXPOSURE
o Hereditary resistance to the anticoagulant effects of
warfarin sodium has been reported.
|
| Laboratory: |
o Plasma levels of warfarin sodium can be measured by a
variety of techniques, but are not generally obtained to
monitor the clinical course in poisoning cases.
o The international normalized ratio (INR) or prothrombin
time (PT) are the best values to monitor. The onset of
INR elevation or PT prolongation is between 12 and 24
hours postingestion.
o Monitor hemoglobin and hematocrit if bleeding occurs.
o Monitor urine and stool for occult blood.
o X-ray studies may be of use if bleeding into tissues or
body cavities is suspected.
|
| Treatment Overview: |
ORAL EXPOSURE
o PATIENTS NOT PRESENTLY ON ANTICOAGULANTS -
1. Average child eating a few mouthfuls of 0.025% to 0.05%
rat bait at a single sitting is generally not at risk,
no treatment is necessary. Ingestion of large amounts
may require gastrointestinal decontamination.
2. ACTIVATED CHARCOAL: Administer charcoal as slurry (240
mL water/30 g charcoal). Usual dose: 25 to 100 g in
adults/adolescents, 25 to 50 g in children (1 to 12
years), and 1 g/kg in infants less than 1 year old.
3. VITAMIN K - If a large or chronic ingestion is
suspected, or PT/INR are elevated, then vitamin K1
(phytonadione) may be given. DOSE: 1 to 5 mg (child),
10 mg (adult). Vitamin K1 may be administered orally
in the absence of vomiting. With severe toxicity
parenteral dosing may be necessary.
o PATIENTS PRESENTLY ON ANTICOAGULANTS -
1. ACTIVATED CHARCOAL: Administer charcoal as slurry (240
mL water/30 g charcoal). Usual dose: 25 to 100 g in
adults/adolescents, 25 to 50 g in children (1 to 12
years), and 1 g/kg in infants less than 1 year old.
2. AVOID EMESIS AND LAVAGE due to possible trauma and
subsequent bleeding.
3. Get PROTHROMBIN TIME or INR immediately.
4. INR < 5.0 and no clinical bleeding: Hold warfarin and
resume at lower dose when INR therapeutic.
5. INR 5.0 TO 9.0 and no clinical bleeding: Hold warfarin
and resume at a lower dose when INR therapeutic OR
hold one dose warfarin and administer 1 to 2.5 mg
vitamin K orally.
6. INR > 9.0 Hold warfarin and administer vitamin K 3.0 to
5.0 mg orally.
o TRANSFUSION - In patients with serious bleeding and
coagulopathy, treat with fresh frozen plasma and/or
prothrombin complex concentrate as well as parenteral
vitamin K and packed red blood cells.
INHALATION EXPOSURE
o Absorbed by inhalation. Respirators must be used when
spraying this agent.
o INHALATION: Move patient to fresh air. Monitor for
respiratory distress. If cough or difficulty breathing
develops, evaluate for respiratory tract irritation,
bronchitis, or pneumonitis. Administer oxygen and
assist ventilation as required. Treat bronchospasm with
beta2 agonist and corticosteroid aerosols.
DERMAL EXPOSURE
o Significant dermal absorption may occur.
o DECONTAMINATION: Remove contaminated clothing and wash
exposed area thoroughly with soap and water. A
physician may need to examine the area if irritation or
pain persists.
o Treatment should include recommendations listed in the
ORAL EXPOSURE section when appropriate.
|
| Range of Toxicity: |
o A relationship between milligram/kilogram ingested and
amount of hypocoagulability has not yet been established.
o BAITS - Large amounts of warfarin containing grain bait do
not usually produce significant toxicity because of the
small concentration of the warfarin and poor absorption in
large amounts of grain.
o Death from severe hemorrhagic complications has been
reported in persons who ate food made with warfarin sodium
baited cornmeal. Ingestion of a total of 1 gram of
warfarin over a 13-day period resulted in death.
o Usual PO maintenance range is 2 to 10 mg/day. A
maintenance dose of 5 to 7.5 mg/day in adults is usually
adequate to keep the prothrombin time at 2 to 3 times
control.
|
Antidote and Emergency Treatment:
1. IF AMOUNTS OF BAIT INGESTED WERE ASSUREDLY NO MORE THAN A FEW MOUTHFULS OF COUMARIN-
OR INDANDIONE-TREATED BAIT, OR A FEW GRAINS OF BAIT TREATED WITH THE MORE TOXIC
BRODIFACOUM OR BROMADIOLONE COMPOUNDS, MEDICAL TREATMENT IS PROBABLY UNNECESSARY.
/RODENTICIDES (COUMARINS AND INDANDIONES)/
1A. IF THERE IS UNCERTAINTY ABOUT THE AMOUNT OF BAIT INGESTED OR THE GENERAL HEALTH OF
THE PATIENT, PHYTONADIONE (VITAMIN K1) GIVEN ORALLY PROTECTS AGAINST THE ANTICOAGULANT
EFFECT OF THESE RODENTICIDES WITH ESSENTIALLY NO RISK TO THE PATIENT. DOSAGE OF
PHYTONADIONE: ADULTS AND CHILDREN OVER 12 YEARS: 15-25 MG. CHILDREN UNDER 12 YEARS: 5-10
MG. ALTERNATIVELY, A COLLOIDAL SOLUTION OF PHYTONADIONE, AQUAMEPHYTON, MAY BE GIVEN
INTRAMUSCULARLY. FOR ADULTS AND CHILDREN OVER 12 YEARS, GIVE 5-10 MG; FOR CHILDREN UNDER
12 YEARS, GIVE 1-5 MG. CAUTION: PHYTONADIONE, SPECIFICALLY, IS REQUIRED. NEITHER VITAMIN
K3 (MENADIONE, HYKINONE) NOR VITAMIN K4 (MENADIOL) IS AN ANTIDOTE FOR THESE
ANTICOAGULANTS. /RODENTICIDES (COUMARINS AND INDANDIONES)/
1B. WHATEVER THE DOSAGE, INSURE THAT PATIENTS (ESPECIALLY CHILDREN) WILL BE CAREFULY
OBSERVED FOR 4-5 DAYS AFTER INGESTION. THE INDANDIONES AND THE MORE RECENTLY INTRODUCED
COUMARINS MAY HAVE OTHER TOXIC EFFECTS. /RODENTICIDES (COUMARINS AND INDANDIONES)/
2. IF LARGE AMOUNTS (1.0-1.5 MG/KG OF BODY WEIGHT) OF ANTICOAGULANT HAVE BEEN INGESTED
WITHIN SEVERAL HOURS PRIOR TO TREATMENT, EMPTY THE STOMACH BY GIVING SYRUP OF IPECAC,
FOLLOWED BY 1-2 GLASSES OF WATER. DOSAGES OF SYRUP OF IPECAC FOR ADULTS AND CHILDREN OVER
12 YEARS: 30 ML; DOSAGE FOR CHILDREN UNDER 12 YEARS: 15 ML. FOLLOWING EMESIS GIVE
ACTIVATED CHARCOAL AND SORBITOL. DOSAGE OF CHARCOAL AS AN AQUEOUS SLURRY: ADULTS AND
CHILDREN OVER 12 YEARS: 50-100 G IN 300-800 ML WATER. CHILDREN UNDER 12 YEARS: 15-30 G IN
100-300 ML WATER. DOSAGE OF SORBITOL (THE PREFERRED AGENT) ADDED TO CHARCOAL SLURRY:
ADULTS AND CHILDREN OVER 12 YEARS: 1.0-2.0 G/KG BODY WEIGH TO A MAXIMUM OF 150 G PER DOSE.
CHILDREN UNDER 12 YEARS: 1.0-1.5 G/KG BODY WEIGHT TO A MAXIMUM OF 50 G PER DOSE.
/RODENTICIDES (COUMARINS AND INDANDIONES)/
3. IF TREATMENT HAS BEEN DELAYED SEVERAL HOURS FOLLOWING INGESTION OMIT INDUCED EMESIS,
BUT GIVE ACTIVATED CHARCOAL AND SORBITOL ORALLY. /RODENTICIDES (COUMARINS AND
INDANDIONES)/
4. IF ANTICOAGULANT HAS BEEN INGESTED ANY TIME IN THE PRECEDING 15 DAYS, DETERMINATION
OF PROTHROMBIN TIME PROVIDES A BASIS FOR JUDGING THE SEVERITY OF POISONING. A. IF THE
PROTHROMBIN TIME IS SIGNIFICANTLY LENGTHENED, GIVE AQUAMEPHYTON,INTRAMUSCULARLY: DOSAGE
FOR ADULTS AND CHILDREN OVER 12 YEARS: 5-10 MG; DOSAGE FOR CHILDREN UNDER 12 YEARS: 1-5
MG. DECIDE DOSE WITHIN THESE RANGES ACCORDING TO THE DEGREE OF PROTHROMBIN TIME
LENGTHENING AND, IN CHILDREN, THE AGE AND WEIGHT OF THE CHILD. B. REPEAT PROTHROMBIN TIME
IN 24 HOURS. IF IT HAS NOT DECREASED FROM THE ORIGINAL VALUE, REPEAT AQUAMEPHYTON DOSAGE.
/RODENTICIDES (COUMARINS AND INDANDIONES)/
5. IF VICTIM IS BLEEDING AS A RESULT OF ANTICOAGULANT POISONING ADMINISTER AQUAMEPHYTON
INTRAVENOUSLY: UP TO 10 MG IN ADULTS AND CHILDREN OVER 12 YEARS, AND UP TO 5 MG IN
CHILDREN UNDER 12 YEARS. INITIAL DOSAGE SHOULD BE DECIDED CHIEFLY ON THE BASIS OF THE
SEVERITY OF BLEEDING. REPEAT INTRAVENOUS AQUAMEPHYTON IN 24 HOURS IF BLEEDING CONTINUES.
INJECT AT RATES NOT EXCEEDING 5% OF THE TOTAL DOSE PER MINUTE. INTRAVENOUS INFUSION OF THE
AQUAMEPHYTON DILUTED IN SALINE OR GLUCOSE SOLUTION IS RECOMMENDED. BLEEDING IS USUALLY
CONTROLLED IN 3-6 HOURS. CAUTION: ADVERSE REACTIONS, SOME FATAL, HAVE OCCURRED FROM
INTRAVENOUS PHYTONADIONE INJECTIONS, EVEN WHEN RECOMMENDED DOSAGE LIMITS AND INJECTION
RATES WERE OBSERVED. FOR THIS REASON THE INTRAVENOUS ROUTE SHOULD BE USED ONLY IN CASES OF
SEVERE POISONING. FLUSHING, DIZZINESS, HYPOTENSION, DYSPNEA, AND CYANOSIS HAVE
CHARACTERIZED ADVERSE REACTIONS. /RODENTICIDE (COUMARIN AND INDANDIONES)/
5A. ANTIDOTAL THERAPY IN CASES OF SEVERE BLEEDING SHOULD BE SUPPLEMENTED WITH
TRANSFUSIONS OF FRESH BLOOD OR FRESH FROZEN PLASMA. USE OF FRESH BLOOD OR PLASMA
REPRESENTS THE MOST RAPIDLY EFFECTIVE METHOD OF STOPPING HEMORRHAGE DUE TO THESE
ANTICOAGULANTS, BUT THE EFFECT MAY NOT ENDURE. THEREFORE, THE TRANSFUSIONS SHOULD BE GIVEN
ALONG WITH PHYTONADIONE THERAPY. /RODENTICIDE (COUMARINS AND INDANDIONES)/
5B. DETERMINE PROTHROMBIN TIMES AND HEMOGLOBIN CONCENTRATIONS EVERY 6-12 HOURS TO
ASSESS EFFECTIVENESS OF ANTIHEMORRHAGIC MEASURES. C. WHEN NORMAL BLOOD COAGULATION IS
RESTORED, IT MAY BE ADVISABLE TO DRAIN LARGE HEMATOMATA. D. FERROUS SULFATE MAY BE
APPROPRIATE IN THE RECUPERATIVE PERIOD TO REBUILD LOST ERYTHROCYTE MASS. /RODENTICIDES
(COUMARINS AND INDANDIONES)/
Vitamin C is no substitute for vitamin K but ascorbic acid may be a useful adjunct to K
therapy, as judged by animal studies. At least a dose of 100 mg of ascorbic acid several
times a day can do no harm.
If warfarin dust gets into the eyes, wash eyes immediately with large amounts of water,
lifting the lower and upper lids occasionally. If irritation is present after washing, get
medical attention. Contact lenses should not be worn when working with chemical.
VETERINARY: Injured capillaries cannot be mended, but other measures may save the
animal. Restraint & handling should be minimized. A sedative or tranquilizer may be of
assistance in restraint, calming ... & reducing locomotion, thus decr tissue oxygen
demand. Oxygen may be given, but manual pumping of chest is not advisable. Dyspnea may be
relieved by thoracentesis. Clotting factors should be provided in form of blood
transfusion (20 ml/kg, 1/2 injected quickly). Warfarin should be antagonized with slow iv
injection of vitamin K1. Dogs & cats are given 5 mg/kg. This dose is repeated for 2
more days, using im route. Larger animals are given 0.5 to 1 mg/kg, & oral vitamin K1
should be admin daily for 4-6 days. The vitamin will not evoke a sudden dramatic cure; but
bleeding tendency will gradually abate as clotting factors begin to be synthesized ...
Menadione (vitamin K3) is not as effective as vitamin K1 ... Residual defects such as
lameness or CNS signs from localized hemorrhages may disappear with gradual resorption of
extravasated blood. Liver damage may be compensated by regeneration of hepatic cells.
Mouthful amounts in children present no risk, and treatment is not necessary. Exposure
to amounts larger than 0.5 mg/kg and chronic exposures should be evaluated.
Treatment involves the administration of syrup of ipecac to prevent absorption or
administration of activated charcoal followed by a cathartic. The prothrumbin time (PT)
should be checked initially and again in 12 to 24 hours. Patients who are asymptomatic and
have normal prothrombin times and no evidence of bleeding may be discharged from the
emergency department. They may return as out-patients for follow-up prothrombin times.
When the prothrombin time is two or more times normal or there is evidence of bleeding,
vitamin K should be given. Vitamin K is rapidly metabolized and has to be given three to
five times daily. Blood transfusions may be indicated in the event of major blood loss.
Repeated hematocrits and prothrombin times are indicated. When patients are already on
anticoagulants, emesis should be avoided; activated charcoal alone should be given to
absorb the toxin. Few deaths have been reported with warfarin compounds, since early
treatment can be effective.
Animal Toxicity Studies:
Non-Human Toxicity Excerpts:
... /Warfarin is/ most toxic when ingested daily over period of 5-7 days. ... Rats
& mice are very susceptible ... They die after ingesting 1 mg/kg/day for 6 days (or
50-150 mg/kg in single dose). Fowl are most resistant ... Birds would have to eat 1/2
their body wt of feed containing 0.1 mg warfarin/kg feed to be poisoned. Horses are
resistant ... although expt in ponies indicate it does have anticoagulant effects in the
equine species ... Ruminants can tolerate a lot ... death occurs at dose of 200 mg/kg/day
for 12 days. Dogs & cats are sensitive ... Pigs are more susceptible ... than rats
& mice. Ingestion of 0.05 to 0.4 mg/kg/day for 7 days can kill pigs ... Clotting
defects appear in pigs fed 0.028 mg/kg for 5-6 days ...
A SERIOUS OUTBREAK OF ... POISONING IN PIGS ... IN IRELAND /WAS/ CAUSED BY PREPN OF
COMMERCIAL PIG-MEAL IN ... /MFR PLANT/ PREVIOUSLY USED FOR MIXING WARFARIN RAT-BAIT.
... SECONDARY TOXICITY CAN OCCUR FROM ANIMALS INGESTING MEAT OF POISONED ANIMALS.
Clinical signs relate to massive hemorrhage & incl bloody discharges from body
orifices, visible hematomas under skin & around joints, purpura, dyspnea, weakness,
& signs of shock. Abortion may occur in cattle. ... The hemorrhages can occur in any
location in body. ... Hepatic necrosis (from tissue hypoxia) may be seen in subacute
cases. Icterus might be seen if postmortem interval was long enough for autolysis of blood
to occur in mucous membranes.
Fatal hemorrhages occurred in 4-wk-old piglets after consuming an estimated single dose
... of 30 mg of pure warfarin. ... low levels of warfarin, if consumed by pregnant
animals, can lead to fetal death & abortions.
RATS MAINTAINED FOR 8 MONTHS ON /SRP: DAILY DOSAGES AT/ A LEVEL OF WARFARIN SUFFICIENT
TO DECREASE THE VITAMIN K-DEPENDENT PROTEIN OF BONE TO 2% OF NORMAL HAVE AN EXCESSIVE
MINERALIZATION DISORDER CHARACTERIZED BY COMPLETE FUSION OF THE PROXIMAL TIBIAL GROWTH
PLATE AND CESSATION OF LONGITUDINAL GROWTH. THE GENERAL FEATURES OF THIS ABNORMALITY
RESEMBLE THE FETAL WARFARIN SYNDROME IN HUMANS, A DISORDER ALSO CHARACTERIZED BY EXCESSIVE
MINERALIZATION OF THE GROWTH PLATE.
In exptl animals ... no significant malformations /were observed/ in mice whose mothers
were given up to 4 mg/kg on days 8 through 11 /of gestation/. On days 3 through 11
placental hemorrhage & subsequent fetal loss occurred. ... rabbits ... /have been
treated/ iv on 6th through 18th day ... /of gestation/ with up to 100 times the
therapeutic dose & ... no effect on resorption rate or the fetus (incl skeletal
studies) /were observed/. /Warfarin Sodium/
Chronic vitamin K deficiency, either dietary or pharmacologically induced with
warfarin, depressed the growth of lung secondary tumor growths in /the murine/ ... Lewis
lung carcinoma. This effect was associated with a marked depression of the procoagulant
activity of cancer cells. ...
The effects of racemic warfarin on brain tumor cells were assessed in rat C6 glioma
cell line. After anticoagulant treatment lasting up to 5 days, cell growth was not
inhibited by warfarin at low doses (10-4 to 10-5 M), but cell growth and cellular
adherence to culture plates were inhibited at high doses (10-3 to 10-2 M). ... Warfarin
(10-3 M) significantly decreased ... (3)H thymidine and (14)C leucine incorporation after
3-or 24-hr anticoagulant treatment. ...
Walker 256 carcinoma cells were injected sc into rats that were given warfarin (0.025
or 0.05 mg /SRP: per rat/ iv). Depression of prothrombin and /clotting/ factors VII, IX,
and X levels was much greater than in control rats given 0.025 or 0.05 mg of warfarin. ...
A daily intake of 0.025% warfarin ... solution up to 15 days with a total consumption
of up to 171 mg/kg warfarin produced no poisoning symptoms in leghorns.
... /Warfarin is a coumarin derivative &/ relative of dicumarol ... The product was
the 1st successful anticoagulant rodenticide & ... unique in that it had to be eaten
repeatedly to cause death. ... It has a good record of safety & is considered one of
the less dangerous rat & mouse control materials.
There has been no development of tolerance in rodents after ingestion & apparently
neither sex nor age of the rat or mouse causes any difference in effectivenss.
The effect of low dose warfarin and high dose warfarin on epithelial cell kinetics (as
determined by stathmokinetic techniques), and preneoplastic morphological changes was
studied during azoxymethane induced carcinogenesis in the rat. Warfarin, at either low or
high dose, had no effect on crypt cell production rate at any time interval whereas tumour
incidence in both low dose warfarin and high dose warfarin groups was significantly
reduced. Morphological changes were observed using scanning electron microscopy, which by
conventional histology were shown to be adenoma precursors. In the control group the
number of microadenomas increased with time after starting azoxymethane. In warfarin
treated animals, the number of microadenomas also increased with time, but the actual
incidence was reduced when compared with controls. These results suggest that the effects
of warfarin on tumour development is unrelated to its anticoagulant effect, because
increased dose did not result in greater tumour reduction. Furthermore, there was no
overall change in crypt cell production rate when warfarin was administered. Warfarin may
exert a specific effect, by preventing neoplastic change in cells which have undergone
morphologically undetectable changes associated with early carcinogenesis.
The effects of warfarin on tumor cell growth was examined in a model in which tumor
metastasis is inhibited (clonogenic assay, growth curves, thymidine labelling index and
anticoagulation assays). Clonogenic assay, growth curve analysis and thymidine labelling
index revealed that warfarin had no effects on Mtln3 rat mammary carcinoma cell growth in
vitro at concn below 1 mM. The growth rate of sc implanted Mtln3 tumor deposits in female
F344 rats, assessed by wt and by stathmokinetic analysis of the tumor tissue, was
identical in warfarin-treated and control animals. Spontaneous metastasis from such tumors
to the lungs was significantly reduced in warfarin-treated animals (median 0 pulmonary
tumors per animal in warfarin treated, 8 tumors per animal in control animals; p <
0.05, Mann-Whitney). The mean plasma warfarin concn in warfarin treated rats was 1.63 uM.
Animals intoxicated by warfarin exhibited increasing pallor and weakness reflecting
blood loss. Appetite and body weight are not specifically affected. The blood loss may be
evident in the form of bloody sputum, bloody or tarry stools, petechiae, or externally
visible hematomata. Hematoma formation is more common than free hemorrhage. If a hematoma
is superficial, it will be marked by swelling and discoloration. However, in laboratory
animals, hematoma in muscle septa are frequently so large that the entire upper or lower
leg is grossly swollen, even though the lesion is so deep that no color is evident beneath
the skin. There is no typical location for hematoma formation, the location of bleeding
being apparently a matter of chance in the absence of obvious trauma. Bleeding associated
with the CNS may be of such location and extent as to cause paralysis of the hindquarters
several days before death occurs. Pregnant rats appear slightly more susceptible than
nonpregnant ones.
As to initiation of hemorrhage, normal movement of muscles (skeletal, smooth, &
cardiac) & organs from body locomotion is sufficient to cause damaged capillaries to
leak blood. Hemorrhages may also occur spontaneously in organs of little movement.
Bleeding continues because a mechanism of natural hemostasis no longer exists. ...
... Individually-caged black rats were fed separately for 1 wk with 0.0375%
Racumin-containing baits ... . Mortality (100%) in both the sexes was obtained with each
formulation. ... In the field trails, 71.28%, 30% and 66.24% mortality was observed with
Racumin as tracking powder, as ready to use bait containing 0.0375%, and Rodafarin C
(Warfarin) containing 0.025%, respectively, within 2 weeks, in R rattus and Mus musculus.
Racumin as tracking powder in bait was readily accepted by rats and mice and caused
earlier mortality than Warfarin.
BRODIFACOUM AT 0.005%, ALTHOUGH GIVING COMPLETE MORTALITY AFTER ONLY 8 DAYS' CONTINUOUS
FEEDING, WAS MORE TOXIC TO MERIONES SHAWI /SHAWS GERBIL/ THAN WARFARIN (0.025%),
COUMATETRALYL (0.0375%), DIFENACOUM (0.005%) AND
BROMADIOLONE (0.005%).
Almost all published toxicity figures are for the /racemic/ mixture ... Based on
prothrombin time measured 24 hr after single oral dose, the (-)(S)-isomer was 5.5 times as
active as the (+)(R)-isomer. Based on mortality within 10 days after starting daily
dietary intake, the (-)(S)-warfarin was 8.5 times as active as the (+)(R)-isomer.
Sodium warfarin was admin daily to Sprague-Dawley rats from gestational day 8 to day 22
to examine the effects of this compound on the developing fetal skeleton and on the
vitamin K dependent bone and cartilage proteins. At a dose of 175 ug/kg of sodium warfarin
there was a 43% mortality rate among the dams. Maternal prothrombin times and serum
osteocalcin levels were slightly elevated but not significantly. In the surviving litters
fetal bone osteocalcin and gamma-carboxyglutamic acid were significantly reduced (50 and
57 respectively on gestational day 22) when compared to age and/or weight matched control
pups. The high correlation of osteocalcin content in long bone (R = 0.64) and calvaria (R
= 0.77) to fetal body weight observed in control fetuses was not seen ln the
warfarin-exposed pups. Examination of alizarin-stained warfarin exposed fetal skeletons
for ossification centers showed no difference from controls. However analysis of the
tibial growth showed several changes compared to control that included: widened
hypertrophic zones, increased calcification of the hypertrophic zones and disorganization
of the hypertrophic cells. These results suggest that the growth plate abnormalities seen
with prenatal warfarin exposure relate to the inhibition of the vitamin K dependent
proteins of the skeletal system.
Pregnant Sprague-Dawley rats were given daily oral doses of sodium warfarin (100 mg/kg)
and concurrent intramuscular injections of vitamin K1 (10 mg/kg). This dosing regimen did
not have any apparent deleterious effect on the dams and did not affect the fetuses when
administered from day 1 to day 12 of pregnancy. However similar treatment from day 9 to 20
caused hemorrhage in the fetuses examined on day 21 of gestation. There were no
hemorrhages in the control fetuses from dams receiving vitamin Kl only. The lowest
effective dose of warfarin in conjunction with daily doses of vitamin K1 was 3 mg/kg. This
dose caused hemorrhage in 28% of fetuses; the incidence of affected fetuses was not
further increased by doses of warfarin up to 100 mg/kg. Hemorrhages affected the fetal
brain, face, eyes and ear and occasionally the limbs. Brain hemorrhages were frequently
intraventricular and caused various degrees of hydrocephaly. Bony defects were not a
feature of prenatal exposure to warfarin. These results show that prenatal exposure of the
rat to warfarin and vitamin K duplicates the hemorrhagic abnormalities and pathology
associated with prenatal exposure to warfarin in the human. It did not induce bony or
facial defects probably because the vitamin K dependent components of bone development
occur postnatally in the rat.
The anticoagulant warfarin Is a well documented human teratogen causing nasal
hypoplasia, stippled epiphyses and a range of CNS defects resulting in mental retardation,
spasticity seizures and blindness. It is not known whether warfarin is a direct teratogen
or if its teratogenicity is a result of antagonism of vitamin K epoxide reductase, which
is essential for vitamin K recycling. ... An animal model /was developed/ of the warfarin
embryopathy in which the warfarin treated Sprague-Dawley rat is given concurrent vitamin
K. This regimen allows the pregnant rat to produce normal prothrombin but the near term
fetuses exhibit a high incidence of intraventricular hemorrhage and less frequent
hemorrhage in the eye and inner ear. Fetuses from control rats given vitamin K1 only
appeared normal. Preliminary examination of postnatally treated rats up to 5 weeks of age
have revealed severe hypoplasia of the nasal bones and cartilage hypoplasia of the
external ears and reduced length of the extremities, particularly the digits.
Non-Human Toxicity Values:
LD50 rat (female) oral 9 mg/kg, single dose /Warfarin sodium/
LD50 Sprague-Dawley rat (male) oral 100 mg/kg /Warfarin sodium/
LD50 Rat dermal 1400 mg/kg
Ecotoxicity Values:
LC50 Rasbora heteromorpha (harlequin fish) 17 mg/l/24 hr; 14 mg/l/48 hr; 12 mg/l/96 hr.
/Conditions of bioassay not specified/
LC50 Ictalurus punctatus 34.3 mg/l/96 hr. Static bioassay without aeration, pH 7.2-7.5,
water hardness 40-50 mg/l as calcium carbonate and alkalinity of 30-35 mg/l.
Metabolism/Pharmacokinetics:
Metabolism/Metabolites:
In man, the dextrowarfarin enantiomorph is metabolized by side chain reduction to a
secondary alcohol, whereas levowarfarin is metabolized by oxidation of the ring, primarily
to 7-hydroxywarfarin. These inactive metabolic products are to some extent conjugated with
glucuronic acid, undergo an enterohepatic circulation, & are ultimately excreted in
urine & stool.
AFTER ORAL ADMIN OF WARFARIN TO HUMANS, SEVERAL METABOLITES WERE OBSERVED IN URINE AND
PLASMA. IN ADDITION TO 7-HYDROXY WARFARIN, THE 6-HYDROXY ANALOG AND DIASTEREOISOMERIC
WARFARIN ALCOHOLS WERE OBSERVED.
RATS, GIVEN IP INJECTIONS OF (14) C- LABELED WARFARIN, EXCRETED 90% OF RADIOACTIVITY IN
URINE (60%) & FECES (30%) WITHIN 2 WK AFTER ADMIN. REMAINING RADIOACTIVITY WAS
EXCRETED OVER 90 DAY PERIOD. NO (14)CO2 WAS DETECTED. CHROMATOGRAPHY INDICATED THAT THE
SAME 6 METABOLITES WERE IN URINE & FECES BUT WERE DIFFERENT QUANTITATIVELY. THESE WERE
... IDENTIFIED AS ... 6-HYDROXY-, 7-HYDROXY-, 8-HYDROXY- & 4'-HYDROXY-WARFARIN; AND
2,3-DIHYDRO-2-METHYL-4-PHENYL-5-OXO-GAMMA-PYRANO (3,2-C) (1) BENZOPYRAN. THE GLUCURONIDE
OF 7-HYDROXY-WARFARIN WAS ALSO FOUND. COMPARISON OF DRUG-METABOLIZING ENZYME SYSTEMS OF
WARFARIN SUSCEPTIBLE AND RESISTANT MALE RATS INDICATED HIGHER CONCN OF ENZYME IN RESISTANT
RATS BUT NO DIFFERENCES IN RATE OF FORMATION OF METABOLITES ... OR IN THEIR RELATIVE
PROPORTIONS.
METABOLISM OF ... WARFARIN ... DECREASED IN ELDERLY.
METABOLISM OF WARFARIN IS UNDER GENETIC CONTROL & LARGE INTERSTRAIN VARIATIONS IN
RATS HAVE BEEN OBSERVED.
FORMATION OF AN ETHEREAL LINKAGE HAS BEEN OBSERVED IN METABOLISM OF WARFARIN. THE
PYRANOBENZOPYRAN DERIVATIVE ... IS AN IMPORTANT METABOLITE IN RATS; ITS FORMATION OCCURS
BY RING CLOSURE OF WARFARIN ALCOHOL ... A MAJOR WARFARIN METABOLITE.
Of all metabolites recovered, only 4'-hydroxywarfarin & DHG
/2,3-dihydro-2-methyl-4-phenyl-5-oxo-gamma-pyrano(3,2-c)(1)benzopyran/ showed
anticoagulant activity.
The oxidative biotransformation of (R)-warfarin and (S)-warfarin was studied in human
liver microsomes. The quantitative pattern of oxidized products obtained from warfarin in
vitro changed dramatically as a function of substrate concentration. Apparent Km values
for the formation of 4', 6, 7, and 8-hydroxywarfarin showed the presence of two easily
distinguishable subsets of human liver cytochrome p450: a high affinity subset with Km of
to 15 uM and a low affinity subset of isozymes with Km >200 uM. The high affinity
subset was primarily responsible for the metabolic profile of the biologically more potent
(S)-warfarin in vivo, whereas the low affinity subset was largely responsible for
metabolism of (R)-warfarin. Apparent Vmax values alone did not reflect the relative in
vivo formation of the phenolic metabolites from either compound because the low affinity,
high capacity component masked the metabolic profile of (S)-warfarin. The rank order of
intrinsic clearance (Vmax/Km) for each metabolite agreed well with regioselective and
steroeselective metabolism in vivo.
... Change in vitamin K1 metabolism associated with poisoning and the alteration of
this metabolism in resistant animals probably involves a warfarin-binding protein in the
microsomal membranes of the liver. ... Ribosomes isolated from the livers of resistant
rats bind only one-third to one-fifth as much warfarin as ribosomes from normal rats,
regardless of whether warfarin is injected before the rats are killed for study or is
added to the in vitro preparation. When warfarin at a concentration of 0.786 ppm was
incubated with microsomal preparations, the concentrations reached were 42.0 and 17.7
pmol/mg of protein, depending on whether the preparations were prepared from normal or
from warfarin-resistant rats, respectively. Futhermore, the warfarin was bound firmly to
membranes of normal rats but loosely to those of warfarin-resistant rats, respectively.
Warfarin causes a relative increase in vitamin K1 oxide in the plasma or liver of
people and rats. The oxide is a naturally occurring compound. In vitamin K-deficient but
otherwise normal rats, the oxide and vitamin K1 are equally effective, but the oxide is
not therapeutic in warfarin-treated rats.
In humans, the (S) isomer is primarily 7-hydroxylated, whereas the (R) form is reduced
to the (R,S)-alcohol. In rats, the (S) isomer is primarily 4'-hydroxylated, whereas the
(R) enantiomer is 7-hydroxylated. Involvement of different cytochrome P-450 forms were
used to explain these results.
The contribution of human P450 2A6 and mouse P450 2a-5 isoenzymes both highly active in
coumarin 7-hydroxylation to the metabolism of warfarin was studied in several in vitro
systems with human and mouse liver preparations.The reconstituted P450 2a-5 purified from
DBA/2 mouse liver did not metabolize warfarin. An anti-P450 2a-5 antibody did not
consistently inhibit any of the warfarin biotransformation reactions catalyzed by human or
mouse liver microsomes although coumarin 7-hydroxylation was inhibited by over 90%. In
some human microsomal samples 4- and 8-hydroxylations of warfarin were inhibited to some
extent by the anti-P450 2a-5 antibody. Warfarin (less than 1 uM) did not inhibit coumarin
7-hydroxylation by human or mouse liver microsomes in vitro. /Results indicate/ that mouse
and human coumarin 7-hydroxylases do not oxidize warfarin.
The regio- and stereoselectivity of warfarin metabolism have been used to assess
structure function relationships of human P4502C subfamily members. Both alleles of
P4502C18 were regioselective for 4 -hydroxywarfarin, without any significant
stereoselectivity. Both also metabolized warfarin at the 6-position, but to a lesser
extent, and metabolism at this site was stereoselective for (R)-warfarin. P4502C8
metabolized warfarin at the 7-position and was stereospecific for (R)-warfarin. It also
metabolized warfarin to a lesser extent at the 4 position, and metabolism at this site was
stereoselective for (R)-warfarin. P4502C19 was regioselective for 6- and 8-hydroxywarfarin
and was stereoselective for (R)-warfarin. The highly conservative mutation of Ile359 to
Leu359 in P4502C9 profoundly altered the regio and stereoselectivity of warfarin
metabolism, from regioselective for 7-hydroxywafarin, with stereospecificity for
(S)-warfarin, to regioselective for 4-hydroxywarfarin, with stereoselectivity for
(R)-warfarin, which was confirmed in a reconstituted system using purified recombinant
enzymes. In contrast, individual mutations of P4502C9 of Argl44 to Cys, Tyr358 to Cys, and
Gly417 to Asp did not markedly affect the regio or stereoselectivity of warfarin
metabolism, although the overall rates of warfarin metabolism were apparently increased by
these changes. /Results suggest/ that residue 359 is at the substrate binding site of
P4502C9, whereas residues 144, 358 and 417 and residue 385 of P4502C18 are not.
The mechanisms by which antimicrobial agents alter the biotransformation of other drugs
... reflect inhibition or induction of specific cytochrome p450 enzymes. Macrolides
inhibit cytochrome P450IIIA4 (CYP3A4) which appears to be the most common metabolic enzyme
in the human liver and is involved in the metabolism of many drugs including cyclosporin,
warfarin and terfenadine. ...
Absorption, Distribution & Excretion:
AFTER ORAL ADMIN OF WARFARIN TO HUMANS, SEVERAL METABOLITES WERE OBSERVED IN URINE AND
PLASMA. RATS, GIVEN IP ... WARFARIN, EXCRETED 90% ... IN URINE ... & FECES.
Absorption of oral warfarin is dissolution-rate controlled, & the rate & extent
of absorption of the drug may vary from one commercially avail tablet to another. ...
Coumarin derivatives are also absorbed percutaneously ... severe toxicity has occurred
from repeated skin contact with rodenticides containing warfarin.
DRUGS ... SHOWN TO ACTIVELY CROSS HUMAN PLACENTA INCLUDE ... WARFARIN ...
Uptake of ... /coumarin deriv/ by erythrocytes is variable. The drugs are distributed
to liver, lungs, spleen & kidneys. ... fetal plasma drug concn /of coumarin deriv/ may
be equal to maternal plasma concn. ... Warfarin sodium does not appear to be distributed
into milk. In one study, warfarin sodium was not detected in milk of 13 nursing women or
in the plasma of their breast-fed infants following 30- or 40-mg initial doses & daily
maintenance dosages of 2 to 12 mg ... In general, coumarin ... deriv are excreted in bile
as inactive metabolites ... reabsorbed, & excreted in urine. /Warfarin Sodium/
The salivary excretion of warfarin was investigated following iv and oral
administration in rabbits. The salivary decay curves following iv injection (50 mg/kg)
fitted the two-compartment open model. ... Following oral administration (100 mg/kg), the
disposition of warfarin fit the one-compartment model. There was a good linear
relationship between warfarin concentrations in saliva and plasma. The saliva vs. plasma
(S/P) ratio was approximately 0.07. A good correlation was also observed between warfarin
concentrations in saliva and protein-unbound fraction. The saliva vs. plasma
protein-unbound fraction (S/PF) ratio was approximately 0.92. ...
Absorption of warfarin from the skin of rats is slow but measurable. Three dermal doses
at the rate of 50 mg/kg had about the same pharmacological effect as three oral doses at
0.6 mg/kg. Because of either species or formulation differences, the results were very
different with guinea pigs and rabbits that received a 0.5% solution of the sodium salt in
water; single applications at rates of 0.7 and 0.25 mg/kg caused a marked change in
prothrombin times in guinea pigs and rabbits, respectively.
Warfarin is almost completely (99%) bound to plasma proteins, principally albumin, and
the drug distributes rapidly into a volume equivalent to the albumin space (0.14 l/kg).
Concn in fetal plasma approach the maternal values, but active warfarin is not found in
milk ... .
Warfarin is usually detectable in plasma within 1 hr of its oral administration, and
concn peak in 2 to 8 hr.
The bioavailability of solutions of racemic sodium warfarin is nearly complete when the
drug is administered orally, im, iv, or rectally.
Rats injected intraperitoneally with (14)C warfarin excreted approximately 90% of the
activity in 14 days, about half in the urine and half in the feces. Approximately 10% of
the activity from (14)C warfarin was excreted in the bile of rats within 5 hr after
intraperitoneal injection, but little radioactivity appeared in the feces. Nearly all of
the metabolites in the bile were conjugated ; they could be released with about equal ease
by incubation with beta-glucuronidase or with gut flora. The metabolites identified were
the same as those found slightly later in the urine.
When guinea pigs were injected with 1 or 2 mg of (14)C warfarin, about 50% of the
activity was recovered from urine excreted during the first 12 hr and 87% was found in
urine within 7 days. A smaller percentage of large doses was excreted promptly.
Dicumarol is slowly and incompletely absorbed from the gastrointestinal tract.
When nine normal men and five normal women were given a single oral dose of warfarin at
the rate of 1.5 mg/kg, maximal concentration in plasma was reached in 2-12 hr. Maximal
depression of prothrombin activity was between 36 and 72 hr. Their individual increases in
prothrombin time were proportional to their half-times for disappearance of warfarin from
the plasma.
Plasma levels of warfarin were 6.8 and 11.2 ppm 4 and 7 hr, respectively, after the
ingestion of 500 mg of warfarin sodium in a suicide attempt. Plasma levels declined
thereafter, and the half-time for disappearance was calculated as 46 hr. Part of the dose
was removed by gastric lavage soon after ingestion. This and other appropriate treatment
prevented any increase in bleeding tendency.
Biological Half-Life:
After a single iv injection of the sodium salt (about 1 mg/kg), the maximal response in
man is usually reached in 48 hr, and recovery is essentially complete by the fifth day.
The fairly long half life (7 days in one would-be suicide) is due at least in part to
intensive enterohepatic recycling.
The (S) enantiomer of warfarin is the more potent anticoagulant in both rats and
humans. However, in humans, (S)-warfarin is cleared more rapidly from the body than its
enantiomer: plasma half-lives for (R)=45.4 hr; (S)=33 hr; the converse is true for rats.
In humans, the (S) isomer is primarily 7-hydroxylated, whereas the (R) form is reduced to
the (R,S)-alcohol. In rats, the (S) isomer is primarily 4'-hydroxylated, whereas the (R)
enantiomer is 7-hydroxylated. Involvement of different cytochrome P-450 forms were used to
explain these results.
BY IV ROUTE ... THE PLASMA HALF-LIFE IS 41-57 HR, EXCEPT ABOUT 27 HR IN ALCOHOLICS
& PROBABLY EVEN LESS IN PERSONS USING PHENOBARBITAL OR OTHER HEPATIC MICROSOMAL ENZYME
INDUCERS. /WARFARIN SODIUM USP/
PLASMA HALF-LIFE OF (-)WARFARIN IN MALE RATS WAS FOUND TO BE 15.4 + or - 2.8 HR; AND
THAT OF (+)WARFARIN, 8.6 + or - 1.6 HR...
The half-times for disappearance from the plasma varied from 15 to 58 hr with a mean of
42 hr. Absorption of warfarin from the gastrointestinal tract was apparently complete; no
warfarin was found in the stool even after massive doses, and plasma levels and
prothrombin activity responses were virtually identical following oral and intravenous
administration at the same rates.
The fairly long plasma half-life (7 days in one would-be suicide) is due at least in
part to intensive enterohepatic recycling.
Risk of major hemorrhage (resulting in death or hospitalization) or minor hemorrhage
(all other cases) was studied in medical records of 2029 patients who had been given
warfarin any time between December 1970 through December 1980 at the Northern California
Kaiser-Permanente Medical Care Program. Almost 7% of patients had a major hemorrhage on
warfarin and an additional 23.7% had at least 1 minor bleeding episode. Age, female sex,
and congestive heart failure were associated with small incr in the risk of major
hemorrhage but not with the risk of minor bleeding. A prothrombin time ratio greater than
2.5 was associated with a fourteen-fold incr in the risk of a major hemorrhage (95% CI
5.1, 42.7), but major hemorrhages occurred in patients on warfarin at all measured values
of the prothrombin time ratio.
Mechanism of Action:
DEPRESSES FORMATION OF PROTHROMBIN & INCREASES CAPILLARY FRAGILITY, LEADING TO
HEMORRHAGES.
Animals poisoned by warfarin ... die of tissue hypoxia resulting from massive internal
bleeding of 2-5 days onset. Bleeding is due to incr capillary permeability & decr
blood coagulability. The exact cause of capillary damage is not known, but its presence is
evidenced by the fact that hemorrhages occur in tissues not subjected to much mechanical
stress. The coagulation defect is the result decreased blood concentrations of the
coagulation proteins factor II (prothrombin), factor VII (proconvertin, autoprothrombin
I), factor IX (Christmas factor, autoprothrombin II, PTC), and factor X (Stuart factor,
autoprothrombin III). These coagulation factors are decreased because their synthesis in
the liver has been inhibited. Biosynthesis of these particular proteins is inhibited
becaused each one requires adequate activity of vitamin K for biosynthesis, but the
rodenticide interferes with the normal function of vitamin K.
Stopped flow kinetic expt were performed on human serum albumin, and on a large peptic
fragment (residues 1 to 387) and a large tryptic fragment (residues 198-585) of albumin.
Equal vol of 2 solutions were rapidly mixed. One soln contained albumin or one of the
fragments, while the second soln contained warfarin. In all cases, after mixing, the
warfarin-to-protein ratio was 0.1. As soon as the warfarin-protein complexes had formed,
the changes in fluorescence intensity were monitored. In all cases the observed binding
rate constant incr with the protein concn until a plateau is reached. This indicates that
all 3 proteins have a comparable binding mechanism. It was also seen that at lower pH
values (approx 6.5 to 7.5), the observed rate constants of warfarin binding to the
fragments were very high. For albumin, the observed rate constant incr as the pH is raised
from 6 to 9, whereas for the fragments the reverse in the case.
Hepatic synthesis of prothrombin and factors VII, IX, and X is dependent upon adequate
supplies of vitamin K. The molecular and even the cellular mechanism of the anti-vitamin K
action of the coumarin compounds remain uncertain. These drugs seem to act as
antimetabolites in synthesis of affected clotting factors. Since large doses of vitamin K
can overcome or surmount action of dicumarol, competitive type of interaction is thought
to be involved. Perhaps coumarin anticoagulants simply inhibit transport of vitamin K to
the cellular sites wheresynthesis takes place. In any event, there is some evidence that
dicumarol interferes with involvement of vitamin K in synthesis of a prothrombin precursor
that may also be common to factors VII, IX, and X.
Anticoagulants interfere with fibrin formation and are used to prevent thrombus
development and extension. Their major therapeutic application has traditionally been for
venous thromboembolic disorder in which stasis, rather than vessel wall damage, plays an
important etiologic role. Antiplatelet drugs (antithrombotics) are used to prevent
arterial occlusions. Thrombolytics dissolve existing fresh thrombi and emboli by
catalyzing the conversion of plasminogen to plasmin and thereby activating the endogenous
fibrinolytic system.
There is no selectivity of the effect of warfarin on any particular - vitamin
K-dependent coagulation factor, nor is the antithrombotic benefit or hemorrhagic risk of
therapy correlated with any particular activity. Vitamin K-dependent carboxylase activity
occurs in many tissues, and other proteins have Gla residues.
Therapeutic doses of warfarin decrease the total amount of each vitamin Kdependent
coagulation factor made by the liver by 30 to 50%; in addition, the secreted molecules are
under-carboxylated, resulting in diminished biological activity (10 to 40% of normal).
Congenital deficiencies of the procoagulant proteins to these levels cause mild bleeding
disorders.
The oral anticoagulants block the regeneration of reduced vitamin K and thereby induce
a state of functional vitamin K deficiency. The mechanism of the inhibition of
reductase(s) by the coumarin drugs is not known. There exist reductases that are less
sensitive to these drugs but that act only at relatively high concentrations of oxidized
vitamin K; this property may explain the observation that administration of sufficient
vitamin K can counteract even large doses of oral anticoagulants. /Oral Anticoagulants/
It has been proposed that coumarin and related anticoagulants act by inhibiting the
conversion of the oxide back to the active vitamin and that the oxide per se is
inhibitory. The hypothesis that warfarin inhibits prothrombin synthesis by causing
accumulation of the oxide does not appear tenable. However, it seems likely that the
brevity of the action of vitamin K in the treatment of poisoning is the result of its
irreversible conversion to the epoxide.
Interactions:
THE PHARMACOKINETIC COMPLEX ACTIVITY AFTER A SINGLE IV COADMINISTRATION WITH WARFARIN
(1.2 MG/KG) AND FUROSEMIDE (1.67 MG/KG) WERE NOT SIGNIFICANTLY DIFFERENT AS COMPARED WITH
THOSE IN THE GROUP INJECTED WITH WARFARIN ALONE; HOWEVER, WHEN COADMINISTERED WITH 5 MG/KG
OF FUROSEMIDE, THE ELIMINATION RATE CONSTANT WAS SIGNIFICANTLY INCREASED AND THE
PHARACOKINETIC COMPLEX ACTIVITY WAS MARKEDLY ENHANCED BEYOND 60 HOURS AFTER
ADMINISTRATION. THESE RESULTS SUGGEST THAT THE INTERACTIONS, SUCH AS THE DISPLACEMENT OF
WARFARIN BINDING AT ALBUMIN BINDING SITES, BETWEEN WARFARIN AND FUROSEMIDE ARE PRODUCED,
WHEN A HIGH DOSE OF FUROSEMIDE WAS COADMINISTERED.
REVIEW ON CLINICALLY IMPORTANT DRUG INTERACTIONS WITH CIMETIDINE. THE METABOLISM OF
WARFARIN (AND PROBABLY OTHER COUMARIN ANTICOAGULANTS) IS DECREASED BY CIMETIDINE.
... Metronidazole had no effect on the serum protein binding of racemic warfarin in
vitro over a wide concentration range but decreased the protein binding of R-(+)-warfarin
and S-(-)-warfarin in vitro ... (in rats) Treatment with ip metronidazole, 100 mg/kg every
6 hours, decreased the plasma clearance of free warfarin. ... Metronidazole did not affect
plasma prothrombin complex activity in vitro but reduced it in vivo. ...
... Chloramphenicol had no apparent effect on the serum protein binding of
R-(+)-warfarin or S-(-)-warfarin in vitro or in vivo /in rats/. Treatment with ip
chloramphenicol, 50 mg/kg every 4 hours or 30 mg/kg every 6 hours decreased the plasma
clearance of free warfarin by one-half or more, with no apparent stereoselectivity. The
volume of distribution was not significantly affected; the serum half-life of each
warfarin enantiomer was appreciably increased by chloramphenicol. ... It appears that the
pronounced potentiation of the anticoagulant effect of warfarin by chloramphenicol is due
only to inhibition of warfarin metabolism and that this effect is not stereoselective.
The effect of sulphinpyrazone on the anticoagulant response to warfarin was evaluated
by a double-blind study in 11 patients with prosthetic heart valves. Six patients received
warfarin and Sulphinpyrazone and 5 warfarin and placebo. Sulphinpyrazone potentiated the
anticoagulant action of warfarin. Patients receiving sulphinpyrazone needed about half the
amount of warfarin as compared to the control group. ...
In humans stabilized on a racemic-warfarin regimen (to prolong the prothrombin time to
approximately 1.5 times the control), administration of oxaprozin (1200 mg, orally for 7
days) did not appear to cause an important change in the pharmacological effect of
racemic-warfarin. ... There was a small increase in the plasma concentration of
racemic-warfarin, perhaps due to a nonstereoselective inhibition of racemic - warfarin
metabolism, thereby raising the prothrombin time slightly in some patients.
The effects of 3 beta-adrenoceptor antagonists (propranol metoprolol tartrate, and
atenolol) on the serum kinetics and pharmacodynamics of (+,-)-warfarin given in a single
oral dose (15 mg) were studied in normal subjects. At the same degree or beta-adrenoceptor
blockade, as assessed by the decrease of exercise tachycardia, propranolol increased the
area under the serum warfarin concentration-time curve (AUC) by 16.3% and the maximum
serum warfarin concentration by 23.0%. Atenolol increased the maximum serum warfarin
concentration by 12.5% but was without effect on warfarin concentration-time curve.
Metoprolol had no effect on warfarin kinetics. The extent of changes in the prothrombin
time and the plasma clotting factor VII activity caused by warfarin were not altered by
any of the beta-adrenoceptor antagonists.
An interaction was observed in two patients receiving aminoglutethimide and warfarin. A
decrease in the anticoagulant effect of warfarin was shown by ... thrombotest measurements
and the pharmacokinetic evaluation of warfarin. A 3-to 5-fold increase in warfarin
clearance was found. ...
... Warfarin kinetics were evaluated in 12 normal subjects who took a single 1 mg/kg
dose of warfarin with and without erythromycin. Erythromycin (250 mg p.o.) every 6 hours
for 8 days decreased warfarin clearance by 14% (p less than 0.001). ... The effect of
erythromycin was greatest among subjects whose control phase warfarin clearance was
relatively fast. The magnitude of the decrease in warfarin clearance correlated negatively
with control warfarin clearance (r=-0.89, p less than 0.005). ...
... Cadmium increased the toxicity of warfarin /in young pigs causing/ severe lameness,
and subcutaneous hematomas in the ventral surface of the head and neck.
... Ranitidine /a H2-antagonist/ does not alter the prothrombin time in subjects
receiving warfarin.
Amiodarone ... an iodinated benzofuran derivative with recognized antiarrhythmic
activity in man ... potentiates the anticoagulant effect of warfarin.
A case involving a biphasic interaction of phenytoin and warfarin in a 70 year old
woman is reported. Following the addition of phenytoin and warfarin regimen, the
stabilized prothrombin ratio appeared to increase for 6 days, and then declined to a level
less than observed before initiation of phenytoin. It was concluded that the net effect of
phenytoin on prothrombin time response to a given dose of warfarin may depend on the
relative contributions of protein binding changes, enzyme inhibition, and enzyme
induction.
A ... 60 year old male patient experienced prolongation of prothrombin time while
receiving cimetidine (1 g/day). The patient had been stabilized on 5 mg/day of warfarin
for 10 years. ... A prothromin time estimation on admission to the hospital was greater
than 200 sec (control was 14.3 sec). ...
Colony formation /of rat C6 glioma cells/ was examined /concerning/ the effects of
24-hr warfarin (10-3 M) infusion ... pretreatment plus incubation with 1 of 7 anticancer
agents. ... Supra-additive toxic effects were produced by warfarin plus chlorambucil. ...
The effects of oxametacin, 100 mg three times a day, on warfarin anticoagulation were
studied in twelve patients. All anticoagulation tests showed a potentiating effect of
oxametacin on warfarin, necessitating reduction or elimination of warfarin in 33% of the
patients.
Sulphinpyrazone decreases the plasma clearance of ... S-warfarin and increases the
clearance of R-warfarin. ...
... Warfarin ... blocked the ability of rifampin to kill phagocytosed Staphylococcus
aureus. ...
... In rabbits, prolongation of 5-fluorouracil plasma half-life was seen with high (0.6
mg/kg/hr) but not low (0.025 mg/kg/hr) rates of warfarin infusion. ...
Formation of ... metabolites is stimulated by phenobabital, chlordane, or DDT. The
metabolism is a true detoxication. The inducers can increase LD50 of warfarin more than
10-fold.
... L-histidine at dietary level of 40 ppm ... potentiated lethal action of warfarin
(50 ppm) in ... laboratory & field tests. ...
A dosage of triclofos /given to 7 volunteers/ at rate of 22 mg/kg/day prolonged
prothrombin time even though dosage of warfarin was reduced. ... In one case, medical use
of warfarin was nullified by use of 5% toxaphene & 1% lindane. ... Response to
warfarin returned to normal within about 3 mo after exposure to the insecticides.
A potentially dangerous drug interaction between cimetidine and warfarin /was
reported/. Of 17 patients stabilized on warfarin, their prothrombin time increased by 20%
when 1 g daily of cimetidine, as drug used to treat peptic ulcers, was added to the drug
regimen. With increasing prescribing of cimetidine, those following workers stabilized on
warfarin must be warned to watch for early signs of bleeding, such as easy bruising,
bleeding gums, or dark stool.
The list of drugs and other factors that may affect the action of oral anticoagulants
is prodigious and expanding. Any substance or condition is potentially dangerous if it
alters (I) the uptake or metabolism of the oral anticoagulant or vitamin K; (2) the
synthesis, function. or clearance of any factor or cell involved in hemostasis or
fibrinolYsis; or (3) the integrity of any epithelial surface. /Oral Anticoagulants/
... Commonly described factors that cause a decreased effect of oral anticoagulants
include reduced absorption of drug caused by binding to cholestyramine in the
gastrointestinal tract; increased volume of distribution and a short half-life secondary
to hypoproteinemia. as in nephrotic syndrome; increased metabolic clearance of drug
secondarY to induction of hepatic enzymes by barbiturates. rifampin, phenytoin, or chronic
ingestion of alcohol; ingestion of large amounts of vitamin K-rich foods or supplements;
and increased levels of coagulation factors during pregnancy. The ... /plasma
thromboplastin/ will be shortened in most of these cases. /Oral Anticoagulants/
... Interactions that enhance the risk of hemorrhage in patients taking oral
anticoagulants include decreased metabolism and/or displacement from protein binding sites
caused by phenylbutazone, sulfinpyrazone, metronidazole, disulfiram, allopurinol,
cimetidine, amiodarone, or acute intake of ethanol. /Oral Anticoagulants/
Six normal subjects were given a single dose of warfarin at the rate of 1.5 mg/kg.
Three weeks later, the same people were given 200 mg of phenylbutazone three times a day
for at least 8 days; on the fourth day, warfarin was repeated at 1.5 mg/kg. Compared to
warfarin alone, administration of warfarin with phenylbutazone increased the prothrombin
time even though the plasma concentration and biological half-life decreased. The result (
in the face of an obvious inactivation of warfarin) was attributed to displacement of
warfarin by phenylbutazone from binding to plasma albumin, making more free drug
momentarily available to receptor sites in the liver. The mutual displacement of
phenylbutazone and warfarin from human plasma albumin has been studied in vitro.
Two cases of intriguing warfarin resistance in humans were reported ... . Both patients
under anticoagulant therapy could not be kept within therapeutic range. The common factor
that was found was heavy daily intake of broccoli (250 - 450 g/day). Broccoli is an
important dietary source of vitamin K (200 ug/100 gm). When the vegetable was removed from
the diet, the anticoagulant therapy became effective.
Danazol, a synthetic testosterone derivative, is used in the treatment of
endometriosis, fibrocystic breast disease, menorrhagia protein C deficiency, and
hemophilia. ... Two cases including an interaction between danazol and warfarin, resulting
in bleeding complications /is described/. There are at least two other reported cases of
this interaction. ... Patients receiving warfarin who are prescribed danazol must be
monitored closely to prevent excessive anticoagulation and subsequent bleeding.
Phenylbutazone ... interacts pharmacokinetically and clinically with warfarin, although
several other nonsteroidal antinflammatory drugs (NSAIDS) also have the potential to
interact with warfarin to cause alterations in prothrombin time. Aspirin is known to
inhibit platelet aggregation irreversibly, whereas nonaspirin NSAIDs are thought to
inhibit platelet aggregation reversibly. In contrast, nabumetone was not shown to cause
significant inhibition of platelet aggregation, which may be related to the fact that
nabumetone preferentially inhibits the prostaglandin synthase-2 isozyme instead of the
prostaglandin synthase-1 isozyme. Furthermore, in studies in patients and normal
volunteers stabilized on warfarin, nabumetone did not cause alterations in the prothrombin
time or international normalized ratio. Based on data evaluating the concomitant use of
nabumetone and warfarin, the relative lack of platelet inhibition, and the relatively
lower risk of nabumetone induced gastrointestinal mucosal damage, nabumetone may be
preferred if concomitant therapy with warfarin is indicated.
Antiepileptic drug interactions are a common problem during epilepsy treatment.
Oxcarbazepine is a keto homolog of carbamazepine with a completely different metabolic
profile. In humans, the keto group is rapidly and quantitatively reduced to form a
monohydroxy derivative which is the main active agent during oxcarbazepine therapy. ...
/This drug/ does not modify the anticoagulant effect of warfarin.
The comparative abilities of the prothrombin time and factor VII clotting activity
/were studied/ to detect drug interactions with warfarin. Pharmacokinetic and
pharmacodynamic data were collected from studies involving the single admin of 25 mg of
warfarin in the absence and presence of fengabin, cimetidine, ranitidine and enoxacin.
Fengabin caused changes in both the pharmacokinetics and pharmacodynamics of warfarin
whereas cimetidine and enoxacin only caused changes in its pharmacokinetics. Ranitidine
had no effect on either the pharmacokinetics or pharmacodynamics of warfarin. In general,
factor VII clotting activity showed greater sensitivity but also greater variability than
the prothrombin time to changes in clotting activity. Consequently factor VII clotting
activity did not have greater discriminatory power than the prothrombin time in detecting
drug interactions involving warfarin.
Nimesulide is a recently developed analgesic, antipyretic and anti-inflammatory agent
that differs from conventional nonsteroidal anti-inflammatory drugs both in structure and
pharmacological profile. ... Although nimesulide does not usually effect the response to
warfarin, a few patients may show some incr in the anticoagulant effect; therefore, it
would seem prudent to monitor coagulation status when the two drugs are administered
together.
Miconazole decreased the total body clearance of both (R)- and (S)-warfarin in normal
subjects but did not change volumes of distribution. Miconazole inhibited the oxidation of
both (R)- and (S)-warfarin to phenolic metabolites although (S)-warfarin was inhibited to
the greater extent. In particular (S)-7-hydroxylation, the pathway primarily responsible
for termination of the anticoagulant effect was most strongly inhibited. Inhibition of
warfarin hydroxylation by miconazole in human liver microsomes and the in vivo results
showed a good rank order correlation. The enhanced anticoagulant effect observed when
miconazole and warfarin are coadministered may result from inhibition of P4502C9 the
isozyme of p450 primarily responsible for the conversion of (S)-warfarin to
(S)-7-hydroxy-warfarin. ...
Amiodarone decreased the total body clearance of both (R)- and (S)-warfarin in normal
subjects but did not change volumes of distribution. Warfarin excretion products were
quantified and clearance and formation clearance values calculated. Amiodarone and
metabolites inhibited the reduction of (R)-warfarin to (R,S3-warfarin alcohol-l and the
oxidation of both (R)- and (S)-warfarin to phenolic metabolites. Inhibition of warfarin
hydroxylation by amiodarone in human liver microsomes was compared with the in vivo
results. In agreement, the in vitro data indicates that amiodarone is a general inhibitor
of the cytochrome p450 catalyzed oxidation of both enantiomers of warfarin, but the
metabolism of (S)-warfarin is more strongly inhibited than that of (R)-warfarin. These
data suggest that the enhanced anticoagulant effect observed when amiodarone and warfarin
are coadministered is attributable to inhibition of p4502C9, the isozyme of p450
responsible for the conversion of (S)-warfarin to its major metabolite
(S)-7-hydroxywarfarin.
The potential effects of extended release felodipine on the pharmacokinetics and
pharmacodynamics of warfarin were studied in a double blind crossover study in 12 healthy
men. Warfarin dosage was adjusted to achieve stable subtherapeutic anticoagulation.
Subjects were then randomized to receive 2 weeks of treatment with 10 mg extended release
felodipine or placebo once daily and warfarin dosage was adjusted if necessary to maintain
stable international normalized ratio. The pharmacokinetics of R- and S-warfarin and the
warfarin dose requirement did not differ importantly between periods of treatment with
felodipine and placebo.
Fluconazole is a triazole antifungal agent. A potential interaction between warfarin
and fluconazole occurred in a 39 yr old man with chronic renal insufficiency. He was
receiving anticoagulant therapy for a lower extremity thrombus and oral fluconazole 50
mg/day for a fungal urinary tract infection. After attaining consistent international
normalized ratio (INR) values between 2.0 and 2.7 with warfarin the INR increased to 5.2
four days after fluconazole was started despite decreasing the dosage of warfarin. There
were no changes in the patients other medications and the INR decreased to 1.5 on
discontinuation of fluconazole. The possible mechanism of an interaction may be dose
related inhibition of warfarin metabolism, and may be more pronounced in patients with
decreased renal clearance of fluconazole.
The influence of tenoxicam on plasma warfarin concentrations and on its anticoagulant
effect has been studied ln healthy volunteers. Tenoxicam did not alter the plasma warfarin
concentration versus time profile. Treatment with it for 14 days had no effect on the
average dose of warfarin required to maintain the prothrombin time within a specified
range.
An apparent interaction between tetracycline and warfarin is reported in a 50 yr old
man receiving oral warfarin sodium (Coumadin) at a dose of 5-7.5 mg on alternate nights
and who was given 250 mg of oral tetracycline hydrochloride 4 times/day for approximately
one yr for chronic blepharitis. Six weeks after tetracycline was initiated the patient's
International Normalized Ratio (INR) had increased to 7.66 from a previous value of 2.2.
Monitoring over the next several months indicated that the changes in INR generally
paralleled changes in the dosage of tetracycline and adjustments in the warfarin dosage
were required. After tetracycline was discontinued the INR returned to stable levels while
the patient took a consistent warfarin dosage. /Warfarin sodium/
The effects of moricilzine hydrochloride on the pharmacokinetics, pharmacodynamics, and
plasma protein binding of warfarin sodium (Coumadin) were studied in healthy males (ages
21-35 yr) who received a single oral dose of 25 mg warfarin in tablet form alone or with
250 mg moricizine every 8 hr. The terminal elimination rate constant of warfarin was
increased by about 10% in the presence of moricizine. However, oral plasma clearance,
apparent volume of distribution, maximum peak plasma concentration, time to reach peak
concentration, and protein binding were unaffected. There was no evidence of a
pharmacodynamic interaction based on the prothrombin time profile. Moricizine does not
have a clinically significant effect on the pharmacokinetics and pharmacodynamics of
warfarin. /Warfarin, sodium/
This study evaluated the potential interaction between the oral anticoagulant warfarin
and the quinolone antimicrobial agent ciprofloxacin. After a 10 day placebo lead in phase,
16 patients stabilized with long term warfarin therapy were randomized to receive
ciprofloxacin 500 mg or a matching placebo twice/day for 10 days. International normalized
ratios (INRs) measured by both standard laboratory analysis and by Coumatrak
(finger-stick) methods were evaluated at 3- to 5-day intervals. No patient experienced a
significant increase in INR. No patient experienced a bleeding event. ... A
warfarin-ciprofloaxcin interaction does not routinely occur at this dosage and duration of
ciprofloxacin therapy.
The effects of acute and chronic administration on warfarin disposition were examined
in adult New Zealand male rabbits. The rabbits received a 3.5 mg/kg iv dose of warfarin
either alone, 1 hr after a single 100 mg/kg ip miconazole dose, or on day 5 of a 6 day 50
mg/kg 12 hr ip miconazole dosing regimen. Acute miconazole administration decreased the
elimination rate constant of warfarin, but other warfarin disposition parameters were not
altered. Chronic miconazole administration caused a 47% increase in warfarin plasma free
fraction probably caused by competitive or noncompetitive protein binding displacement by
miconazole metabolites and a 42% decrease ln warfarin intrinsic clearance probably caused
by a miconazole induced inhibition in warfarin metabolism. As a consequence of these
quantitatively similar but opposite changes, the total body clearance of warfarin (a low
clearance drug) was marginally decreased. A significant decrease in the elimination rate
constant and an increase in the tissue free fraction of warfarin were also observed during
chronic miconazole treatment. ... Chronic miconazole administration should not
significantly affect the steady state plasma concentrations of total warfarin, but should
increase the steady state plasma concentrations of free warfarin. The expected increases
in the steady state plasma concentrations of free, pharmacologically active warfarin may
account for the reported potentiation of the pharmacological action of warfarin when
coadministered with chronic miconazole.
Pharmacology:
Therapeutic Uses:
Anticoagulants; Rodenticides
... Racemic warfarin sodium is the drug of choice, the prototype, & by far the most
widely used oral anticoagulant in the United States.
Anticoagulants are indicated in the treatment of patients with recent deep vein
thrombosis or thrombophlebitis to prevent extension and embolization of the thrombus and
to reduce the risk of pulmonary embolism or recurrent thrombus formation. In acute
pulmonary embolism or venous thrombosis, anticoagulants are indicated following initial
thrombolytic and/or heparin therapy to decrease the risk of extension, recurrence, or
death. /Anticoagulants/
Anticoagulants are indicated for prophylaxis of venous thrombosis and pulmonary
embolism postoperatively or in high-risk patents, such as those with a history of
thromboembolism or those requiring prolonged immobilization. However, subcutaneous
administration of low-dose heparin is more commonly used to prevent postsurgical
thromboembolic complications. /Anticoagulants/
Anticoagulants may prevent the formation of mural thrombin in the heart, which may lead
to systemic thromboembolism in patients with chronic atrial fibrillation, especially those
with rheumatic mitral stenosis, prosthetic heart valves, left atrial enlargement, or
cardiomyopathy. In these patients, anticoagulants may decrease the risk of arterial
embolism, pulmonary embolism, or subsequent stroke. /Anticoagulants/
Anticoagulants are indicated as adjunctive therapy to reduce the risk of systemic
thromboembolic complications following acute myocardial infarction (especially an anterior
wall myocardial infarction or a large apical infarction), primarily in high-risk patients
such as those with shock, congestive heart failure, prolonged arrhythmias (especially
atrial fibrillation), previous myocardial infarction, or history of thromboembolism.
/Anticoagulants/
Anticoagulants are used to reduce the risk of post-conversion emboli. /Anticoagulants,
not included in U.S. product labeling/
Anticoagulants are used to reduce the risk of thromboembolic complications in patients
with certain types of prosthetic heart valves. The effectiveness of these agents may be
increased by concurrent use of a platelet aggregation inhibitor such as dipyridamole.
Aspirin is also sometimes used concurrently with anticoagulants for this purpose; however,
the risk of hemorrhage is increased. /Anticoagulants, not included in U.S. product
labeling/
Long-term use of anticoagulants following myocardial infarction to prevent reinfarction
remains controversial; many clinicians report that recurrence of acute attacks and/or risk
of death may not be reduced by such therapy. A few studies have indicated that long-term
anticoagulation may reduce the risk of recurrent myocardial infarction and of
nonhemorrhagic cerebrovascular accidents in patients older that 60 years of age. However,
aspirin is also effective, and is more commonly used for this purpose. /Anticoagulants,
not included on U.S. product labeling/
Anticoagulants have also been used to reduce the risk of thrombosis and/or occlusion of
the aortocoronary bypass following coronary bypass surgery. However, their efficacy has
not been proven and platelet aggregation inhibitors are now being administered for this
purpose. /Anticoagulants, not included in U.S. product labeling/
Warfarin has been used as a adjunct in the treatment of patients with transient
ischemic attacks. It may reduce the incidence of repeat attacks and/or subsequent stroke,
especially during the first few months of therapy. However, the risk of death may not be
decreased. FDA has classified warfarin as being possibly effective for this indication;
this classification requires the submission of adequate and well-controlled studies in
order to provide substantial evidence of effectiveness. Platelet aggregation inhibitors
(especially aspirin) are more commonly being used for this indication. /Not included in
U.S. product labeling/
Twenty patients with intracardiac thrombi confirmed by platelet scintigraphy
participated in a prospective study of warfarin therapy. Eleven patients (group I)
received 2 to 6 mg/day of warfarin; 9 patients (group II) received no warfarin. Platelet
scintigraphy repeated 14 to 71 days after the original scintigraphy showed that in group
I, 10 platelet scintigraphies became negative for intracardiac thrombi and one remained
positive. In group II 8 scintigraphies remained positive and only one changed to negative.
In group I the degree of accumulation of platelets onto the surface of the thrombus (%IE)
showed a reduction of 0.69 + or - 0.48 to 0.11 + or - 0.21 after warfarin therapy. In
group II the %IE at the second scintigraph (1.07 + or - 1.03) were not significantly
different from those at the first scintigraphy (1.13 + or - 0.79).
Drug Warnings:
DOSAGE REQUIREMENTS VARY GREATLY AMONG INDIVIDUAL PATIENTS & DOSAGE MUST BE
CAREFULLY INDIVIDUALIZED BASED ON CLINICAL AND & LABORATORY FINDINGS IN ORDER TO
OBTAIN OPTIMUM THERAPEUTIC EFFECTS WITHOUT INCURRING HEMORRHAGE. ... SOME CLINICIANS
ADVISE AGAINST ADMINISTRATION OF "LOADING DOSE" /BECAUSE OF HEMORRHAGING/ &
... RECOMMEND INITIAL DOSAGE 0F 10-15 MG DAILY UNTIL DESIRED PROTHROMBIN TIME IS REACHED.
/POTASSIUM AND SODIUM WARFARIN/
Patients in congestive heart failure who are given oral anticoagulants ... have an
augmented hypoprothrombinemic response; this lessens as myocardial function improves. ...
Hypermetabolic states, such as fever & hyperthyroidism, increase the responsiveness to
oral anticoagulants, whereas myxedematous patients require larger doses ... There is also
a positive correlation between patient age & degree of response to oral
anticoagulants; this effect is independent of body wt, & the pharmacokinetics of
warfarin is unaltered. ... During pregnancy a state of decreased responsiveness to oral
anticoagulants results from increased activity of factors VII, VIII, IX & X. However,
this affects only the mother, & the fetus is highly susceptible to oral anticoagulants
because ... /they/ cross the placenta freely & the fetus has limited capacity to
synthesize clotting factors. ... Uremia ... significantly increases ... the fraction of
drug in plasma that is free & the clearance of warfarin from the circulation.
When given during 1st trimester (esp 6th-9th wk) of pregnancy, warfarin is assoc with
embryopathy ... Only about 1/3 of infants exposed during this period are normal & live
born. Other abnormalities, incl CNS & eye defects (eg, blindness), are thought to
result from longer exposure, probably during the 2nd & 3rd trimesters.
Panwarfin 7.5-mg tablets contain ... tartrazine (FD&C yellow no 5) which may cause
allergic reactions incl bronchial asthma in susceptible individuals. Although incidence of
tartrazine sensitivity is low, it frequently occurs in patients who are sensitive to
aspirin. /Panwarfin/
UNTIL FURTHER ... DATA CAN BE ACCUMULATED & EVALUATED, IT WOULD BE ADVISABLE TO
MONITOR FREQUENTLY BLOOD GLUCOSE LEVELS AND PROTHROMBIN TIMES DURING COMBINED USE OF
CHLORPROPAMIDE AND WARFARIN.
Coumarin- and indandione-derivative anticoagulants cross the placenta and are not
recommended during pregnancy. Congenital malformations and other adverse effects on fetal
development including severe nasal hypoplasia, stippling of bones, optic atrophy,
microcephaly, and growth and mental retardation have been reported in infants born to
mother taking these agents during pregnancy. This is especially critical during the first
trimester. However, many clinicians recommend that these agents not be used at all during
pregnancy because facial anomalies in the infant have occurred following maternal use in
the third trimester. Also, fetal or neonatal hemorrhage, fetal death in utero, and
increased risk of maternal hemorrhage during the second and third trimesters have been
reported. However, other clinicians state that these agents may be used for brief periods
in the second and third trimesters. /Anticoagulants/
If a coumarin or indandione derivative is used during the third trimester, it should be
discontinued after the 37th week of gestation, and heparin substituted if maternal
anticoagulation is required, to reduce the risk of fetal hemorrhage during labor and of
neonatal hemorrhage following delivery. Anticoagulants also increase the risk of maternal
hemorrhage during or following delivery. /Anticoagulants/
Anticoagulants may increase the risk of maternal hemorrhage if administered in the
postpartum period. /Anticoagulants/
Infants, especially neonates, may be more susceptible to the effects of anticoagulants
because of vitamin K deficiency. /Anticoagulants/
Geriatric patients may be more susceptible to the effects of anticoagulants, resulting
in increased risk of hemorrhage, possible because of the presence of advanced vascular
disease resulting in altered homeostatic mechanisms, hepatic function impairment resulting
in decreased procoagulant factor synthesis or anticoagulant metabolism, or renal function
impairment. Lower maintenance doses than those usually recommended for adults may be
required for these patients. /Anticoagulants/
Anticoagulant therapy increases the risk of localized hemorrhage during and following
oral surgical procedures. Consultation with the prescribing physician may be advisable
prior to oral surgery, to determine whether a temporary dosage reduction or withdrawal of
anticoagulant therapy is feasible. Also, local measures to minimize bleeding should be
used at the time of surgery. /Anticoagulants/
The occurrence of gastrointestinal hemorrhage during anticoagulant therapy, especially
if the prothrombin time is within the therapeutic range, may indicate the presence of an
underlying occult lesion such as a tumor or ulcer. /Anticoagulants/
Adrenal hemorrhage resulting in acute adrenal insufficiency has been reported to occur
rarely during anticoagulant therapy. Diagnosis may be difficult because the initial
symptoms (abdominal pain, apprehension, diarrhea, dizziness or fainting, headache, loss of
appetite, nausea or vomiting, and weakness) are nonspecific and variable. If acute adrenal
insufficiency is suspected, anticoagulant therapy must be discontinued and high-dose
adrenocorticoid therapy (preferably with hydrocortisone, since other glucocorticoid may
not provide sufficient sodium retention) instituted immediately. Delay of treatment while
laboratory confirmation of the diagnosis is awaited may prove fatal for the patient. It
has been proposed that abdominal computerized axial tomographic (CAT) scanning may be of
use in diagnosing this condition more rapidly. /Anticoagulants/
Contraindications to oral anticoagulants include pre-existing or coexisting
abnormalities of blood coagulation, active bleeding, recent or imminent surgery of the
central nervous system or eye, diagnostic or therapeutic procedures with potential for
uncontrollable bleeding including lumbar puncture, malignant hypertension, peptic
ulceration, pregnancy, threatened abortion, intrauterine device, cerebrovascular
hemorrhage, and bacterial endocarditis. Relative contraindications include
thrombocytopenia, pericarditis, pericardial effusions, and unreliability of the patient or
of patient supervision. /Oral anticoagulants/
Most commonly, oral anticoagulant-induced bleeding is minor and consists of bruising,
hematuria, epistoxis, conjunctival hemorrhage, minor gastrointestinal bleeding, bleeding
from wounds and sites of trauma, and vaginal bleeding. More serious major or fatal
bleeding is most commonly gastrointestinal, intracranial, vaginal, retroperitoneal, or
related to a wound or site of trauma, although a large variety of other sites of bleeding
have been reported. Intracranial bleeding occurs most frequently in patients receiving
oral anticoagulants for cerebrovascular disease and most commonly presents as a subdural
hematoma, often unassociated with head trauma. Fatal gastrointestinal bleeding is most
commonly from a peptic ulcer, although any gastrointestinal lesion may be a potential
source of major bleeding. Overall, a bleeding lesion can be identified in about two thirds
of cases of oral anticoagulants-related hemorrhage. /Oral anticoagulants/
Overall, the bleeding rate of oral anticoagulant therapy is influenced by several
factors: the intensity of anticoagulation, either intentionally or inadvertent; the
underlying clinical disorder for which anticoagulant therapy is used with bleeding
occurring most frequently in ischemic cerebrovascular disease and venous thromboembolism;
and, with bleeding occurring most commonly in the elderly; the presence of adverse drug
interactions or comorbid factors such as clinical states potentiating warfarin action,
pre-existing hemorrhagic diathesis, malignancy, recent surgery, trauma, or pre-existing
potential bleeding sites (e.g., surgical wound, peptic ulcer, recent cerebral hemorrhage,
carcinoma of colon); the simultaneous use of aspirin (but not of dipyridamote); and
patient reliability (e.g., increased bleeding in alcoholics not due to ethanol-warfarin
drug interaction but rather to unreliability of drug intake). /Oral anticoagulants/
IT IS INADVISABLE TO CARRY OUT LONG-TERM THERAPY IN CHRONIC ALCOHOLIC, IN INDIVIDUAL
WHO MAY REQUIRE INTENSIVE SALICYLATE THERAPY, OR IN CASES OF MALIGNANT HYPERTENSION &
ACTIVE TUBERCULOSIS. ORAL ANTICOAGULANT THERAPY DURING PREGNANCY CARRIES SIGNIFICANT
HEMORRHAGIC RISK FOR FETUS. /ORAL ANTICOAGULANTS/
... CONTRAINDICATED IN HEMORRHAGIC TENDENCIES, BLOOD DYSCRASIAS, ULCERATIVE LESIONS OF
GI TRACT, DIVERTICULITIS, COLITIS, SUBACUTE BACTERIAL ENDOCARDITIS, THREATENED ABORTION,
RECENT OPERATIONS ON BRAIN OR SPINAL CORD. REGIONAL & LUMBAR-BLOCK ANESTHESIA, VITAMIN
K DEFICIENCY ... HEPATIC OR RENAL DISEASE. /ORAL ANTICOAGULANTS/
IT IS IMPERATIVE THAT SUITABLE LAB FACILITIES BE AVAIL FOR ACCURATE CONTROL OF THERAPY
WITH COUMARIN DRUGS. IN ADDN, SUITABLE PREPN OF VITAMIN K SHOULD BE AVAIL, AS WELL AS
WHOLE FRESH BLOOD OR PLASMA FOR EMERGENCY TRANSFUSION. /ORAL ANTICOAGULANTS/
PULMONARY INTERSTITIAL HEMORRHAGE...MAY BE CONFUSED CLINICALLY WITH PULMONARY EMBOLISM.
... IT IS GENERALLY AGREED THAT ANY HEPATIC DAMAGE OCCURRING IN PT WITHOUT PREEXISTING
LIVER DISEASE IS PURELY SECONDARY TO LOCAL HEMORRHAGE IN LIVER OR HYPOXIA FROM HEMORRHAGIC
ANEMIA. /ORAL ANTICOAGULANTS/
Anticoagulant therapy must always be monitored by determination of one-stage
prothrombin times, & the patient must be observed carefully for development of
bleeding. Bleeding often occurs even when the prothrombin time is within the expected
therapeutic range. /Anticoagulants/
If a patient shows any sign of bleeding, the next dose of anticoagulant should be
withheld and the plasma thromboplastin measured. If bleeding is minor or self-limited,
therapy may be continued after adjusting the dosage and/or correcting the reason for the
altered response. /Oral Anticoagulants/
Given the variability in half-lives of the drugs and proteins involved, careful
monitoring for evidence of bleeding or thrombosis and frequent measurements of the plasma
thromboplastin are essential. /Oral Anticoagulants/
Prior to initiation of therapy, laboratory tests are used in conjunction with the
patient's history and physical examination to uncover hemostatic defects that might make
the use of oral anticoagulant drugs more dangerous (congenital coagulation factor
deficiency, thrombocytopenia, hepatic or renal insufficiency, vascular abnormalities,
etc.). Thereafter, the plasma thromboplastin is used to monitor efficacy and compliance.
Therapeutic ranges for various clinical indications have been established empirically and
reflect dosages that reduce the morbidity from thromboembolic disease while increasing as
little as possible the risk of serious hemorrhage. /Oral Anticoagulants/
Infants, especially neonates, may be more susceptible to the effects of anticoagulants
because of vitamin K deficiency. /Anticoagulants/
Records of 565 patients starting outpatient therapy with warfarin upon discharge from a
university hospital were reviewed to determine the incidence of major bleeding and to
identify predictive factors known at the start of therapy. Follow-up information was
obtained for 562 patients (99.5%). Bleeding was classified as major or minor using
explicit criteria. The cumulative incidence of bleeding was estimated by means of survival
analysis. Independent risk factors for major bleeding were identified using Cox regression
analysis in 375 randomly chosen patients; they were tested in the remaining 187 patients.
Results showed that major bleeding occurred in 65 patients (12%) and was fatal in 10
patients (2%). The cumulative incidences of major bleeding at 1, 12 and 48 mo were 3%, 11%
and 22%, respectively. The monthly risk of major bleeding decreased over time, from 3%
during the first mo of outpatient therapy to 0.3% per mo after the first year of therapy.
Five independent risk factors that predicted major bleeding in the testing group were: age
65 yr or greater; history of stroke; history of GI bleeding; a serious comorbid condition
(recent myocardial infarction, renal insufficiency, or severe anemia); and atrial
fibrillation. The cumulative incidence of major bleeding at 48 mo was 2% in 57 low risk
patients, 17% in 110 middle risk patients, and 63% in 20 high risk patients.
There is evidence that treatment with coumarin drugs during pregnancy causes nasal
hypoplasia and stippled epiphyses (chondrodysplasia punctata) in the fetus, and when taken
late in pregnancy may cause optic atrophy and microcephaly. /Coumarin drugs/
Interactions:
THE PHARMACOKINETIC COMPLEX ACTIVITY AFTER A SINGLE IV COADMINISTRATION WITH WARFARIN
(1.2 MG/KG) AND FUROSEMIDE (1.67 MG/KG) WERE NOT SIGNIFICANTLY DIFFERENT AS COMPARED WITH
THOSE IN THE GROUP INJECTED WITH WARFARIN ALONE; HOWEVER, WHEN COADMINISTERED WITH 5 MG/KG
OF FUROSEMIDE, THE ELIMINATION RATE CONSTANT WAS SIGNIFICANTLY INCREASED AND THE
PHARACOKINETIC COMPLEX ACTIVITY WAS MARKEDLY ENHANCED BEYOND 60 HOURS AFTER
ADMINISTRATION. THESE RESULTS SUGGEST THAT THE INTERACTIONS, SUCH AS THE DISPLACEMENT OF
WARFARIN BINDING AT ALBUMIN BINDING SITES, BETWEEN WARFARIN AND FUROSEMIDE ARE PRODUCED,
WHEN A HIGH DOSE OF FUROSEMIDE WAS COADMINISTERED.
REVIEW ON CLINICALLY IMPORTANT DRUG INTERACTIONS WITH CIMETIDINE. THE METABOLISM OF
WARFARIN (AND PROBABLY OTHER COUMARIN ANTICOAGULANTS) IS DECREASED BY CIMETIDINE.
... Metronidazole had no effect on the serum protein binding of racemic warfarin in
vitro over a wide concentration range but decreased the protein binding of R-(+)-warfarin
and S-(-)-warfarin in vitro ... (in rats) Treatment with ip metronidazole, 100 mg/kg every
6 hours, decreased the plasma clearance of free warfarin. ... Metronidazole did not affect
plasma prothrombin complex activity in vitro but reduced it in vivo. ...
... Chloramphenicol had no apparent effect on the serum protein binding of
R-(+)-warfarin or S-(-)-warfarin in vitro or in vivo /in rats/. Treatment with ip
chloramphenicol, 50 mg/kg every 4 hours or 30 mg/kg every 6 hours decreased the plasma
clearance of free warfarin by one-half or more, with no apparent stereoselectivity. The
volume of distribution was not significantly affected; the serum half-life of each
warfarin enantiomer was appreciably increased by chloramphenicol. ... It appears that the
pronounced potentiation of the anticoagulant effect of warfarin by chloramphenicol is due
only to inhibition of warfarin metabolism and that this effect is not stereoselective.
The effect of sulphinpyrazone on the anticoagulant response to warfarin was evaluated
by a double-blind study in 11 patients with prosthetic heart valves. Six patients received
warfarin and Sulphinpyrazone and 5 warfarin and placebo. Sulphinpyrazone potentiated the
anticoagulant action of warfarin. Patients receiving sulphinpyrazone needed about half the
amount of warfarin as compared to the control group. ...
In humans stabilized on a racemic-warfarin regimen (to prolong the prothrombin time to
approximately 1.5 times the control), administration of oxaprozin (1200 mg, orally for 7
days) did not appear to cause an important change in the pharmacological effect of
racemic-warfarin. ... There was a small increase in the plasma concentration of
racemic-warfarin, perhaps due to a nonstereoselective inhibition of racemic - warfarin
metabolism, thereby raising the prothrombin time slightly in some patients.
The effects of 3 beta-adrenoceptor antagonists (propranol metoprolol tartrate, and
atenolol) on the serum kinetics and pharmacodynamics of (+,-)-warfarin given in a single
oral dose (15 mg) were studied in normal subjects. At the same degree or beta-adrenoceptor
blockade, as assessed by the decrease of exercise tachycardia, propranolol increased the
area under the serum warfarin concentration-time curve (AUC) by 16.3% and the maximum
serum warfarin concentration by 23.0%. Atenolol increased the maximum serum warfarin
concentration by 12.5% but was without effect on warfarin concentration-time curve.
Metoprolol had no effect on warfarin kinetics. The extent of changes in the prothrombin
time and the plasma clotting factor VII activity caused by warfarin were not altered by
any of the beta-adrenoceptor antagonists.
An interaction was observed in two patients receiving aminoglutethimide and warfarin. A
decrease in the anticoagulant effect of warfarin was shown by ... thrombotest measurements
and the pharmacokinetic evaluation of warfarin. A 3-to 5-fold increase in warfarin
clearance was found. ...
... Warfarin kinetics were evaluated in 12 normal subjects who took a single 1 mg/kg
dose of warfarin with and without erythromycin. Erythromycin (250 mg p.o.) every 6 hours
for 8 days decreased warfarin clearance by 14% (p less than 0.001). ... The effect of
erythromycin was greatest among subjects whose control phase warfarin clearance was
relatively fast. The magnitude of the decrease in warfarin clearance correlated negatively
with control warfarin clearance (r=-0.89, p less than 0.005). ...
... Cadmium increased the toxicity of warfarin /in young pigs causing/ severe lameness,
and subcutaneous hematomas in the ventral surface of the head and neck.
... Ranitidine /a H2-antagonist/ does not alter the prothrombin time in subjects
receiving warfarin.
Amiodarone ... an iodinated benzofuran derivative with recognized antiarrhythmic
activity in man ... potentiates the anticoagulant effect of warfarin.
A case involving a biphasic interaction of phenytoin and warfarin in a 70 year old
woman is reported. Following the addition of phenytoin and warfarin regimen, the
stabilized prothrombin ratio appeared to increase for 6 days, and then declined to a level
less than observed before initiation of phenytoin. It was concluded that the net effect of
phenytoin on prothrombin time response to a given dose of warfarin may depend on the
relative contributions of protein binding changes, enzyme inhibition, and enzyme
induction.
A ... 60 year old male patient experienced prolongation of prothrombin time while
receiving cimetidine (1 g/day). The patient had been stabilized on 5 mg/day of warfarin
for 10 years. ... A prothromin time estimation on admission to the hospital was greater
than 200 sec (control was 14.3 sec). ...
Colony formation /of rat C6 glioma cells/ was examined /concerning/ the effects of
24-hr warfarin (10-3 M) infusion ... pretreatment plus incubation with 1 of 7 anticancer
agents. ... Supra-additive toxic effects were produced by warfarin plus chlorambucil. ...
The effects of oxametacin, 100 mg three times a day, on warfarin anticoagulation were
studied in twelve patients. All anticoagulation tests showed a potentiating effect of
oxametacin on warfarin, necessitating reduction or elimination of warfarin in 33% of the
patients.
Sulphinpyrazone decreases the plasma clearance of ... S-warfarin and increases the
clearance of R-warfarin. ...
... Warfarin ... blocked the ability of rifampin to kill phagocytosed Staphylococcus
aureus. ...
... In rabbits, prolongation of 5-fluorouracil plasma half-life was seen with high (0.6
mg/kg/hr) but not low (0.025 mg/kg/hr) rates of warfarin infusion. ...
Formation of ... metabolites is stimulated by phenobabital, chlordane, or DDT. The
metabolism is a true detoxication. The inducers can increase LD50 of warfarin more than
10-fold.
... L-histidine at dietary level of 40 ppm ... potentiated lethal action of warfarin
(50 ppm) in ... laboratory & field tests. ...
A dosage of triclofos /given to 7 volunteers/ at rate of 22 mg/kg/day prolonged
prothrombin time even though dosage of warfarin was reduced. ... In one case, medical use
of warfarin was nullified by use of 5% toxaphene & 1% lindane. ... Response to
warfarin returned to normal within about 3 mo after exposure to the insecticides.
A potentially dangerous drug interaction between cimetidine and warfarin /was
reported/. Of 17 patients stabilized on warfarin, their prothrombin time increased by 20%
when 1 g daily of cimetidine, as drug used to treat peptic ulcers, was added to the drug
regimen. With increasing prescribing of cimetidine, those following workers stabilized on
warfarin must be warned to watch for early signs of bleeding, such as easy bruising,
bleeding gums, or dark stool.
The list of drugs and other factors that may affect the action of oral anticoagulants
is prodigious and expanding. Any substance or condition is potentially dangerous if it
alters (I) the uptake or metabolism of the oral anticoagulant or vitamin K; (2) the
synthesis, function. or clearance of any factor or cell involved in hemostasis or
fibrinolYsis; or (3) the integrity of any epithelial surface. /Oral Anticoagulants/
... Commonly described factors that cause a decreased effect of oral anticoagulants
include reduced absorption of drug caused by binding to cholestyramine in the
gastrointestinal tract; increased volume of distribution and a short half-life secondary
to hypoproteinemia. as in nephrotic syndrome; increased metabolic clearance of drug
secondarY to induction of hepatic enzymes by barbiturates. rifampin, phenytoin, or chronic
ingestion of alcohol; ingestion of large amounts of vitamin K-rich foods or supplements;
and increased levels of coagulation factors during pregnancy. The ... /plasma
thromboplastin/ will be shortened in most of these cases. /Oral Anticoagulants/
... Interactions that enhance the risk of hemorrhage in patients taking oral
anticoagulants include decreased metabolism and/or displacement from protein binding sites
caused by phenylbutazone, sulfinpyrazone, metronidazole, disulfiram, allopurinol,
cimetidine, amiodarone, or acute intake of ethanol. /Oral Anticoagulants/
Six normal subjects were given a single dose of warfarin at the rate of 1.5 mg/kg.
Three weeks later, the same people were given 200 mg of phenylbutazone three times a day
for at least 8 days; on the fourth day, warfarin was repeated at 1.5 mg/kg. Compared to
warfarin alone, administration of warfarin with phenylbutazone increased the prothrombin
time even though the plasma concentration and biological half-life decreased. The result (
in the face of an obvious inactivation of warfarin) was attributed to displacement of
warfarin by phenylbutazone from binding to plasma albumin, making more free drug
momentarily available to receptor sites in the liver. The mutual displacement of
phenylbutazone and warfarin from human plasma albumin has been studied in vitro.
Two cases of intriguing warfarin resistance in humans were reported ... . Both patients
under anticoagulant therapy could not be kept within therapeutic range. The common factor
that was found was heavy daily intake of broccoli (250 - 450 g/day). Broccoli is an
important dietary source of vitamin K (200 ug/100 gm). When the vegetable was removed from
the diet, the anticoagulant therapy became effective.
Danazol, a synthetic testosterone derivative, is used in the treatment of
endometriosis, fibrocystic breast disease, menorrhagia protein C deficiency, and
hemophilia. ... Two cases including an interaction between danazol and warfarin, resulting
in bleeding complications /is described/. There are at least two other reported cases of
this interaction. ... Patients receiving warfarin who are prescribed danazol must be
monitored closely to prevent excessive anticoagulation and subsequent bleeding.
Phenylbutazone ... interacts pharmacokinetically and clinically with warfarin, although
several other nonsteroidal antinflammatory drugs (NSAIDS) also have the potential to
interact with warfarin to cause alterations in prothrombin time. Aspirin is known to
inhibit platelet aggregation irreversibly, whereas nonaspirin NSAIDs are thought to
inhibit platelet aggregation reversibly. In contrast, nabumetone was not shown to cause
significant inhibition of platelet aggregation, which may be related to the fact that
nabumetone preferentially inhibits the prostaglandin synthase-2 isozyme instead of the
prostaglandin synthase-1 isozyme. Furthermore, in studies in patients and normal
volunteers stabilized on warfarin, nabumetone did not cause alterations in the prothrombin
time or international normalized ratio. Based on data evaluating the concomitant use of
nabumetone and warfarin, the relative lack of platelet inhibition, and the relatively
lower risk of nabumetone induced gastrointestinal mucosal damage, nabumetone may be
preferred if concomitant therapy with warfarin is indicated.
Antiepileptic drug interactions are a common problem during epilepsy treatment.
Oxcarbazepine is a keto homolog of carbamazepine with a completely different metabolic
profile. In humans, the keto group is rapidly and quantitatively reduced to form a
monohydroxy derivative which is the main active agent during oxcarbazepine therapy. ...
/This drug/ does not modify the anticoagulant effect of warfarin.
The comparative abilities of the prothrombin time and factor VII clotting activity
/were studied/ to detect drug interactions with warfarin. Pharmacokinetic and
pharmacodynamic data were collected from studies involving the single admin of 25 mg of
warfarin in the absence and presence of fengabin, cimetidine, ranitidine and enoxacin.
Fengabin caused changes in both the pharmacokinetics and pharmacodynamics of warfarin
whereas cimetidine and enoxacin only caused changes in its pharmacokinetics. Ranitidine
had no effect on either the pharmacokinetics or pharmacodynamics of warfarin. In general,
factor VII clotting activity showed greater sensitivity but also greater variability than
the prothrombin time to changes in clotting activity. Consequently factor VII clotting
activity did not have greater discriminatory power than the prothrombin time in detecting
drug interactions involving warfarin.
Nimesulide is a recently developed analgesic, antipyretic and anti-inflammatory agent
that differs from conventional nonsteroidal anti-inflammatory drugs both in structure and
pharmacological profile. ... Although nimesulide does not usually effect the response to
warfarin, a few patients may show some incr in the anticoagulant effect; therefore, it
would seem prudent to monitor coagulation status when the two drugs are administered
together.
Miconazole decreased the total body clearance of both (R)- and (S)-warfarin in normal
subjects but did not change volumes of distribution. Miconazole inhibited the oxidation of
both (R)- and (S)-warfarin to phenolic metabolites although (S)-warfarin was inhibited to
the greater extent. In particular (S)-7-hydroxylation, the pathway primarily responsible
for termination of the anticoagulant effect was most strongly inhibited. Inhibition of
warfarin hydroxylation by miconazole in human liver microsomes and the in vivo results
showed a good rank order correlation. The enhanced anticoagulant effect observed when
miconazole and warfarin are coadministered may result from inhibition of P4502C9 the
isozyme of p450 primarily responsible for the conversion of (S)-warfarin to
(S)-7-hydroxy-warfarin. ...
Amiodarone decreased the total body clearance of both (R)- and (S)-warfarin in normal
subjects but did not change volumes of distribution. Warfarin excretion products were
quantified and clearance and formation clearance values calculated. Amiodarone and
metabolites inhibited the reduction of (R)-warfarin to (R,S3-warfarin alcohol-l and the
oxidation of both (R)- and (S)-warfarin to phenolic metabolites. Inhibition of warfarin
hydroxylation by amiodarone in human liver microsomes was compared with the in vivo
results. In agreement, the in vitro data indicates that amiodarone is a general inhibitor
of the cytochrome p450 catalyzed oxidation of both enantiomers of warfarin, but the
metabolism of (S)-warfarin is more strongly inhibited than that of (R)-warfarin. These
data suggest that the enhanced anticoagulant effect observed when amiodarone and warfarin
are coadministered is attributable to inhibition of p4502C9, the isozyme of p450
responsible for the conversion of (S)-warfarin to its major metabolite
(S)-7-hydroxywarfarin.
The potential effects of extended release felodipine on the pharmacokinetics and
pharmacodynamics of warfarin were studied in a double blind crossover study in 12 healthy
men. Warfarin dosage was adjusted to achieve stable subtherapeutic anticoagulation.
Subjects were then randomized to receive 2 weeks of treatment with 10 mg extended release
felodipine or placebo once daily and warfarin dosage was adjusted if necessary to maintain
stable international normalized ratio. The pharmacokinetics of R- and S-warfarin and the
warfarin dose requirement did not differ importantly between periods of treatment with
felodipine and placebo.
Fluconazole is a triazole antifungal agent. A potential interaction between warfarin
and fluconazole occurred in a 39 yr old man with chronic renal insufficiency. He was
receiving anticoagulant therapy for a lower extremity thrombus and oral fluconazole 50
mg/day for a fungal urinary tract infection. After attaining consistent international
normalized ratio (INR) values between 2.0 and 2.7 with warfarin the INR increased to 5.2
four days after fluconazole was started despite decreasing the dosage of warfarin. There
were no changes in the patients other medications and the INR decreased to 1.5 on
discontinuation of fluconazole. The possible mechanism of an interaction may be dose
related inhibition of warfarin metabolism, and may be more pronounced in patients with
decreased renal clearance of fluconazole.
The influence of tenoxicam on plasma warfarin concentrations and on its anticoagulant
effect has been studied ln healthy volunteers. Tenoxicam did not alter the plasma warfarin
concentration versus time profile. Treatment with it for 14 days had no effect on the
average dose of warfarin required to maintain the prothrombin time within a specified
range.
An apparent interaction between tetracycline and warfarin is reported in a 50 yr old
man receiving oral warfarin sodium (Coumadin) at a dose of 5-7.5 mg on alternate nights
and who was given 250 mg of oral tetracycline hydrochloride 4 times/day for approximately
one yr for chronic blepharitis. Six weeks after tetracycline was initiated the patient's
International Normalized Ratio (INR) had increased to 7.66 from a previous value of 2.2.
Monitoring over the next several months indicated that the changes in INR generally
paralleled changes in the dosage of tetracycline and adjustments in the warfarin dosage
were required. After tetracycline was discontinued the INR returned to stable levels while
the patient took a consistent warfarin dosage. /Warfarin sodium/
The effects of moricilzine hydrochloride on the pharmacokinetics, pharmacodynamics, and
plasma protein binding of warfarin sodium (Coumadin) were studied in healthy males (ages
21-35 yr) who received a single oral dose of 25 mg warfarin in tablet form alone or with
250 mg moricizine every 8 hr. The terminal elimination rate constant of warfarin was
increased by about 10% in the presence of moricizine. However, oral plasma clearance,
apparent volume of distribution, maximum peak plasma concentration, time to reach peak
concentration, and protein binding were unaffected. There was no evidence of a
pharmacodynamic interaction based on the prothrombin time profile. Moricizine does not
have a clinically significant effect on the pharmacokinetics and pharmacodynamics of
warfarin. /Warfarin, sodium/
This study evaluated the potential interaction between the oral anticoagulant warfarin
and the quinolone antimicrobial agent ciprofloxacin. After a 10 day placebo lead in phase,
16 patients stabilized with long term warfarin therapy were randomized to receive
ciprofloxacin 500 mg or a matching placebo twice/day for 10 days. International normalized
ratios (INRs) measured by both standard laboratory analysis and by Coumatrak
(finger-stick) methods were evaluated at 3- to 5-day intervals. No patient experienced a
significant increase in INR. No patient experienced a bleeding event. ... A
warfarin-ciprofloaxcin interaction does not routinely occur at this dosage and duration of
ciprofloxacin therapy.
The effects of acute and chronic administration on warfarin disposition were examined
in adult New Zealand male rabbits. The rabbits received a 3.5 mg/kg iv dose of warfarin
either alone, 1 hr after a single 100 mg/kg ip miconazole dose, or on day 5 of a 6 day 50
mg/kg 12 hr ip miconazole dosing regimen. Acute miconazole administration decreased the
elimination rate constant of warfarin, but other warfarin disposition parameters were not
altered. Chronic miconazole administration caused a 47% increase in warfarin plasma free
fraction probably caused by competitive or noncompetitive protein binding displacement by
miconazole metabolites and a 42% decrease ln warfarin intrinsic clearance probably caused
by a miconazole induced inhibition in warfarin metabolism. As a consequence of these
quantitatively similar but opposite changes, the total body clearance of warfarin (a low
clearance drug) was marginally decreased. A significant decrease in the elimination rate
constant and an increase in the tissue free fraction of warfarin were also observed during
chronic miconazole treatment. ... Chronic miconazole administration should not
significantly affect the steady state plasma concentrations of total warfarin, but should
increase the steady state plasma concentrations of free warfarin. The expected increases
in the steady state plasma concentrations of free, pharmacologically active warfarin may
account for the reported potentiation of the pharmacological action of warfarin when
coadministered with chronic miconazole.
Drug Idiosyncrasies:
IN RARE INDIVIDUALS, THERE IS A GENETICALLY DETERMINED RESISTANCE TO ORAL
ANTICOAGULANTS & DOSE MUST BE ACCORDINGLY INCR. /ORAL ANTICOAGULANTS/
A reversible, sometimes painful, blue-tinged discoloration of the plantar surfaces and
sides of the toes that blanches with pressure and fades with elevation of the legs (purple
toe syndrome) may develop 3 to 8 weeks after initiation of therapy with coumarin
anticoagulants. /Oral Anticoagulants/
Hemorrhagic necrosis (bleeding into the skin and subcutaneous tissue with resultant
necrosis, vasculitis, and thrombosis) has been reported to occur rarely during
anticoagulant therapy. This complication occurs more frequently in females than in males,
the fatty tissues of the abdomen, breasts, buttocks, and thighs are most often affected.
Tissue necrosis may be more likely to occur in patients with protein C deficiency.
Concurrent use of heparin during the first 5 to 7 days of anticoagulant therapy may
decrease the risk of tissue necrosis. /Anticoagulants/
Warfarin induced skin necrosis is a rare but serious complication of oral anticoagulant
therapy. This condition has been associated with protein C deficiency but only rarely
reported in patients with a deficiency of protein S. ... Two patients /were managed/ with
a history of warfarin induced skin necrosis who were diagnosed as being protein S
deficient. ... While they were therapeutically anticoagulated with heparin, warfarin was
started at 1 mg/day and the dose was increased gradually. Heparin was not discontinued
until the prothrombin times were in the therapeutic range for at least 72 hr. Both
patients tolerated the reinstitution of warfarin without difficulty and they have now been
followed for over 2 yr on oral anticoagulants without complication.
To investigate the cause of warfarin resistance in a 30 yr old black male, which was
suspected to be hereditary, the patient and his 2 sisters, ages 30-35 yr, and 13 black
male controls, ages 25-35 yr, first received a single 5 mg dose of iv vitamin K, then
received 5 mg of oral warfarin daily for 2 wk and on day 15 received a single 5 mg iv dose
of vitamin K; blood samples were drawn frequently and analyzed for levels of R-warfarin,
S-warfarin, vitamin K dependent clotting factors, plasma proteins, and prothrombin times.
Results indicated that systemic clearance of vitamin K was similar in all subjects.
However, oral clearance of S-warfarin and the clearance ratio for S/R warfarin in the
index patient and 1 sister differed by more than 7 standard deviations from the control
group. It was concluded that the warfarin resistance reported is due to an intrinsically
high oral clearance of the more active S-warfarin isomer.
Environmental Fate & Exposure:
Environmental Fate/Exposure Summary:
Warfarin will be released in the environment as dust or pellets in connection with its
use as a rodenticide. It may also be released in wastewater or spills during its
manufacture, storage and transport. If released on land or into water it will adsorb
moderately to soil or sediment. Its persistence due to biotic or abiotic processes is
unknown. It would not bioconcentrate appreciably in fish. If released into the atmosphere,
it would generally be as a dust or aerosol and be subject to gravitational settling. The
estimated vapor phase half-life for warfarin is 11.6 min due to reactions with
photochemically produced hydroxyl radicals and ozone in the atmosphere. Human exposure
would be primarily occupational or coming into contact with warfarin in bait. (SRC)
Probable Routes of Human Exposure:
Warfarin ... /is/ readily avail to general public. Baits are not always secure from ...
children. ... Warfarin & other rodenticides may be hidden in meat or sausage &
purposely left in yards to poison animals maliciously.
Use of warfarin as drug offers greater dosage &, therefore greater opportunity for
side effects than pest control operators encounter.
Artificial Pollution Sources:
Spills and wastewater from its production, transport, storage and use as an
anti-coagulant rodenticide and anti-coagulant drug. The sodium salt also is used as a
rodenticide. Since it is incorporated into bait, it is intentionally dispersed in the
application area(1,2).
Environmental Fate:
TERRESTRIAL FATE: Although warfarin contains several potentially reactive chemical
groups, warfarin's degradation rate in soil is unknown. It has moderate adsorption to soil
but would adsorb less under alkaline conditions since it forms a soluble salt. (SRC)
AQUATIC FATE: If released into water, warfarin would not be expected to volatilize
significantly and would only adsorb moderately to sediment. Although it adsorbs UV light
and contains potentially reactive groups, no data could be found concerning its
reactivity, so its fate in natural waters must be considered unknown. (SRC)
ATMOSPHERIC FATE: Warfarin would most likely be released into air as particulates or
aerosols and would be subject to gravitational settling. The estimated vapor phase
half-life for warfarin is 11.6 min due to reactions with photochemically produced hydroxyl
radicals and ozone in the atmosphere. (SRC)
Environmental Biodegradation:
Warfarin is reduced by Nocardia and Arthrobacter sp to the alcohol(1), however no
information concerning rates of degradation by environmentally relevant mixed cultures
could be found in the literature.
Environmental Abiotic Degradation:
Warfarin absorbs UV radiation to approximately 330nm(1) and is therefore a candidate
for direct photolysis. However no data could be found concerning the photolysis of
warfarin in the environment. Warfarin has an acidic end group which forms metallic salts,
an alpha, beta-unsaturated carbonyl group and a cyclic ether group which are potentially
reactive in the environment. Again no data specific to warfarin could be found. The
estimted vapor phase half-life for warfarin is 11.6 min due to reactions with
photochemically produced hydroxyl radicals and ozone in the atmosphere(2).
Environmental Bioconcentration:
No experimental data could be located on the bioconcentration of warfarin in fish. The
free acid has a log Kow of 2.52 at pH 3(1) from which one can estimate a log BCF of 1.68
using a regression equation(2,SRC). This indicates that the free acid would have a
relative low potential for bioconcentrating in fish. The sodium salt is soluble in water
and would therefore have even less potential for bioconcentration(SRC).
Soil Adsorption/Mobility:
No experimental data could be found on the adsorption of warfarin to soil. The free
acid is slightly soluble in water(3) and has a log Kow of 2.52 at pH 3(1) from which one
can estimate a Koc of 560(SRC,2) indicating moderate adsorption to soil. However the
sodium salt is water soluble and would be expected to leach through soils(SRC).
Volatilization from Water/Soil:
Warfarin has a high melting point(1) and is slightly soluble to soluble in water
depending on the pH(2). The vapor pressure and Henry's Law constants are therefore
expected to be low, so evaporation from water or solid surfaces would not be a significant
transport process(SRC).
Environmental Standards & Regulations:
FIFRA Requirements:
As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of
older pesticides to consider their health and environmental effects and make decisions
about their future use. Under this pesticide reregistration program, EPA examines health
and safety data for pesticide active ingredients initially registered before November 1,
1984, and determines whether they are eligible for reregistration. In addition, all
pesticides must meet the new safety standard of the Food Quality Protection Act of 1996.
Warfarin is found on List A, which contains most food use pesticides and consists of the
194 chemical cases (or 350 individual active ingredients) for which EPA issued
registration standards prior to FIFRA, as amended in 1988. Case No: 0011; Pesticide type:
Rodenticide; Registration Standard Date: 09/01/81; Case Status: RED Approved 09/97; OPP
has made a decision that some/all uses of the pesticide are eligible for reregistration,
as reflected in a Reregistration Eligibility Decision (RED) document.; Active ingredient
(AI): Warfarin; Data Call-in (DCI) Date(s): 05/21/91; AI Status: OPP has completed a
Reregistration Eligibility Decision (RED) document for the case/AI.
CERCLA Reportable Quantities:
Persons in charge of vessels or facilities are required to notify the National Response
Center (NRC) immediately, when there is a release of this designated hazardous substance,
in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The
toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area
(202) 426-2675. The rule for determining when notification is required is stated in 40 CFR
302.4 (section IV. D.3.b).
Releases of CERCLA hazardous substances are subject to the release reporting
requirement of CERCLA section 103, codified at 40 CFR part 302, in addition to the
requirements of 40 CFR part 355. Warfarin is an extremely hazardous substance (EHS)
subject to reporting requirements when stored in amounts in excess of its threshold
planning quantity (TPQ) of 500/10,000 lbs.
RCRA Requirements:
P001; As stipulated in 40 CFR 261.33, when WARFARIN, & salts, when present at
concentrations greater than 0.3%, as a commercial chemical product or manufacturing
chemical intermediate or an off-specification commercial chemical product or a
manufacturing chemical intermediate, becomes a waste, it must be managed according to
federal and/or state hazardous waste regulations. Also defined as a hazardous waste is any
container or inner liner used to hold this waste or any residue, contaminated soil, water,
or other debris resulting from the cleanup of a spill, into water or on dry land, of this
waste. Generators of small quantities of this waste may qualify for partial exclusion from
hazardous waste regulations (40 CFR 261.5(e)).
U248; As stipulated in 40 CFR 261.33, when WARFARIN, & salts, when present in
concentrations of 0.3% or less, as a commercial chemical product or manufacturing chemical
intermediate or an off-specification commercial chemical product or a manufacturing
chemical intermediate, becomes a waste, it must be managed according to Federal and/or
State hazardous waste regulations. Also defined as a hazardous waste is any residue,
contaminated soil, water, or other debris resulting from the cleanup of a spill, into
water or on dry land, of this waste. Generators of small quantities of this waste may
qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5).
FDA Requirements:
Manufacturers, packers, and distributors of drug and drug products for human use are
responsible for complying with the labeling, certification, and usage requirements as
prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat.
1040 et seq., as amended; 21 U.S.C. 321-392).
Chemical/Physical Properties:
Molecular Formula:
C19-H16-O4
Molecular Weight:
308.32
Color/Form:
CRYSTALS FROM ALCOHOL
White powder
Colorless, crystalline powder.
Odor:
Odorless
Odorless.
Taste:
Tasteless
Melting Point:
161 DEG C
Corrosivity:
Non-corrosive
Octanol/Water Partition Coefficient:
Log Kow = 2.52
Solubilities:
SOLUBLE IN ACETONE; MODERATELY SOLUBLE IN METHANOL, ETHANOL, ISOPROPANOL, SOME OILS;
FREELY SOLUBLE IN ALKALINE AQUEOUS SOLN (FORMS A WATER-SOL SODIUM SALT); PRACTICALLY INSOL
IN CYCLOHEXANE, SKELLYSOLVES A & B
1.7 mg/100 ml water at 20 deg C
0.3% in benzene; 6.5 in acetone, 5.6 in chloroform, 10.0 in dioxane (each in g/100 ml
at 20 deg C). Very slightly soluble in ether and cyclohexane.
Sol up to 40% in water /Warfarin sodium/
1 g in 1.5 ml water, 1.9 ml alcohol, >10,000 ml chloroform, >10,000 ml ether
/Warfarin potassium/
Spectral Properties:
MAX ABSORPTION (ALCOHOL): 271 NM (LOG E= 3.04); 287 NM (LOG E= 3.05); 306 NM (LOG E=
3.04)
Max UV absorption (water, pH 10): 308 nm (epsilon 13610)
Intense mass spectral peaks: 265 m/z (100%), 43 m/z (46%), 121 m/z (38%), 187 m/z (27%)
IR: 19548 (Sadtler Research Laboratories Prism Collection)
UV: 6416 (Sadtler Research Laboratories Spectral Collection)
MASS: 4853 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63)
Intense mass spectral peaks: 103 m/z, 131 m/z, 146 m/z, 181 m/z, 308 m/z
Vapor Pressure:
9X10-2 mbar at 21.5 deg C
Other Chemical/Physical Properties:
Warfarin has an acidic enol form which forms metallic salts and an acetate, mp 117-118
deg C, & a ketone which forms an oxime, mp 182-183 deg C & a
2,4-dinitrophenylhydrazone, mp 215-216 deg C
Following reconstitution of amorphous warfarin sodium powder for injection with sterile
water soln containing 25 mg of warfarin sodium per ml have a pH of 7.2-8.3 /Warfarin
Sodium/
pH (1 in 100 soln) between 7.2 & 8.3 /Warfarin potassium warfarin sodium/
Decomposes
Chemical Safety & Handling:
DOT Emergency Guidelines:
Health: Toxic; may be fatal if inhaled, ingested or absorbed through skin. Inhalation
or contact with some of these materials will irritate or burn skin and eyes. Fire will
produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or
suffocation. Runoff from fire control or dilution water may cause pollution. /Coumarin
derivative pesticide, liquid, flammable, poisonous; Coumarin derivative pesticide, liquid,
flammable, toxic; Coumarin derivative pesticide, liquid, poisonous flammable; Coumarin
derivative pesticide, liquid, toxic, flammable/
Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames.
Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and
flash back. Most vapors are heavier than air. They will spread along ground and collect in
low or confined areas (sewers, basements, tanks). Vapor explosion and poison hazard
indoors, outdoors or in sewers. Some may polymerize (P) explosively when heated or
involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may
explode when heated. Many liquids are lighter than water. /Coumarin derivative pesticide,
liquid, flammable, poisonous; Coumarin derivative pesticide, liquid, flammable, toxic;
Coumarin derivative pesticide, liquid, poisonous flammable; Coumarin derivative pesticide,
liquid, toxic, flammable/
Public safety: Call Emergency Response Telephone Number on Shipping Paper first. If
Shipping Paper not available or no answer, refer to appropriate telephone number listed on
the inside back cover. Isolate spill or leak area immediately for at least 100 to 200
meters (330 to 660 feet) in all directions. Keep unauthorized personnel away. Stay upwind.
Keep out of low areas. Ventilate closed spaces before entering. /Coumarin derivative
pesticide, liquid, flammable, poisonous; Coumarin derivative pesticide, liquid, flammable,
toxic; Coumarin derivative pesticide, liquid, poisonous flammable; Coumarin derivative
pesticide, liquid, toxic, flammable/
Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA).
Wear chemical protective clothing which is specifically recommended by the manufacturer.
It may provide little or no thermal protection. Structural firefighters' protective
clothing is recommended for fire situations only; it is not effective in spill situations.
/Coumarin derivative pesticide, liquid, flammable, poisonous; Coumarin derivative
pesticide, liquid, flammable, toxic; Coumarin derivative pesticide, liquid, poisonous
flammable; Coumarin derivative pesticide, liquid, toxic, flammable/
Evacuation: Spill: See the Table of Initial Isolation and Protective Action Distances
for highlighted substances. For non-highlighted substances, increase, in the downwind
direction, as necessary, the isolation distance shown under "Public safety".
Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2
mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in
all directions. /Coumarin derivative pesticide, liquid, flammable, poisonous; Coumarin
derivative pesticide, liquid, flammable, toxic; Coumarin derivative pesticide, liquid,
poisonous flammable; Coumarin derivative pesticide, liquid, toxic, flammable/
Fire: CAUTION: All these products have a very low flash point. Use of water spray when
fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or
alcohol-resistant foam. Large fires: Water spray, fog or alcohol-resistant foam. Move
containers from fire area if you can do it without risk. Dike fire control water for later
disposal; do not scatter the material. Do not use straight streams. Fire involving tanks
or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or
monitor nozzles. Cool containers with flooding quantities of water until well after fire
is out. Withdraw immediately in case of rising sound from venting safety devices or
discoloration of tank. ALWAYS stay away from the ends of tanks. For massive fire use
unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and
let fire burn. /Coumarin derivative pesticide, liquid, flammable, poisonous; Coumarin
derivative pesticide, liquid, flammable, toxic; Coumarin derivative pesticide, liquid,
poisonous flammable; Coumarin derivative pesticide, liquid, toxic, flammable/
Spill or leak: Fully encapsulating, vapor protective clothing should be worn for spills
and leaks with no fire. ELIMINATE all ignition sources (no smoking, flares, sparks or
flames in immediate area). All equipment used when handling the product must be grounded.
Do not touch or walk through spilled material. Stop leak if you can do it without risk.
Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing
foam may be used to reduce vapors. Small spills: Absorb with earth, sand or other
non-combustible material and transfer to containers for later disposal. Use clean
non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid
spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in
closed spaces. /Coumarin derivative pesticide, liquid, flammable, poisonous; Coumarin
derivative pesticide, liquid, flammable, toxic; Coumarin derivative pesticide, liquid,
poisonous flammable; Coumarin derivative pesticide, liquid, toxic, flammable/
First aid: Move victim to fresh air. Call emergency medical care. Apply artificial
respiration if victim is not breathing. Do not use mouth-to-mouth method if victim
ingested or inhaled the substance; induce artificial respiration with the aid of a pocket
mask equipped with a one-way valve or other proper respiratory medical device. Administer
oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In
case of contact with substance, immediately flush skin or eyes with running water for at
least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of
exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that
medical personnel are aware of the material(s) involved, and take precautions to protect
themselves. /Coumarin derivative pesticide, liquid, flammable, poisonous; Coumarin
derivative pesticide, liquid, flammable, toxic; Coumarin derivative pesticide, liquid,
poisonous flammable; Coumarin derivative pesticide, liquid, toxic, flammable/
Health: Highly toxic, may be fatal if inhaled, swallowed or absorbed through skin.
Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce
irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may
be corrosive and/or toxic and cause pollution. /Coumarin derivative pesticide, liquid,
poisonous; Coumarin derivative pesticide, liquid, toxic; Coumarin derivative pesticide,
solid, poisonous; Coumarin derivative pesticide, solid, toxic/
Fire or explosion: Non-combustible, substance itself does not burn but may decompose
upon heating to produce corrosive and/or toxic fumes. Containers may explode when heated.
Runoff may pollute waterways. /Coumarin derivative pesticide, liquid, poisonous; Coumarin
derivative pesticide, liquid, toxic; Coumarin derivative pesticide, solid, poisonous;
Coumarin derivative pesticide, solid, toxic/
Public safety: CALL Emergency Response Telephone Number on Shipping Paper. If Shipping
Paper not available or no answer, refer to appropriate telephone number listed on the
inside back cover. Isolate spill or leak area immediately for at least 25 to 50 meters (80
to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of
low areas. /Coumarin derivative pesticide, liquid, poisonous; Coumarin derivative
pesticide, liquid, toxic; Coumarin derivative pesticide, solid, poisonous; Coumarin
derivative pesticide, solid, toxic/
Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA).
Wear chemical protective clothing which is specifically recommended by the manufacturer.
Structural firefighters' protective clothing is recommended for fire situations ONLY; it
is not effective in spill situations. /Coumarin derivative pesticide, liquid, poisonous;
Coumarin derivative pesticide, liquid, toxic; Coumarin derivative pesticide, solid,
poisonous; Coumarin derivative pesticide, solid, toxic/
Evacuation: Spill: See the Table of Initial Isolation and Protective Action Distances
for highlighted substances. For non-highlighted substances, increase, in the downwind
direction, as necessary, the isolation distance shown under "PUBLIC SAFETY".
Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2
mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in
all directions. /Coumarin derivative pesticide, liquid, poisonous; Coumarin derivative
pesticide, liquid, toxic; Coumarin derivative pesticide, solid, poisonous; Coumarin
derivative pesticide, solid, toxic/
Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Water spray, fog or
regular foam. Move containers from fire area if you can do it without risk. Dike fire
control water for later disposal; do not scatter the material. Do not use straight
streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or
use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool
containers with flooding quantities of water until well after fire is out. Withdraw
immediately in case of rising sound from venting safety devices or discoloration of tank.
ALWAYS stay away from the ends of tanks. For massive fire, use unmanned hose holders or
monitor nozzles; if this is impossible withdraw from area and let fire burn. /Coumarin
derivative pesticide, liquid, poisonous; Coumarin derivative pesticide, liquid, toxic;
Coumarin derivative pesticide, solid, poisonous; Coumarin derivative pesticide, solid,
toxic/
Spill or leak: Do not touch damaged containers or spilled material unless wearing
appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry
into waterways, sewers, basements or confined areas. Cover with plastic sheet to prevent
spreading. Absorb or cover with dry earth, sand or other non-combustible material and
transfer to containers. DO NOT GET WATER INSIDE CONTAINERS. /Coumarin derivative
pesticide, liquid, poisonous; Coumarin derivative pesticide, liquid, toxic; Coumarin
derivative pesticide, solid, poisonous; Coumarin derivative pesticide, solid, toxic/
First aid: Move victim to fresh air. Call emergency medical care. Apply artificial
respiration if victim is not breathing. Do not use mouth-to-mouth method if victim
ingested or inhaled the substance; induce artificial respiration with the aid of a pocket
mask equipped with a one-way valve or other proper respiratory medical device. Administer
oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In
case of contact with substance, immediately flush skin or eyes with running water for at
least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin.
Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to
substance may be delayed. Ensure that medical personnel are aware of the material(s)
involved, and take precautions to protect themselves. /Coumarin derivative pesticide,
liquid, poisonous; Coumarin derivative pesticide, liquid, toxic; Coumarin derivative
pesticide, solid, poisonous; Coumarin derivative pesticide, solid, toxic/
Fire Potential:
Contact with strong oxidizers may cause fires and explosions.
Hazardous Reactivities & Incompatibilities:
Strong oxidizers.
Prior History of Accidents:
IN AUGUST, 1981, PEDIATRIC HOSPITALS IN HO CHI MINH CITY (FORMERLY SAIGON), VIETNAM,
BEGAN TO REPORT CASES OF A HEMORRHAGIC SYNDROME IN INFANTS. THE CAUSE OF THIS PHENOMENON
WAS IDENTIFIED AS TALCUM POWDER CONTAMINATED WITH THE ANTICOAGULANT WARFARIN. ANALYSIS OF
TALCUM POWDERS REVEALED WARFARIN IN CONCENTRATIONS BETWEEN 1.7% AND 6.5%. 741 CASES WERE
DETECTED AND 177 PATIENTS DIED. ...
In Korea, a family of 14 persons lived for a period of 15 days on a diet consisting
almost entirely of corn (maize) meal containing warfarin. The first symptoms appeared 7-10
days after the eating of warfarin was begun. Massive bruises or hematoma developed at the
knee and elbow joints and on the buttocks in all cases. Extensive gum and nasal hemorrhage
usually appeared about a day later, and by day 15 blood loss was extensive.
Immediately Dangerous to Life or Health:
100 mg/cu m
Protective Equipment & Clothing:
Respirator selection: Upper limit: 0.5 mg/cu m: Dust mask, except single-use
respirators; Upper limit: 1 mg/cu m: Dust mask, except single-use and quarter-mask
respirators /High-efficiency particulate respirator/Supplied-air respirator/
Self-contained breathing apparatus; Upper limit: 5 mg/cu m: High-efficiency particulate
respirator with full facepiece /Supplied-air respirator with full facepiece, helmet, or
hood/ Self-contained breathing apparatus with full facepiece; Upper limit: 100 mg/cu m:
Powered air-purifying respirator with high-efficiency filter /Supplied air respirator:
Type C operated in pressure-demand or other positive pressure or continuous-flow mode;
Upper limit: 200 mg/cu m: Supplied air respirator with full facepiece, helmet, or hood:
Type C with full facepiece operated in pressure-demand or other positive pressure mode or
with full facepiece, helmet or hood operated in continuous flow mode; Upper limit: Escape:
Gas mask with organic vapor canister (chin-style or front or back-mounted canister) self
contained breathing apparatus.
Wear appropriate clothing to prevent repeated or prolonged skin contact. Employees
should wash promptly when skin is wet or contaminated. Work clothing should be changed
daily if it is possible that clothing is contaminated. Remove nonimpervious clothing
promptly if wet or contaminated.
Wear appropriate personal protective clothing to prevent skin contact.
Recommendations for respirator selection. Max concn for use: 0.5 mg/cu m. Respirator
Class(es): Any dust and mist respirator.
Recommendations for respirator selection. Max concn for use: 1 mg/cu m. Respirator
Class(es): Any dust and mist respirator except single-use and quarter-mask respirators.
Any supplied-air respirator.
Recommendations for respirator selection. Max concn for use: 2.5 mg/cu m. Respirator
Class(es): Any supplied-air respirator operated in a continuous flow mode. Any powered,
air-purifying respirator with a dust and mist filter.
Recommendations for respirator selection. Max concn for use: 5 mg/cu m. Respirator
Class(es): Any air-purifying, full-facepiece respirator with a high-efficiency particulate
filter. Any supplied-air respirator that has a tight-fitting facepiece and is operated in
a continuous-flow mode. Any powered, air-purifying respirator with a tight-fitting
facepiece and a high-efficiency particulate filter. Any self-contained breathing apparatus
with a full facepiece. Any supplied-air respirator with a full facepiece.
Recommendations for respirator selection. Max concn for use: 100 mg/cu m. Respirator
Class(es): Any supplied-air respirator operated in a pressure-demand or other
positive-pressure mode.
Recommendations for respirator selection. Condition: Emergency or planned entry into
unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing
apparatus that has a full facepiece and is operated in a pressure-demand or other
positive-pressure mode. Any supplied-air respirator that has a full facepiece and is
operated in a pressure-demand or other positive-pressure mode in combination with an
auxiliary self-contained breathing apparatus operated in pressure-demand or other
positive-pressure mode.
Recommendations for respirator selection. Condition: Escape from suddenly occurring
respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator
with a high-efficiency particulate filter. Any appropriate escape-type, self-contained
breathing apparatus.
Employees should be provided with and required to use impervious clothing, gloves, face
shields (eight-inch minimum), and other appropriate protective clothing necessary to
prevent repeated or prolonged skin contact with warfarin or liquids containing warfarin.
Adequate protective clothing should be worn at all times. In the lab this will consist
of a lab coat, rubber or polyethylene gloves & a /NIOSH approved respirator/ or
respirator of a type applicable to the specific chemical being handled. /Rodenticides/
Preventive Measures:
Contact lenses should not be worn when working with this chemical.
SRP: The scientific literature for the use of contact lenses in industry is
conflicting. The benefit or detrimental effects of wearing contact lenses depend not only
upon the substance, but also on factors including the form of the substance,
characteristics and duration of the exposure, the uses of other eye protection equipment,
and the hygiene of the lenses. However, there may be individual substances whose
irritating or corrosive properties are such that the wearing of contact lenses would be
harmful to the eye. In those specific cases, contact lenses should not be worn. In any
event, the usual eye protection equipment should be worn even when contact lenses are in
place.
Eating and smoking should not be permitted in areas where warfarin or liquids
containing warfarin are handled, processed, or stored.
Keep /warfarin rodenticide/ away from children, domestic animals, pets, or wildlife.
... Avoid contact with mouth, eyes, & skin. ... Baits should be used only in protected
stations that prevent access to larger animals.
The worker should immediately wash the skin when it becomes contaminated.
Work clothing that becomes wet or significantly contaminated should be removed and
replaced.
Workers whose clothing may have become contaminated should change into uncontaminated
clothing before leaving the work premises.
Whereever possible, toxic chemicals, concentrates & bait preparations should be
handled in a fume cupboard. When bait mixing has been done in the field, operators should
take care to remain sheltered from the wind. /Rodenticides/
Scrupulous personal hygiene must be adhered to when dealing with poisons. All cuts
& abrasions on the hands & forearms must be covered with waterproof adhesive
dressings before any operations are started. When the work is finished or when a break is
taken in the middle /of the day/, protective clothing should be removed & hands washed
thoroughly with soap & hot water. Contaminated protective clothing must not be taken
into "clean" areas. /Rodenticides/
Smoking, eating & drinking must be strictly prohibited in all rooms in which
poisons are present. /Rodenticides/
In event of accidental poisoning in humans, it is important that proper medical help is
enlisted at once. ... Local hospitals should be notified of the potential dangers that
exist in places where rodenticides are present & be given precise details of the
specific poisons that are used, with revelant information about antidotes, symptoms, etc.
/Rodenticides/
Normal first-aid facilities should be available ... & as many staff as possible
should have proper first-aid training. /Rodenticides/
Stability/Shelf Life:
Very stable, even to strong acids.
Warfarin potassium & warfarin sodium are discolored by light. /Warfarin potassium
& warfarin sodium/
Shipment Methods and Regulations:
No person may /transport,/ offer or accept a hazardous material for transportation in
commerce unless that person is registered in conformance ... and the hazardous material is
properly classed, described, packaged, marked, labeled, and in condition for shipment as
required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./
The International Air Transport Association (IATA) Dangerous Goods Regulations are
published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and
constitute a manual of industry carrier regulations to be followed by all IATA Member
airlines when transporting hazardous materials.
The International Maritime Dangerous Goods Code lays down basic principles for
transporting hazardous chemicals. Detailed recommendations for individual substances and a
number of recommendations for good practice are included in the classes dealing with such
substances. A general index of technical names has also been compiled. This index should
always be consulted when attempting to locate the appropriate procedures to be used when
shipping any substance or article.
Storage Conditions:
Warfarin /therapeutic/ prepn should be stored at a temp less than 40 deg C, preferably
between 15-30 deg C; warfarin potassium & warfarin sodium tablets should be stored in
tight, light-resistant containers & warfarin sodium powder for injection should be
protected from light. Reconstituted solutions of warfarin sodium should be used
immediately. /Warfarin potassium & warfarin sodium/
Do not store /warfarin rodenticide/ near feeds & foodstuffs. ... Store away from
heat & open flames.
Cleanup Methods:
Collect with a brush onto a paper sheet. Place in an iron pan in hood. Burn the paper.
Disposal Methods:
SRP: At the time of review, criteria for land treatment or burial (sanitary landfill)
disposal practices are subject to significant revision. Prior to implementing land
disposal of waste residue (including waste sludge), consult with environmental regulatory
agencies for guidance on acceptable disposal practices.
FOR SMALL QUANTITIES, SWEEP ONTO PAPER OR OTHER SUITABLE MATERIAL, PLACE IN AN
APPROPRIATE CONTAINER AND BURN IN A SAFE PLACE (SUCH AS A FUME HOOD). LARGE QUANTITIES MAY
BE RECLAIMED; HOWEVER, IF THIS IS NOT PRACTICAL, DISSOLVE IN A FLAMMABLE SOLVENT (SUCH AS
ALCOHOL) AND ATOMIZE IN A SUITABLE COMBUSTION CHAMBER.
Incineration: 1) Stuff a package with paper or flammable materials. Burn in the
furnace. 2) Dissolve in a combustible solvent. Burn in the furnace by spraying the soln.
Occupational Exposure Standards:
OSHA Standards:
Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 0.1 mg/cu m.
Threshold Limit Values:
8 hr Time Weighted Avg (TWA) 0.1 mg/cu m
Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three
times the TLV-TWA for no more than a total of 30 min during a work day, and under no
circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not
exceeded.
NIOSH Recommendations:
Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 0.1 mg/cu m.
Immediately Dangerous to Life or Health:
100 mg/cu m
Manufacturing/Use Information:
Major Uses:
RODENTICIDE FOR NORWAY RATS & FOR HOUSE MICE
MEDICATION
Warfarin reacts with methanol in the presence of hydrochloric acid to produce
cyclocumarol, a synthetic anticoagulant
Manufacturers:
HACCO, Inc., P.O. Box 7190, Randolph, WI (608)221-6200
Prentiss, Inc., CB 2000, Floral Park, NY 11001, (516) 326-1919
Methods of Manufacturing:
REACTION OF 4-HYDROXYCOUMARIN WITH BENZYLIDENE ACETONE IN THE PRESENCE OF A BASE, EG,
PYRIDINE
Conversion to the sodium or potassium salt is effected by reacting purified warfarin
with an equimolar portion of dilute NaOH or KOH solution at room temp. /Warfarin sodium
& warfarin potassium/
General Manufacturing Information:
Warfarin is a racemic mixture whether it is used as rodenticide or as a drug.
... Michael condensation of benzylidene-acetone with 4-hydroxycoumarin: Stahmann et al:
US patent 2,427,578 (1947); Schroeder, Link: US patent 2,765,321 (1956 to Wisconsin Alumni
Res Found); Link: US patent 2,777,859 (1957). ... Resolution & absolute configuration:
... Preis et al: US patent 3,239,529 (1966 to Wisconsin Alumni Res Found).
Formulations/Preparations:
Formulation types /incl/ bait /&/ concentrate. Mixed formulations /incl/ (warfarin
+) pindone; calciferol; sulfaquinoxaline.
Rat baits are usually made up by mixing 1 part of commercial prepn containing 0.5 or
0.1% warfarin with 20 parts of oatmeal or other suitable diluent.
A "rodent drink" is made with water containing 0.54% warfarin sodium coated
on sugar (Dethmor Water Soluble); a similar "rodent drink" containing 0.54%
warfarin coated on sand (silica) /is/ (Rax Water Soluble). ... Ratoxin 1% Powder, 1% wt/wt
coated talc powder.
Tracking powder (10 g ai/kg) for use in holes & runs; bait concentrate (1 and 5
g/kg) for admixture with a suitable protein-rich bait.
/Trade names for warfarin rodenticide incl/ Co-Rax, Cov-R-Tox, Kypfarin, Liqua-Tox,
RAX, Rodex, Rodex Blox, Tox-Hid, Warfarin Plus (discontinued by Velsicol Corp), Warfarin
Q.
Prolin warfarin /rodenticide/ combined with the antibacterial agent, sulfaquinoxaline
Eraze, Final, Place-Pax, Warfarin Q Concentrate.
/As therapeutic anticoagulant/ the drug is avail as racemic mixtures of the 2 optical
isomers of the potassium or sodium salt. ... Panwarfin tablets contain amorphous warfarin
sodium; Coumadin tablets contain the crystalline clathrate. Commercially avail warfarin
sodium powder for injection (Coumadin) contains lyophilized, amorphous warfarin sodium
formulated with sodium hydroxide to adjust pH. /Warfarin potassium & warfarin sodium/
THERAPEUTIC: Warfarin Sodium, USP (Coumadin, Panwarfin) is avail in tablets containing
2, 2.5, 5, 7.5, 10 & 25 mg of drug. ... Warfarin Potassium, USP (Athrombin-K) is avail
in tablets containing 5 & 10 mg of drug. Warfarin Sodium for Injection, USP,
containing sodium chloride & thiomerosal, is avail in vials of 50 mg with ampules of
sterile water ... /Warfarin sodium & warfarin potassium/
Formulated in ready to use baits and as concentrates in corn starch for mixing at a
1:91 ratio with cornmeal or other materials. Baits should be used only in protected
stations that prevent access to larger animals. RAX powder, 0.50% concentrate. Liquatox
liquid concentrate and sodium warfarin available in 1.7 oz nylon pouches
TP(10 g a.i./kg) for use in holes and runs; CB (1 and 5 g/kg) for admixture with
suitable protein-rich bait
Formulations with 2-(dimethylamino)ethanol: warfarin-deanol, MD 6134, Adoisine
U. S. Production:
(1985) Data not given
Laboratory Methods:
Clinical Laboratory Methods:
Rapid fluorometric assay for plasma warfarin; interfering substances are warfarin
metabolites; concentrations determined by this procedure are slightly higher than those
obtained by spectrophotometry; this method is not suitable for measurement of warfarin in
urine: Corn M, Berberich R; Clin Chem 13: 126 (1967).
GLC determination of warfarin in plasma; specificity of method is as good as any GLC
procedure, coupled with selective extraction, TLC, derivative formation, & selective
detection. The lower limit of detection sensitivity in human plasma is 0.02 ug/ml. The
method is capable of measuring warfarin concn of 0.25 to 1.0 ug/ml of plasma with
coefficient of variation of 9%.
An LC assay was developed for the simultaneous determination of R(+)-warfarin
(R-warfarin) and S(-)-warfarin (S-warfarin) in plasma and was evaluated in a subject
receiving a racemic product. The method involved the formation of diastereoisomeric
esters, using carbobenzyl oxy-L-proline with subsequent separation using silica as the
stationary phase.
HPLC & GLC are used to determine warfarin in serum & plasma extracted into EDTA
buffer.
A high performance liquid chromatographic method was developed for the determination of
warfarin and its metabolites (diastereomeric warfarin alcohols and 6-, 7-, 8-, 4'- and
3'-hydroxywarfarin) in microbial cultures. Ion pair chromatography with tetrabutylammonium
ion as the counter ion allowed for the complete resolution of all compounds at pH 7.5 on a
reversed phase (C18) column, thus permitting direct fluorescence detection without the use
of post column pH switching techniques. Detection limits for all compounds were in the low
nanogram range. Regression coefficients for all compounds were better than 0.99. Although
the lowest calibration point of this assay was 10 ng/ml for all metabolites, levels as low
as 1 ng/ml were detectable.
The combination of Pb(II) and Whatman No. 1 filter-paper was utilized to enhance the
room-temperature phosphorescence of the rodenticide warfarin adsorbed on a solid surface.
The chromatographic paper discs were spotted with 5 ul of 1 M lead(II) acetate followed by
4 ul of standard or sample solutions on the same substrate area. The amounts of warfarin
delivered to each filter-paper ranged from 4 to 800 ng. The lowest practical detection
limit in the serum was 87 ng.
Analytic Laboratory Methods:
A high performance liquid chromatographic technique used to analyze samples of airborne
pharmaceuticals collected in the breathing zone of workers. The detection limit was in the
range of 0.2-5 ug/cu m for ... warfarin ... .
PRODUCT ANALYSIS IS BY UV SPECTROSCOPY: AOAC METHODS 6: 141-2 (1980); CIPAC HANDBOOK 1:
696 (1970); SCHROEDER CH, EBLE JN, ANAL METHODS PESTIC PLANT GROWTH REGUL FOOD ADDIT 3:
197 (1964); SCHROEDER CH, SHERMA J, ANAL METHODS PESTIC PLANT GROWTH REGUL 7: 677 (1973).
POLAROGRAPHIC ANALYSIS: OMURA T ET AL; BUNSEKI KAGAKU 18: 943-7 (1969) (JAPAN).
SIMULTANEOUS DETERMINATION OF WARFARIN IN WHEAT IS ACHIEVED BY DIMETHYLFORMAMIDE
EXTRACTION FOLLOWED BY ISOCRATIC HPLC SEPARATION USING A REVERSE-PHASE RP-8 COLUMN AND
0.005 M PENTANE SULFONIC ACID IN METHYL ALCOHOL:WATER (60:40) AS ELUENT. THE 3 COMPONENTS
ARE DETECTED AT 280 NM. THE METHOD GIVES A 97.8% RECOVERY FOR WARFARIN.
A HIGH-PERFORMANCE LIQUID CHROMATOGRAPH EQUIPPED WITH A C8 REVERSED-PHASE COLUMN AND
FLUORESCENCE DETECTOR WAS INVESTIGATED FOR THE SELECTIVE DETERMINATION OF TOXIC CHEMICALS
AT RESIDUE (NANOGRAM) LEVELS. TWO HYDROXYCOUMARIN COMPOUNDS WERE CHROMATOGRAPHED WITH AN
ACETONITRILE-AQUEOUS 1% MOBILE PHASE AND DETECTED AFTER POST-COLUMN ADDITION OF BASE FOR
MAXIMUM FLUORESCENCE.
Residues of warfarin, coumatetralyl, difenacoum,
brodifacoum, bromadiolone, diphacinone, and chlorophacinone in animal tissues were
extracted with CHCl3-MeCO. Extracts were cleaned-up by an integrated gel permeation and
adsorption chromatography procedure which divided the rodenticides into 2 groups. Residues
were then determined and confirmed using normal-phase, ion-pair and weak ion-exchange HPLC
techniques. Ion-pair gradient separation resolved all 7 rodenticides in a single
chromatographic analysis. UV detection methods were employed for all 7 rodenticides. Use
of a diode array detection system permitted additional confirmation of residues down to
0.1 mg/kg by matching UV spectra and derivations of spectra. Sensitive fluorescence
detection was possible for the coumarin-based rodenticides, but not for diphacinone and
chlorophacinone. Post-column pH-switching fluorescence detection methods were superior to
other methods of fluorescence detection of coumarin-based rodenticides. Recoveries from
spiked liver tissue were around 90% at levels from 0.05 to 1 mg/kg. Detection limits of
around 0.002 mg/kg for most rodenticides and of 0.01 mg/kg for warfarin could be achieved
with animal tissue extracts.
Method 960.15. Warfarin in Rodenticide Formulations. Spectrophotometric Method.
Sampling Procedures:
ANALYTE: WARFARIN, MATRIX: AIR, PROCEDURE: FILTER COLLECTION, EXTRACTION WITH METHANOL,
HIGH PRESSURE LIQUID CHROMATOGRAPHY, RANGE: 0.054 TO 0.244 MG/CU M.
Special References:
Special Reports:
Renowden S et al; Br Med J (Clin Res) 291 (6494): 513-14 (1985)
Schardein JL; Drugs affecting blood. Chemically Induced Birth Defects 2: 106-25 (1993).
Review of the fetal toxicity of anticoagulants.
Freedman MD, Olatidoye AG; Drug Saf 10 (5): 381-94 (1994). Oral anticoagulants include
coumarin derivatives (dicoumarol, phenprocoumon and acenocoumarol. ... The oral
anticoagulants, and warfarin in particular are highly interactive with other drugs.
Mechanisms of those interactions include both pharmacokinetic and pharmacodynamic
mechanisms and may result in either hyperprothrombinemia or hypoprothrombinemia.
Mason JD et al; J Laryngol Otol 106 (12): 1098-9 (1992)] Premature cartilaginous
calcification and nasal hypoplasia following first trimester exposure to warfarin are
known as Fetal Warfarin Syndrome. There are over 40 cases reported in the literature, many
of which describes breathing and feeding difficulties in the first few months of life.
Little BB et al; Drugs and Pregnancy (1992). Review of /the adverse effects of/
anticoagulants ... during pregnancy.
Howard PA; Hosp Pharm 27: 493-8 (1992). Guidelines are established by the American
College of Chest Physicians for the use of warfarin as anticoagulant therapy in patients
with atrial fibrillation and the potential benefits and risks associated with such therapy
are reviewed.
Hirsh J; N eng J Med 324: 1865-75 (1991). A review of anticoagulant drugs, including
the pharmacology of warfarin. ...
Harrington R, Ansell J; Drug Safety 6: 54-69 (1991). A review of the risks and benefits
of heparin and warfarin in the treatment of thromboembolic syndromes and use in pregnancy
is /discussed/. ... Heparin, because of its fast action, is the drug of choice for short
term treatment. Warfarin is the drug of choice for long term oral maintenance therapy. ...
The use of anticoagulants in pregnancy is especially complex. Heparin is probably the
preferred agent since, unlike warfarin, it does not cross the placenta and is
nonteratogenic.
USEPA/OPP; Reregistration Eligibility Document (RED): Warfarin & Appendices EPA
540/RS-92-164 (1992)
Greaves M; Pharmacol Ther 59 (3): 311-27 (1993). A review article concerning the use of
anticoagulants in pregnancy.
Synonyms and Identifiers:
Related HSDB Records:
1725 [COUMATETRALYL]
Synonyms:
3-(alpha-acetonylbenzene)-4-hydroxycoumarin
**PEER REVIEWED**
3-(ALPHA-ACETONYLBENZYL)-4-HYDROXYCOUMARIN
**PEER REVIEWED**
3-(Acetonylbenzyl)-4-Hydroxycoumarin
**PEER REVIEWED**
Arab Rat Death
**PEER REVIEWED**
Athrombin-K /Potassium salt/
**PEER REVIEWED**
2H-1-BENZOPYRAN-2-ONE, 4-HYDROXY-3-(3-OXO-1-PHENYLBUTYL)-
**PEER REVIEWED**
D-CON
**PEER REVIEWED**
Co-Rax
**PEER REVIEWED**
COUMADIN /Sodium salt/
**PEER REVIEWED**
COUMAFENE (FRENCH)
**PEER REVIEWED**
200 coumarin
**PEER REVIEWED**
COUMARIN, 3-(ALPHA-ACETONYLBENZYL)-4-HYDROXY-
**PEER REVIEWED**
Coumarin, 4-hydroxy-3-(1-phenyl-3-oxobutyl)
**PEER REVIEWED**
Cov-R-Tox
**PEER REVIEWED**
DETHNEL
**PEER REVIEWED**
EASTERN STATES DUOCIDE
**PEER REVIEWED**
FASCO FASCRAT POWDER
**PEER REVIEWED**
FRASS-RATRON
**PEER REVIEWED**
1-(4'-HYDROXY-3'-COUMARINYL)-1-PHENYL-3-BUTANONE
**PEER REVIEWED**
4-HYDROXY-3-(3-OXO-1-FENYL-BUTYL) CUMARINE (DUTCH)
**PEER REVIEWED**
4-Hydroxy-3-(3-oxo-1-phenyl butyl)-2H-1-benzopyran-2-one
**PEER REVIEWED**
4-HYDROXY-3-(3-OXO-1-PHENYL-BUTYL)-CUMARIN (GERMAN)
**PEER REVIEWED**
4-IDROSSI-3-(3-OXO-)-FENIL-BUTIL)-CUMARINE (ITALIAN)
**PEER REVIEWED**
KUMADER
**PEER REVIEWED**
KUMADU
**PEER REVIEWED**
Liqua-Tox
**PEER REVIEWED**
MAAG RATTENTOD CUM
**PEER REVIEWED**
Marevan /Sodium salt/
**PEER REVIEWED**
MAR-FRIN
**PEER REVIEWED**
Martin's Mar-Frin
**PEER REVIEWED**
MAVERAN /Sodium salt/
**PEER REVIEWED**
Mouse Pak
**PEER REVIEWED**
3-(ALPHA-PHENYL-BETA-ACETYLETHYL)-4-HYDROXYCOUMARIN
**PEER REVIEWED**
3-(1'-PHENYL-2'-ACETYLETHYL)-4-HYDROXYCOUMARIN
**PEER REVIEWED**
(Phenyl-1 acetyl-2 ethyl) 3-Hydroxy-4 coumarine (French)
**PEER REVIEWED**
PROTHROMADIN /Sodium salt/
**PEER REVIEWED**
Rat-o-cide #2
**PEER REVIEWED**
RAT-GARD
**PEER REVIEWED**
RAT-B-GON
**PEER REVIEWED**
RAT-KILL
**PEER REVIEWED**
Rat & Mice Bait
**PEER REVIEWED**
RAT-MIX
**PEER REVIEWED**
RAT-OLA
**PEER REVIEWED**
Ratorex
**PEER REVIEWED**
Ratox
**PEER REVIEWED**
Ratoxin
**PEER REVIEWED**
RATRON
**PEER REVIEWED**
Ratron G
**PEER REVIEWED**
RATS-NO-MORE
**PEER REVIEWED**
RATTEN-KOEDERROHR
**PEER REVIEWED**
RATTENSTREUPULVER NEW SCHACHT
**PEER REVIEWED**
RATTENTRAENKE
**PEER REVIEWED**
Rat-trol
**PEER REVIEWED**
RATTUNAL
**PEER REVIEWED**
RAT-A-WAY
**PEER REVIEWED**
Rax
**PEER REVIEWED**
RODAFARIN
**PEER REVIEWED**
Ro-deth
**PEER REVIEWED**
Rodex
**PEER REVIEWED**
Rodex Blox
**PEER REVIEWED**
Rosex
**PEER REVIEWED**
Rough & Ready Mouse Mix
**PEER REVIEWED**
Solfarin
**PEER REVIEWED**
Spray-trol Brand Roden-trol
**PEER REVIEWED**
TEMUS W
**PEER REVIEWED**
Tintorane /Sodium salt/
**PEER REVIEWED**
Tox-Hid
**PEER REVIEWED**
Twin light rat away
**PEER REVIEWED**
Vampirinip II
**PEER REVIEWED**
Vampirinip III
**PEER REVIEWED**
Waran /Sodium salt/
**PEER REVIEWED**
Warf-12
**PEER REVIEWED**
WARF 42
**PEER REVIEWED**
WARFARAT
**PEER REVIEWED**
Warfarin Q
**PEER REVIEWED**
Warfarine (French)
**PEER REVIEWED**
Warfarin plus /discontinued/
**PEER REVIEWED**
WARF COMPOUND 42
**PEER REVIEWED**
WARFICIDE
**PEER REVIEWED**
Warfilone /Sodium salt/
**PEER REVIEWED**
ZOOCOUMARIN (NETHERLANDS AND USSR)
**PEER REVIEWED**
Formulations/Preparations:
Formulation types /incl/ bait /&/ concentrate. Mixed formulations /incl/ (warfarin
+) pindone; calciferol; sulfaquinoxaline.
Rat baits are usually made up by mixing 1 part of commercial prepn containing 0.5 or
0.1% warfarin with 20 parts of oatmeal or other suitable diluent.
A "rodent drink" is made with water containing 0.54% warfarin sodium coated
on sugar (Dethmor Water Soluble); a similar "rodent drink" containing 0.54%
warfarin coated on sand (silica) /is/ (Rax Water Soluble). ... Ratoxin 1% Powder, 1% wt/wt
coated talc powder.
Tracking powder (10 g ai/kg) for use in holes & runs; bait concentrate (1 and 5
g/kg) for admixture with a suitable protein-rich bait.
/Trade names for warfarin rodenticide incl/ Co-Rax, Cov-R-Tox, Kypfarin, Liqua-Tox,
RAX, Rodex, Rodex Blox, Tox-Hid, Warfarin Plus (discontinued by Velsicol Corp), Warfarin
Q.
Prolin warfarin /rodenticide/ combined with the antibacterial agent, sulfaquinoxaline
Eraze, Final, Place-Pax, Warfarin Q Concentrate.
/As therapeutic anticoagulant/ the drug is avail as racemic mixtures of the 2 optical
isomers of the potassium or sodium salt. ... Panwarfin tablets contain amorphous warfarin
sodium; Coumadin tablets contain the crystalline clathrate. Commercially avail warfarin
sodium powder for injection (Coumadin) contains lyophilized, amorphous warfarin sodium
formulated with sodium hydroxide to adjust pH. /Warfarin potassium & warfarin sodium/
THERAPEUTIC: Warfarin Sodium, USP (Coumadin, Panwarfin) is avail in tablets containing
2, 2.5, 5, 7.5, 10 & 25 mg of drug. ... Warfarin Potassium, USP (Athrombin-K) is avail
in tablets containing 5 & 10 mg of drug. Warfarin Sodium for Injection, USP,
containing sodium chloride & thiomerosal, is avail in vials of 50 mg with ampules of
sterile water ... /Warfarin sodium & warfarin potassium/
Formulated in ready to use baits and as concentrates in corn starch for mixing at a
1:91 ratio with cornmeal or other materials. Baits should be used only in protected
stations that prevent access to larger animals. RAX powder, 0.50% concentrate. Liquatox
liquid concentrate and sodium warfarin available in 1.7 oz nylon pouches
TP(10 g a.i./kg) for use in holes and runs; CB (1 and 5 g/kg) for admixture with
suitable protein-rich bait
Formulations with 2-(dimethylamino)ethanol: warfarin-deanol, MD 6134, Adoisine
Shipping Name/ Number DOT/UN/NA/IMO:
UN 3024; Coumarin derivative pesticides, liquid, flammable, toxic, NOS, flashpoint less
than 23 deg C
UN 3025; Coumarin derivative pesticides, liquid, toxic, flammable, NOS, flashpoint 23 deg
C or more
UN 3026; Coumarin derivative pesticides, liquid, toxic, NOS
UN 3027; Coumarin derivative pesticides, solid, toxic, NOS
IMO 3.0; Coumarin derivative pesticides, liquid, flammable, toxic, NOS, flashpoint less
than 23 deg C
IMO 6.1; Coumarin derivative pesticides, liquid, toxic, NOS; coumarin derivative
pesticides, liquid, toxic, flammable, NOS, flashpoint 23 deg C or more; coumarin
derivative pesticides, solid, toxic, NOS
EPA Hazardous Waste Number:
P001; (at concentrations greater than 0.3%)
U248; (at concentrations of 0.3% or less)
RTECS Number:
NIOSH/GN4550000
Administrative Information:
Hazardous Substances Databank Number: 1786
Last Revision Date: 20010809
Last Review Date: Reviewed by SRP 11/1/1994
Update History:
Complete Update on 08/09/2001, 1 field added/edited/deleted.
Complete Update on 05/16/2001, 1 field added/edited/deleted.
Complete Update on 09/12/2000, 1 field added/edited/deleted.
Complete Update on 03/09/2000, 1 field added/edited/deleted.
Complete Update on 02/09/2000, 1 field added/edited/deleted.
Complete Update on 02/02/2000, 1 field added/edited/deleted.
Complete Update on 12/27/1999, 1 field added/edited/deleted.
Complete Update on 09/21/1999, 1 field added/edited/deleted.
Complete Update on 08/26/1999, 1 field added/edited/deleted.
Complete Update on 08/24/1999, 5 fields added/edited/deleted.
Complete Update on 06/03/1999, 1 field added/edited/deleted.
Complete Update on 01/27/1999, 1 field added/edited/deleted.
Complete Update on 11/12/1998, 1 field added/edited/deleted.
Complete Update on 10/20/1998, 1 field added/edited/deleted.
Complete Update on 06/02/1998, 1 field added/edited/deleted.
Complete Update on 03/31/1998, 4 fields added/edited/deleted.
Field Update on 10/23/1997, 1 field added/edited/deleted.
Field Update on 05/01/1997, 2 fields added/edited/deleted.
Complete Update on 10/15/1996, 1 field added/edited/deleted.
Complete Update on 06/11/1996, 1 field added/edited/deleted.
Complete Update on 05/10/1996, 1 field added/edited/deleted.
Complete Update on 03/19/1996, 7 fields added/edited/deleted.
Complete Update on 01/21/1996, 1 field added/edited/deleted.
Complete Update on 08/21/1995, 1 field added/edited/deleted.
Complete Update on 06/09/1995, 1 field added/edited/deleted.
Complete Update on 06/07/1995, 56 fields added/edited/deleted.
Field Update on 12/28/1994, 1 field added/edited/deleted.
Field Update on 08/04/1994, 1 field added/edited/deleted.
Complete Update on 03/25/1994, 1 field added/edited/deleted.
Complete Update on 08/07/1993, 1 field added/edited/deleted.
Field update on 12/22/1992, 1 field added/edited/deleted.
Complete Update on 04/27/1992, 1 field added/edited/deleted.
Complete Update on 01/23/1992, 1 field added/edited/deleted.
Field update on 11/09/1990, 1 field added/edited/deleted.
Complete Update on 10/10/1990, 2 fields added/edited/deleted.
Complete Update on 06/04/1990, 6 fields added/edited/deleted.
Field Update on 05/14/1990, 1 field added/edited/deleted.
Field Update on 03/06/1990, 1 field added/edited/deleted.
Field Update on 01/15/1990, 1 field added/edited/deleted.
Complete Update on 01/11/1990, 3 fields added/edited/deleted.
Complete Update on 11/20/1989, 12 fields added/edited/deleted.
Complete Update on 09/03/1987
Record Length: 242184
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