Phenindione
Soft, odourless or almost odourless, white or creamy-white
crystals. Very slightly soluble in water; slightly soluble in al-
cohol and in ether; freely soluble in chloroform. Solutions are
yellow to red.
Adverse Effects,Treatment & Precautions are
As for Warfarin Sodium whose details are given below
INDICATIONS AND USAGE:
WARF (Warfarin Sodium) is indicated for the prophylaxis and/or treatment of
venous thrombosis and its extension, and pulmonary embolism.
WARF is indicated for the prophylaxis and/or treatment of the thromboembolic
complications associated with atrial fibrillation and/or cardiac valve
replacement.
WARF is indicated to reduce the risk of death, recurrent myocardial
infarction, and thromboembolic events such as stroke or systemic embolization
after myocardial infarction.
CONTRAINDICATIONS:
Anticoagulation is contraindicated in any localized or general physical
condition or personal circumstance in which the hazard of hemorrhage might be
greater than the potential clinical benefits of anticoagulation, such as:
PREGNANCY: WARF is contraindicated in women who are or may become pregnant
because the drug passes through the placental barrier and may cause fatal
hemorrhage to the fetus In Utero. Furthermore, there have been reports of birth
malformations in children born to mothers who have been treated with warfarin
during pregnancy.
Embryopathy characterized by nasal hypoplasia with or without stippled epiphyses
(chondrodysplasia punctata) has been reported in pregnant women exposed to
warfarin during the first trimester. Central nervous system abnormalities also
have been reported, including dorsal midline dysplasia characterized by agenesis
of the corpus callosum, Dandy-Walker malformation, and midline cerebellar
atrophy. Ventral midline dysplasia, characterized by optic atrophy, and eye
abnormalities have been observed. Mental retardation, blindness, and other
central nervous system abnormalities have been reported in association with
second and third trimester exposure. Although rare, teratogenic reports
following In Utero exposure to warfarin include urinary tract anomalies such as
single kidney, asplenia, anencephaly, spina bifida, cranial nerve palsy,
hydrocephalus, cardiac defects and congenital heart disease, polydactyly,
deformities of toes, diaphragmatic hernia, corneal leukoma, cleft palate, cleft
lip, schizencephaly, and microcephaly.
Spontaneous abortion and still birth are known to occur and a higher risk of
fetal mortality is associated with the use of warfarin. Low birth weight and
growth retardation have also been reported.
Women of childbearing potential who are candidates for anticoagulant therapy
should be carefully evaluated and the indications critically reviewed with the
patient. If the patient becomes pregnant while taking this drug, she should be
apprised of the potential risks to the fetus, and the possibility of termination
of the pregnancy should be discussed in light of those risks.
HEMORRHAGIC TENDENCIES OR BLOOD DYSCRASIAS.
RECENT OR CONTEMPLATED SURGERY OF: (1) central nervous system; (2) eye; (3)
traumatic surgery resulting in large open surfaces.
BLEEDING TENDENCIES ASSOCIATED WITH ACTIVE ULCERATION OR OVERT BLEEDING OF: (1)
gastrointestinal, genitourinary or respiratory tracts; (2) cerebrovascular
hemorrhage; (3) aneurysms-cerebral, dissecting aorta; (4) pericarditis and
pericardial effusions; (5) bacterial endocarditis.
THREATENED ABORTION, eclampsia and preeclampsia.
INADEQUATE LABORATORY FACILITIES.
UNSUPERVISED PATIENTS WITH SENILITY, alcoholism, or psychosis or other lack of
patient cooperation.
SPINAL PUNCTURE and other diagnostic or therapeutic procedures with potential
for uncontrollable bleeding.
MISCELLANEOUS: major regional, lumbar block anesthesia and malignant
hypertension and known hypersensitivity to warfarin or to any other components
of this product.
WARNINGS:
The most serious risks associated with anticoagulant therapy with sodium
warfarin are hemorrhage in any tissue or organ and, less frequently (<0.1%),
necrosis and/or gangrene of skin and other tissues. The risk of hemorrhage is
related to the level of intensity and the duration of anticoagulant therapy.
Hemorrhage and necrosis have in some cases been reported to result in death or
permanent disability. Necrosis appears to be associated with local thrombosis
and usually appears within a few days of the start of anticoagulant therapy. In
severe cases of necrosis, treatment through debridement or amputation of the
affected tissue, limb, breast or penis has been reported. Careful diagnosis is
required to determine whether necrosis is caused by an underlying disease.
Warfarin therapy should be discontinued when warfarin is suspected to be the
cause of developing necrosis and heparin therapy may be considered for
anticoagulation. Although various treatments have been attempted, no treatment
for necrosis has been considered uniformly effective. See below for information
on predisposing conditions. These and other risks associated with anticoagulant
therapy must be weighed against the risk of thrombosis or embolization in
untreated cases.
It cannot be emphasized too strongly that treatment of each patient is a highly
individualized matter. WARF, a narrow therapeutic range (index) drug, may be
affected by factors such as other drugs and dietary Vitamin K. Dosage should be
controlled by periodic determinations of prothrombin time (PT)/International
Normalized Ratio (INR) or other suitable coagulation tests. Determinations of
whole blood clotting and bleeding times are not effective measures for control
of therapy. Heparin prolongs the one-stage PT. When heparin and WARF are
administered concomitantly, refer below to CONVERSION FROM HEPARIN THERAPY for
recommendations.
Caution should be observed when WARF is administered in any situation or in
the presence of any predisposing condition where added risk of hemorrhage or
necrosis is present.
Anticoagulation therapy with WARF may enhance the release of atheromatous
plaque emboli, thereby increasing the risk of complications from systemic
cholesterol microembolization, including the "purple toes syndrome."
Discontinuation of WARF therapy is recommended when such phenomena are
observed.
Systemic atheroemboli and cholesterol microemboli can present with a variety of
signs and symptoms including purple toes syndrome, livedo reticularis, rash,
gangrene, abrupt and intense pain in the leg, foot, or toes, foot ulcers,
myalgia, penile gangrene, abdominal pain, flank or back pain, hematuria, renal
insufficiency, hypertension, cerebral ischemia, spinal cord infarction,
pancreatitis, symptoms simulating polyarteritis, or any other sequelae of
vascular compromise due to embolic occlusion. The most commonly involved
visceral organs are the kidneys followed by the pancreas, spleen, and liver.
Some cases have progressed to necrosis or death.
Purple toes syndrome is a complication of oral anticoagulation characterized by
a dark, purplish or mottled color of the toes, usually occurring between 3-10
weeks, or later, after the initiation of therapy with warfarin or related
compounds. Major features of this syndrome include purple color of plantar
surfaces and sides of the toes that blanches on moderate pressure and fades with
elevation of the legs; pain and tenderness of the toes; waxing and waning of the
color over time. While the purple toes syndrome is reported to be reversible,
some cases progress to gangrene or necrosis which may require debridement of the
affected area, or may lead to amputation.
A severe elevation (>50 seconds) in activated partial thromboplastin time (aPTT)
with a PT/INR in the desired range has been identified as an indication of
increased risk of postoperative hemorrhage.
The decision to administer anticoagulants in the following conditions must be
based upon clinical judgment in which the risks of anticoagulant therapy are
weighed against the benefits:
LACTATION: WARF appears in the milk of nursing mothers in an inactive form.
Infants nursed by WARF treated mothers had no change in prothrombin times
(PTs). Effects in premature infants have not been evaluated.
SEVERE TO MODERATE HEPATIC OR RENAL INSUFFICIENCY.
INFECTIOUS DISEASES OR DISTURBANCES OF INTESTINAL FLORA: sprue, antibiotic
therapy.
TRAUMA which may result in internal bleeding.
SURGERY OR TRAUMA resulting in large exposed raw surfaces.
INDWELLING CATHETERS.
SEVERE TO MODERATE HYPERTENSION.
KNOWN OR SUSPECTED DEFICIENCY IN PROTEIN C MEDIATED ANTICOAGULANT RESPONSE:
Hereditary or acquired deficiencies of protein C or its cofactor, protein S,
have been associated with tissue necrosis following warfarin administration. Not
all patients with these conditions develop necrosis, and tissue necrosis occurs
in patients without these deficiencies. Inherited resistance to activated
protein C has been described in many patients with venous thromboembolic
disorders but has not yet been evaluated as a risk factor for tissue necrosis.
The risk associated with these conditions, both for recurrent thrombosis and for
adverse reactions, is difficult to evaluate since it does not appear to be the
same for everyone. Decisions about testing and therapy must be made on an
individual basis. It has been reported that concomitant anticoagulation therapy
with heparin for 5 to 7 days during initiation of therapy with WARF may
minimize the incidence of tissue necrosis. Warfarin therapy should be
discontinued when warfarin is suspected to be the cause of developing necrosis
and heparin therapy may be considered for anticoagulation.
MISCELLANEOUS: polycythemia vera, vasculitis, and severe diabetes.
Minor and severe allergic/hypersensitivity reactions and anaphylactic reactions
have been reported.
In patients with acquired or inherited warfarin resistance, decreased
therapeutic responses to WARF have been reported. Exaggerated therapeutic
responses have been reported in other patients.
Patients with congestive heart failure may exhibit greater than expected PT/INR
response to WARF, thereby requiring more frequent laboratory monitoring, and
reduced doses of WARF.
Concurrent use of anticoagulants with streptokinase or urokinase is not
recommended and may be hazardous. (Please note recommendations accompanying
these preparations.)
PRECAUTIONS:
PERIODIC DETERMINATION OF PT/INR OR OTHER SUITABLE COAGULATION TEST IS
ESSENTIAL.
NUMEROUS FACTORS, ALONE OR IN COMBINATION, INCLUDING TRAVEL, CHANGES IN DIET,
ENVIRONMENT, PHYSICAL STATE AND MEDICATION MAY INFLUENCE RESPONSE OF THE PATIENT
TO ANTICOAGULANTS. IT IS GENERALLY GOOD PRACTICE TO MONITOR THE PATIENT'S
RESPONSE WITH ADDITIONAL PT/INR DETERMINATIONS IN THE PERIOD IMMEDIATELY AFTER
DISCHARGE FROM THE HOSPITAL, AND WHENEVER OTHER MEDICATIONS ARE INITIATED,
DISCONTINUED OR TAKEN IRREGULARLY. THE FOLLOWING FACTORS ARE LISTED FOR
REFERENCE; HOWEVER, OTHER FACTORS MAY ALSO AFFECT THE ANTICOAGULANT RESPONSE.
DRUGS MAY INTERACT WITH WARF THROUGH PHARMACODYNAMIC OR PHARMACOKINETIC
MECHANISMS. PHARMACODYNAMIC MECHANISMS FOR DRUG INTERACTIONS WITH WARF ARE
SYNERGISM (IMPAIRED HEMOSTASIS, REDUCED CLOTTING FACTOR SYNTHESIS), COMPETITIVE
ANTAGONISM (VITAMIN K), AND ALTERED PHYSIOLOGIC CONTROL LOOP FOR VITAMIN K
METABOLISM (HEREDITARY RESISTANCE). PHARMACOKINETIC MECHANISMS FOR DRUG
INTERACTIONS WITH WARF ARE MAINLY ENZYME INDUCTION, ENZYME INHIBITION, AND
REDUCED PLASMA PROTEIN BINDING. IT IS IMPORTANT TO NOTE THAT SOME DRUGS MAY
INTERACT BY MORE THAN ONE MECHANISM.
THE FOLLOWING FACTORS, ALONE OR IN COMBINATION, MAY BE RESPONSIBLE FOR INCREASED
PT/INR RESPONSE:
ENDOGENOUS FACTORS:
blood dyscrasias--see CONTRAINDICATIONS
cancer
collagen vascular disease
congestive heart failure
diarrhea
elevated temperature
hepatic disorders
infectious hepatitis
jaundice
hyperthyroidism
poor nutritional state
steatorrhea
vitamin K deficiency
EXOGENOUS FACTORS:
POTENTIAL DRUG INTERACTIONS WITH WARF ARE LISTED BELOW BY DRUG CLASS AND BY
SPECIFIC DRUGS.
CLASSES OF DRUGS
Adrenergic Stimulants, Central
Alcohol Abuse Reduction Preparations
Analgesics
Anesthetics, Inhalation
Antiarrhythmics*
Antibiotics*
Aminoglycosides (oral)
Cephalosporins, parenteral
Macrolides
Miscellaneous
Penicillins, intravenous, high dose
Quinolones (fluoroquinolones)
Sulfonamides, long acting
Tetracyclines
Anticoagulants
Anticonvulsants*
Antidepressants*
Antimalarial Agents
Antineoplastics*
Antiparasitic/Antimicrobials
Antiplatelet Drugs/Effects
Antithyroid Drugs*
Beta-Adrenergic Blockers
Bromelains
Cholelitholytic Agents
Diabetes Agents, Oral
Diuretics*
Fungal Medications, Systemic*
Gastric Acidity and Peptic Ulcer Agents*
Gastrointestinal, Ulcerative Colitis Agents
Gout Treatment Agents
Hemorrheologic Agents
Hepatotoxic Drugs
Hyperglycemic Agents
Hypertensive Emergency Agents
Hypnotics*
Hypolipidemics*
Monoamine Oxidase Inhibitors
Narcotics, prolonged
Nonsteroidal Anti-Inflammatory Agents
Psychostimulants
Pyrazolones
Salicylates
Selective Serotonin Reuptake Inhibitors
Steroids, Adrenocortical*
Steroids, Anabolic (17-Alkyl Testosterone Derivatives)
Thrombolytics
Thyroid Drugs
Tuberculosis Agents*
Uricosuric Agents
Vaccines
Vitamins*
SPECIFIC DRUGS REPORTED
acetaminophen
alcohol*
allopurinol
aminosalicylic acid
amiodarone HCl
aspirin
azithromycin
cefamandole
cefazolin
cefoperazone
cefotetan
cefoxitin
ceftriaxone
chenodiol
chloramphenicol
chloral hydrate*
chlorpropamide
cholestyramine*
cimetidine
ciprofloxacin
clarithromycin
clofibrate
WARF overdose
cyclophosphamide*
danazol
dextran
dextrothyroxine
diazoxide
diclofenac
dicumarol
diflunisal
disulfiram
doxycycline
erythromycin
ethacrynic acid
fenoprofen
fluconazole
fluorouracil
fluoxetine
fluvoxamine
glucagon
halothane
heparin
ibuprofen
ifosfamide
indomethacin
influenza virus vaccine
itraconazole
ketoprofen
ketorolac
levamisole
levothyroxine
liothyronine
lovastatin
mefenamic acid
methimazole*
methyldopa
methylphenidate
methylsalicylate ointment (topical)
metronidazole
miconazole
moricizine hydrochloride*
nalidixic acid
naproxen
neomycin
norfloxacin
ofloxacin
olsalazine
omeprazole
oxaprozin
oxymetholone
paroxetine
penicillin G, intravenous
pentoxifylline
phenylbutazone
phenytoin*
piperacillin
piroxicam
prednisone*
propafenone
propoxyphene
propranolol
propylthiouracil*
quinidine
quinine
ranitidine*
sertraline
simvastatin
stanozolol
streptokinase
sulfamethizole
sulfamethoxazole
sulfinpyrazone
sulfisoxazole
sulindac
tamoxifen
tetracycline
thyroid
ticarcillin
ticlopidine
tissue plasminogen activator (t-PA)
tolbutamide
trimethoprim/sulfamethoxazole
urokinase
valproate
vitamin E
also: other medications affecting blood elements which may modify hemostasis
dietary deficiencies
prolonged hot weather
unreliable PT/INR determinations
----------
* Increased and decreased PT/INR responses have been reported.
----------
THE FOLLOWING FACTORS, ALONE OR IN COMBINATION, MAY BE RESPONSIBLE FOR DECREASED
PT/INR RESPONSE:
ENDOGENOUS FACTORS:
edema
hereditary coumarin resistance
hyperlipemia
hypothyroidism
nephrotic syndrome
EXOGENOUS FACTORS:
POTENTIAL DRUG INTERACTIONS WITH WARF ARE LISTED BELOW BY DRUG CLASS AND BY
SPECIFIC DRUGS.
CLASSES OF DRUGS
Adrenal Cortical Steroid Inhibitors
Antacids
Antianxiety Agents
Antiarrhythmics*
Antibiotics*
Anticonvulsants*
Antidepressants*
Antihistamines
Antineoplastics*
Antipsychotic Medications
Antithyroid Drugs*
Barbiturates
Diuretics*
Enteral Nutritional Supplements
Fungal Medications, Systemic*
Gastric Acidity and Peptic Ulcer
Agents*
Hypnotics*
Hypolipidemics*
Immunosuppressives
Oral Contraceptives, Estrogen Containing
Steroids, Adrenocortical*
Tuberculosis Agents*
Vitamins*
SPECIFIC DRUGS REPORTED
alcohol*
aminoglutethimide
amobarbital
azathioprine
butabarbital
butalbital
carbamazepine
chloral hydrate*
chlordiazepoxide
chlorthalidone
cholestyramine*
corticotropin
cortisone
WARF underdosage
cyclophosphamide*
dicloxacillin
ethchlorvynol
glutethimide
griseofulvin
haloperidol
meprobamate
6-mercaptopurine
methimazole*
moricizine hydrochloride*
nafcillin
paraldehyde
pentobarbital
phenobarbital
phenytoin*
prednisone*
primidone
propylthiouracil*
ranitidine*
rifampin
secobarbital
spironolactone
sucralfate
trazodone
vitamin C (high dose)
vitamin K
also: diet high in vitamin K
unreliable PT/INR determinations
----------
* Increased and decreased PT/INR responses have been reported.
----------
Because a patient may be exposed to a combination of the above factors, the net
effect of WARF on PT/INR response may be unpredictable. More frequent PT/INR
monitoring is therefore advisable. Medications of unknown interaction with
coumarins are best regarded with caution. When these medications are started or
stopped, more frequent PT/INR monitoring is advisable.
It has been reported that concomitant administration of warfarin and ticlopidine
may be associated with cholestatic hepatitis.
EFFECT ON OTHER DRUGS: Coumarins may also affect the action of other drugs.
Hypoglycemic agents (chlorpropamide and tolbutamide) and anticonvulsants
(phenytoin and phenobarbital) may accumulate in the body as a result of
interference with either their metabolism or excretion.
SPECIAL RISK PATIENTS: WARF is a narrow therapeutic range (index) drug, and
caution should be observed when warfarin sodium is administered to certain
patients such as the elderly or debilitated or when administered in any
situation or physical condition where added risk of hemorrhage is present.
Intramuscular (I.M.) injections of concomitant medications should be confined to
the upper extremities which permits easy access for manual compression,
inspections for bleeding and use of pressure bandages.
Caution should be observed when WARF (or warfarin) is administered
concomitantly with nonsteroidal anti-inflammatory drugs (NSAIDs), including
aspirin, to be certain that no change in anticoagulation dosage is required. In
addition to specific drug interactions that might affect PT/INR, NSAIDs,
including aspirin, can inhibit platelet aggregation, and can cause
gastrointestinal bleeding, peptic ulceration and/or perforation.
Acquired or inherited warfarin resistance should be suspected if large daily
doses of WARF are required to maintain a patient's PT/INR within a normal
therapeutic range.
INFORMATION FOR PATIENTS: The objective of anticoagulant therapy is to decrease
the clotting ability of the blood so that thrombosis is prevented, while
avoiding spontaneous bleeding. Effective therapeutic levels with minimal
complications are in part dependent upon cooperative and well-instructed
patients who communicate effectively with their physician. Patients should be
advised: Strict adherence to prescribed dosage schedule is necessary. Do not
take or discontinue any other medication, including salicylates (e.g., aspirin
and topical analgesics) and other over-the-counter medications except on advice
of the physician. Avoid alcohol consumption. Do not take WARF during
pregnancy and do not become pregnant while taking it (see CONTRAINDICATIONS).
Avoid any activity or sport that may result in traumatic injury. Prothrombin
time tests and regular visits to physician or clinic are needed to monitor
therapy. Carry identification stating that WARF is being taken. If the
prescribed dose of WARF is forgotten, notify the physician immediately. Take
the dose as soon as possible on the same day but do not take a double dose of
WARF the next day to make up for missed doses. The amount of vitamin K in
food may affect therapy with WARF. Eat a normal, balanced diet maintaining a
consistent amount of vitamin K. Avoid drastic changes in dietary habits, such as
eating large amounts of green leafy vegetables. Contact physician to report any
illness, such as diarrhea, infection or fever. Notify physician immediately if
any unusual bleeding or symptoms occur. Signs and symptoms of bleeding include:
pain, swelling or discomfort, prolonged bleeding from cuts, increased menstrual
flow or vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual
bleeding or bruising, red or dark brown urine, red or tar black stools,
headache, dizziness, or weakness. If therapy with WARF is discontinued,
patients should be cautioned that the anticoagulant effects of WARF may
persist for about 2 to 5 days.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY: Carcinogenicity and
mutagenicity studies have not been performed with WARF. The reproductive
effects of WARF have not been evaluated.
USE IN PREGNANCY: Pregnancy Category X--See CONTRAINDICATIONS.
PEDIATRIC USE: Safety and effectiveness in pediatric patients below the age of
18 have not been established, in randomized, controlled clinical trials.
However, the use of WARF in pediatric patients is well-documented for the
prevention and treatment of thromboembolic events. Difficulty achieving and
maintaining therapeutic PT/INR ranges in the pediatric patient has been
reported. More frequent PT/INR determinations are recommended because of
possible changing warfarin requirements.
DRUG INTERACTIONS:
POTENTIAL DRUG INTERACTIONS WITH WARF ARE LISTED BELOW BY DRUG CLASS AND BY
SPECIFIC DRUGS.
CLASSES OF DRUGS
Adrenergic Stimulants, Central
Alcohol Abuse Reduction Preparations
Analgesics
Anesthetics, Inhalation
Antiarrhythmics*
Antibiotics*
Aminoglycosides (oral)
Cephalosporins, parenteral
Macrolides
Miscellaneous
Penicillins, intravenous, high dose
Quinolones (fluoroquinolones)
Sulfonamides, long acting
Tetracyclines
Anticoagulants
Anticonvulsants*
Antidepressants*
Antimalarial Agents
Antineoplastics*
Antiparasitic/Antimicrobials
Antiplatelet Drugs/Effects
Antithyroid Drugs*
Beta-Adrenergic Blockers
Bromelains
Cholelitholytic Agents
Diabetes Agents, Oral
Diuretics*
Fungal Medications, Systemic*
Gastric Acidity and Peptic Ulcer Agents*
Gastrointestinal, Ulcerative Colitis Agents
Gout Treatment Agents
Hemorrheologic Agents
Hepatotoxic Drugs
Hyperglycemic Agents
Hypertensive Emergency Agents
Hypnotics*
Hypolipidemics*
Monoamine Oxidase Inhibitors
Narcotics, prolonged
Nonsteroidal Anti-Inflammatory Agents
Psychostimulants
Pyrazolones
Salicylates
Steroids, Adrenocortical*
Steroids, Anabolic (17-Alkyl Testosterone Derivatives)
Thrombolytics
Thyroid Drugs
Tuberculosis Agents*
Uricosuric Agents
Vaccines
Vitamins*
SPECIFIC DRUGS REPORTED
acetaminophen
alcohol*
allopurinol
aminosalicylic acid
amiodarone HCl
aspirin
cefamandole
cefazolin
cefoperazone
cefotetan
cefoxitin
ceftriaxone
chenodiol
chloramphenicol
chloral hydrate*
chlorpropamide
cholestyramine*
cimetidine
ciprofloxacin
clarithromycin
clofibrate
WARF overdose
cyclophosphamide*
danazol
dextran
dextrothyroxine
diazoxide
diclofenac
dicumarol
diflunisal
disulfiram
doxycycline
erythromycin
ethacrynic acid
fenoprofen
fluconazole
fluorouracil
glucagon
halothane
heparin
ibuprofen
ifosfamide
indomethacin
influenza virus vaccine
itraconazole
ketoprofen
ketorolac
levamisole
levothyroxine
liothyronine
lovastatin
mefenamic acid
methimazole*
methyldopa
methylphenidate
methylsalicylate ointment (topical)
metronidazole
miconazole
moricizine hydrochloride*
nalidixic acid
naproxen
neomycin
norfloxacin
ofloxacin
olsalazine
omeprazole
oxaprozin
oxymetholone
paroxetine
penicillin G, intravenous
pentoxifylline
phenylbutazone
phenytoin*
piperacillin
piroxicam
prednisone*
propafenone
propoxyphene
propranolol
propylthiouracil*
quinidine
quinine
ranitidine*
sertraline
simvastatin
stanozolol
streptokinase
sulfamethizole
sulfamethoxazole
sulfinpyrazone
sulfisoxazole
sulindac
tamoxifen
tetracycline
thyroid
ticarcillin
ticlopidine
tissue plasminogen activator (t-PA)
tolbutamide
trimethoprim/sulfamethoxazole
urokinase
valproate
vitamin E
also: other medications affecting blood elements which may modify hemostasis
dietary deficiencies
prolonged hot weather
unreliable PT/INR determinations
----------
* Increased and decreased PT/INR responses have been reported.
----------
THE FOLLOWING FACTORS, ALONE OR IN COMBINATION, MAY BE RESPONSIBLE FOR DECREASED
PT/INR RESPONSE:
ENDOGENOUS FACTORS:
edema
hereditary coumarin resistance
hyperlipemia
hypothyroidism
nephrotic syndrome
EXOGENOUS FACTORS:
POTENTIAL DRUG INTERACTIONS WITH WARF ARE LISTED BELOW BY DRUG CLASS AND BY
SPECIFIC DRUGS.
CLASSES OF DRUGS
Adrenal Cortical Steroid Inhibitors
Antacids
Antianxiety Agents
Antiarrhythmics*
Antibiotics*
Anticonvulsants*
Antidepressants*
Antihistamines
Antineoplastics*
Antipsychotic Medications
Antithyroid Drugs*
Barbiturates
Diuretics*
Enteral Nutritional Supplements
Fungal Medications, Systemic*
Gastric Acidity and Peptic Ulcer
Agents*
Hypnotics*
Hypolipidemics*
Immunosuppressives
Oral Contraceptives, Estrogen Containing
Steroids, Adrenocortical*
Tuberculosis Agents*
Vitamins*
SPECIFIC DRUGS REPORTED
alcohol*
aminoglutethimide
amobarbital
azathioprine
butabarbital
butalbital
carbamazepine
chloral hydrate*
chlordiazepoxide
chlorthalidone
cholestyramine*
corticotropin
cortisone
WARF underdosage
cyclophosphamide*
dicloxacillin
ethchlorvynol
glutethimide
griseofulvin
haloperidol
meprobamate
methimazole*
moricizine hydrochloride*
nafcillin
paraldehyde
pentobarbital
phenobarbital
phenytoin*
prednisone*
primidone
propylthiouracil*
ranitidine*
rifampin
secobarbital
spironolactone
sucralfate
trazodone
vitamin C (high dose)
vitamin K
also: diet high in vitamin K
unreliable PT/INR determinations
----------
* Increased and decreased PT/INR responses have been reported.
----------
Because a patient may be exposed to a combination of the above factors, the net
effect of WARF on PT/INR response may be unpredictable. More frequent PT/INR
monitoring is therefore advisable. Medications of unknown interaction with
coumarins are best regarded with caution. When these medications are started or
stopped, more frequent PT/INR monitoring is advisable.
It has been reported that concomitant administration of warfarin and ticlopidine
may be associated with cholestatic hepatitis.
EFFECT ON OTHER DRUGS: Coumarins may also affect the action of other drugs.
Hypoglycemic agents (chlorpropamide and tolbutamide) and anticonvulsants
(phenytoin and phenobarbital) may accumulate in the body as a result of
interference with either their metabolism or excretion.
ADVERSE REACTIONS:
Potential adverse reactions to WARF may include:
-- Fatal or nonfatal hemorrhage from any tissue or organ. This is a consequence
of the anticoagulant effect. The signs, symptoms, and severity will vary
according to the location and degree or extent of the bleeding. Hemorrhagic
complications may present as paralysis; paresthesia; headache, chest, abdomen,
joint, muscle or other pain; dizziness; shortness of breath, difficult breathing
or swallowing; unexplained swelling; weakness; hypotension; or unexplained
shock. Therefore, the possibility of hemorrhage should be considered in
evaluating the condition of any anticoagulated patient with complaints which do
not indicate an obvious diagnosis. Bleeding during anticoagulant therapy does
not always correlate with PT/INR. (See OVERDOSAGE--Treatment.)
-- Bleeding which occurs when the PT/INR is within the therapeutic range
warrants diagnostic investigation since it may unmask a previously unsuspected
lesion, e.g., tumor, ulcer, etc.
-- Necrosis of skin and other tissues. (See WARNINGS.)
-- Adverse reactions reported infrequently include: hypersensitivity/allergic
reactions, systemic cholesterol microembolization, purple toes syndrome,
hepatitis, cholestatic hepatic injury, jaundice, elevated liver enzymes,
vasculitis, edema, fever, rash, dermatitis, including bullous eruptions,
urticaria, abdominal pain including cramping, flatulence/bloating, fatigue,
lethargy, malaise, asthenia, nausea, vomiting, diarrhea, pain, headache,
dizziness, taste perversion, pruritus, alopecia, cold intolerance, and
paresthesia including feeling cold and chills.
Rare events of tracheal or tracheobronchial calcification have been reported in
association with long-term warfarin therapy. The clinical significance of this
event is unknown.
Priapism has been associated with anticoagulant administration, however, a
causal relationship has not been established.
Pharmacokinetics
Phenindione is absorbed from the gastro-intestinal tract. It
diffuses across the placenta and is distributed into breast milk.
Metabolites of phenindione excreted in the urine are respon-
sible for any discoloration.
Uses and Administration
Phenindione is an orally administered indanedione anticoag-
ulant with actions similar to those of warfarin sodium.
It is used in the management of thrombo-embolic disorders, but
because of its higher incidence of severe adverse
effects it is now rarely employed.
The usual initial dose of phenindione is 200 mg on the first
day, 100 mg on the second day, and then maintenance doses
of 50 to 150 mg daily according to coagulation tests.