Warfarin Sodium (Page 5 of 11)

Lactation

Based on very limited published data, warfarin has not been detected in the breast milk of mothers treated with warfarin. The same limited published data report that some breast-fed infants, whose mothers were treated with warfarin, had prolonged prothrombin times, although not as prolonged as those of the mothers. The decision to breast-feed should be undertaken only after careful consideration of the available alternatives. Women who are breast-feeding and anticoagulated with warfarin should be very carefully monitored so that recommended PT/INR values are not exceeded. It is prudent to perform coagulation tests and to evaluate vitamin K status in infants before advising women taking warfarin to breast-feed. Effects in premature infants have not been evaluated.

Severe to moderate hepatic or renal insufficiency

Infectious diseases or disturbances of intestinal flora: sprue, antibiotic therapy

Trauma which may result in internal bleeding

Surgery or trauma resulting in large exposed raw surfaces

Indwelling catheters

Severe to moderate hypertension

Known or suspected deficiency in protein C mediated anticoagulant response

Hereditary or acquired deficiencies of protein C or its cofactor, protein S, have been associated with tissue necrosis following warfarin administration. Not all patients with these conditions develop necrosis, and tissue necrosis occurs in patients without these deficiencies. Inherited resistance to activated protein C has been described in many patients with venous thromboembolic disorders but has not yet been evaluated as a risk factor for tissue necrosis. The risk associated with these conditions, both for recurrent thrombosis and for adverse reactions, is difficult to evaluate since it does not appear to be the same for everyone. Decisions about testing and therapy must be made on an individual basis. It has been reported that concomitant anticoagulation therapy with heparin for 5 to 7 days during initiation of therapy with warfarin sodium tablets 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.

PRECAUTIONS

Periodic determination of PT/INR is essential (see DOSAGE AND ADMINISTRATION: LABORATORY CONTROL). Numerous factors, alone or in combination, including changes in diet, medications, botanicals and genetic variations in the CYP2C9 and VKORC1 enzymes (see CLINICAL PHARMACOLOGY, Pharmacogenomics) may influence the response of the patient to warfarin.

Drug/Drug and Drug/Disease Interactions

It is generally good practice to monitor the patient’s response with additional PT/INR determinations in the period immediately after discharge from the hospital, and whenever other medications, including botanicals, are initiated, discontinued or taken irregularly. The following factors are listed for reference; however, other factors may also affect the anticoagulant response.

Drugs may interact with warfarin sodium tablets through pharmacodynamic or pharmacokinetic mechanisms. Pharmacodynamic mechanisms for drug interactions with warfarin sodium tablets 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 warfarin sodium tablets 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 —	diarrhea	hyperthyroidism
see CONTRAINDICATIONS	elevated temperature	poor nutritional state
cancer	hepatic disorders	steatorrhea
collagen vascular disease	infectious hepatitis	vitamin K deficiency
congestive heart failure	jaundice

EXOGENOUS FACTORS:

Potential drug interactions with warfarin sodium tablets are listed below by drug class and by specific drugs.

Classes of Drug
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.
5-lipoxygenase Inhibitor	Antiplatelet Drugs/Effects	Leukotriene Receptor Antagonist
Adrenergic Stimulants, Central	Antithyroid Drugs†	Monoamine Oxidase Inhibitors
Alcohol Abuse Reduction	Beta-Adrenergic Blockers	Narcotics, prolonged
Preparations	Cholelitholytic Agents	Nonsteroidal Anti-
Analgesics	Diabetes Agents, Oral	Inflammatory Agents
Anesthetics, Inhalation	Diuretics†	Proton Pump Inhibitors
Antiandrogen	Fungal Medications,	Psychostimulants
Antiarrhythmics†	Intravaginal, Systemic†	Pyrazolones
Antibiotics†	Gastric Acidity and Peptic	Salicylates
Aminoglycosides (oral)	Ulcer Agents†	Selective Serotonin
Cephalosporins, parenteral	Gastrointestinal	Reuptake Inhibitors
Macrolides	Prokinetic Agents	Steroids, Adrenocortical†
Miscellaneous	Ulcerative Colitis Agents	Steroids, Anabolic (17-Alkyl
Penicillins, intravenous,	Gout Treatment Agents	Testosterone Derivatives)
high dose	Hemorrheologic Agents	Thrombolytics
Quinolones (fluoroquinolones)	Hepatotoxic Drugs	Thyroid Drugs
Sulfonamides, long acting	Hyperglycemic Agents	Tuberculosis Agents†
Tetracyclines	Hypertensive Emergency Agents	Uricosuric Agents
Anticoagulants	Hypnotics†	Vaccines
Anticonvulsants†	Hypolipidemics†	Vitamins†
Antidepressants†	Bile Acid-Binding Resins†
Antimalarial Agents	Fibric Acid Derivatives
Antineoplastics†	HMG-CoA Reductase Inhibitors†
Antiparasitic/Antimicrobials
Specific Drugs Reported
acetaminophen	fenoprofen	paroxetine
alcohol *	fluconazole	penicillin G, intravenous
allopurinol	fluorouracil	pentoxifylline
aminosalicylic acid	fluoxetine	phenylbutazone
amiodarone HCl	flutamide	phenytoin *
argatroban	fluvastatin	piperacillin
aspirin	fluvoxamine	piroxicam
atenolol	gefitinib	pravastatin *
atorvastatin *	gemfibrozil	prednisone *
azithromycin	glucagon	propafenone
bivalirudin	halothane	propoxyphene
capecitabine	heparin	propranolol
cefamandole	ibuprofen	propylthiouracil *
cefazolin	ifosfamide	quinidine
cefoperazone	indomethacin	quinine
cefotetan	influenza virus vaccine	rabeprazole
cefoxitin	itraconazole	ranitidine *
ceftriaxone	ketoprofen	rofecoxib
celecoxib	ketorolac	sertraline
cerivastatin	lansoprazole	simvastatin
chenodiol	lepirudin	stanozolol
chloramphenicol	levamisole	streptokinase
chloral hydrate *	levofloxacin	sulfamethizole
chlorpropamide	levothyroxine	sulfamethoxazole
cholestyramine *	liothyronine	sulfinpyrazone
cimetidine	lovastatin	sulfisoxazole
ciprofloxacin	mefenamic acid	sulindac
cisapride	methimazole *	tamoxifen
clarithromycin	methyldopa	tetracycline
clofibrate	methylphenidate	thyroid
warfarin sodium overdose	methylsalicylate ointment (topical)	ticarcillin
cyclophosphamide *	metronidazole	ticlopidine
danazol	miconazole	tissue plasminogen
dextran	(intravaginal, oral, systemic)	activator (t-PA)
dextrothyroxine	moricizine hydrochloride *	tolbutamide
diazoxide	nalidixic acid	tramadol
diclofenac	naproxen	trimethoprim/sulfamethoxazole
dicumarol	neomycin	urokinase
diflunisal	norfloxacin	valdecoxib
disulfiram	ofloxacin	valproate
doxycycline	olsalazine	vitamin E
erythromycin	omeprazole	zafirlukast
esomeprazole	oxandrolone	zileuton
ethacrynic acid	oxaprozin
ezetimibe	oxymetholone
fenofibrate	pantoprazole

The following factors, alone or in combination, may be responsible for DECREASED PT/INR response:

ENDOGENOUS FACTORS:

edema	hypothyroidism
hereditary coumarin resistance	nephrotic syndrome
hyperlipemia

EXOGENOUS FACTORS:

Potential drug interactions with warfarin sodium tablets are listed below by drug class and by specific drugs.

Classes of Drugs
also: diet high in vitamin K unreliable PT/INR determinations
* Increased and decreased PT/INR responses have been reported.
Adrenal Cortical Steroid Inhibitors	Antipsychotic Medications	Hypolipidemics†
Antacids	Antithyroid Drugs†	Bile Acid-Binding Resins†
Antianxiety Agents Antiarrhythmics†	Barbiturates Diuretics†	HMG-CoA Reductase Inhibitors†
Anticonvulsants†	Enteral Nutritional Supplements	Immunosuppressives
Antidepressants†	Fungal Medications, Systemic†	Oral Contraceptives,
Antihistamines	Gastric Acidity and Peptic Ulcer Agents†	Estrogen Containing
Antineoplastics†	Hypnotics†	Selective Estrogen Receptor Modulators
		Steroids, Adrenocortical†
		Tuberculosis Agents† Vitamins†
Specific Drugs Reported:
alcohol *	warfarin sodium underdosage	phenytoin *
aminoglutethimide	cyclophosphamide *	pravastatin *
amobarbital	dicloxacillin	prednisone *
atorvastatin *	ethchlorvynol	primidone
azathioprine	glutethimide	propylthiouracil *
butabarbital	griseofulvin	raloxifene
butalbital	haloperidol	ranitidine *
carbamazepine	meprobamate	rifampin
chloral hydrate *	6-mercaptopurine	secobarbital
chlordiazepoxide	methimazole *	spironolactone
chlorthalidone	moricizine hydrochloride *	sucralfate
cholestyramine *	nafcillin	trazodone
clozapine	paraldehyde	vitamin C (high dose)
corticotropin	pentobarbital	vitamin K
cortisone	phenobarbital

Because a patient may be exposed to a combination of the above factors, the net effect of warfarin sodium tablets 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.