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.

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