Warfarin Sodium (Page 4 of 8)

PRECAUTIONS

Periodic determination of PT/INR or other suitable coagulation test is essential (see DOSAGE ANDADMINISTRATION: LABORATORY CONTROL ).

Drug-Drug and Drug-Disease Interactions

Numerous factors, alone or in combination, including changes in diet, and medications, including botanicals, 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, 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 through pharmacodynamic or pharmacokinetic mechanisms. Pharmacodynamic mechanisms for drug interactions with warfarin sodium 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 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- hepatic disorders
See CONTRAINDICATIONS infectious hepatitis
cancer jaundice
collagen vascular disease hyperthyroidism
congestive heart failure poor nutritional state
diarrhea steatorrhea
elevated temperature vitamin K deficiency

EXOGENOUS FACTORS:

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

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

also: other medications affecting blood elements which may modify hemostasis

dietary deficiencies

prolonged hot weather

unreliable PT/INR determinations

†lncreased 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 hypothyroidism
hereditary coumarin resistance nephrotic syndrome
hyperlipemia

EXOGENOUS FACTORS:

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

Classes of Drugs
Adrenal Cortical Steroid Antihistamines Gastric Acidity and Peptic Ulcer Oral Contraceptives, Estrogen
Inhibitors Antineoplastics† Agents† Containing
Antacids Antipsychotic Medications Hypnotics† Selective Estrogen Receptor
Antianxiety Agents Antithyroid Drugs† Hypolipidemics† Modulators
Antiarrhythmics† Barbiturates Bile Acid-Binding Resins† Steroids, Adrenocortical†
Antibiotics† Diuretics† HMG-CoA Reductase Tuberculosis Agents†
Anticonvulsants† Enteral Nutritional Supplements Inhibitors† Vitamins†
Antidepressants† Fungal Medications, Systemic† Immunosuppressives

Specific Drugs Reported
alcohol† cholestyramine† 6-mercaptopurine propylthiouracil†
aminoglutethimide clozapine methimazole† raloxifene
amobarbital corticotropin moricizine hydrochloride† ranitidine†
atorvastatin† cortisone nafcillin rifampin
azathioprine cyclophosphamide† paraldehyde secobarbital
butabarbital dicloxacillin pentobarbital spironolactone
butalbital ethchlorvynol phenobarbital sucralfate
carbamazepine glutethimide phenytoin† trazodone
chloral hydrate† griseofulvin pravastatin† vitamin C (high dose)
chlordiazepoxide haloperidol prednisone† vitamin K
chlorthalidone meprobamate primidone warfarin underdosage

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 warfarin sodium 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.

Botanical (Herbal) Medicines: Caution should be exercised when botanical medicines (botanicals) are taken concomitantly with warfarin sodium. Few adequate, well-controlled studies exist evaluating the potential for metabolic and/or pharmacologic interactions between botanicals and warfarin sodium. Due to a lack of manufacturing standardization with botanical medicinal preparations, the amount of active ingredients may vary. This could further confound the ability to assess potential interactions and effects on anticoagulation. It is good practice to monitor the patient’s response with additional PT/INR determinations when initiating or discontinuing botanicals.

Specific botanicals reported to affect warfarin sodium therapy include the following:

• Bromelains, danshen, dong quai (Angelica sinensis), garlic, Ginkgo biloba, ginseng, and cranberry products are associated most often with an INCREASE in the effects of warfarin sodium.

• Coenzyme Q10 (ubidecarenone) and St. John’s wort are associated most often with a DECREASE in the effects of warfarin sodium.

Some botanicals may cause bleeding events when taken alone (e.g., garlic and Ginkgo biloba) and may have anticoagulant, antiplatelet, and/or fibrinolytic properties. These effects would be expected to be additive to the anticoagulant effects of warfarin sodium. Conversely, other botanicals may have coagulant properties when taken alone or may decrease the effects of warfarin sodium.

Some botanicals that may affect coagulation are listed below for reference; however, this list should not be considered all-inclusive. Many botanicals have several common names and scientific names. The most widely recoginized common botanical names are listed.

Botanicals that contain coumarins with potential anticoagulant effects:

Alfalfa

Angelica (Dong Quai)

Aniseed

Arnica

Asa Foetida

Bogbean1

Boldo

Buchu

Capsicum2

Cassia3

Celery

Chamomile

(German and Roman)

Dandelion3

Fenugreek

Horse Chestnut

Horseradish

Licorice3

Meadowsweet1

Nettle

Parsley

Passion Flower

Prickly Ash (Northern)

Quassia

Red Clover

Sweet Clover

Sweet Woodruff

Tonka Beans

Wild Carrot

Miscellaneous botanicals with anticoagulant properties:
Bladder Wrack (Fucus) Pau d’arco

Botanicals that contain salicylate and/or have antiplatelet properties

Agrimony4

Aloe Gel

Aspen

Black Cohosh

Black Haw

Bogbean1

Cassia3

Clove

Dandelion3

Feverfew

Garlic5

German Sarsaparilla

Ginger

Ginkgo Biloba

Ginseng (Panax)5

Licorice3

Meadowsweet1

Onion5

Policosanol

Poplar

Senega

Tamarind

Willow

Botanicals with fibrinolytic proper

Bromeleins

2

Garlic5

Panax)5

Inositol Nicotinate

5
Botanicals with coagultant properties

Agrimony4

Mistletoe

1 Contains coumarins and salicylate.

2 Contains coumarins and has fibrinolytic properties.

3 Contains coumarins and has antiplatelet properties.

4 Contains salicylate and has coagulant properties.

5 Has antiplatelet and fibrinolytic properties.

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