Coumadin - Warnings & Precautions

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ENDOGENOUS FACTORS:

EXOGENOUS FACTORS:

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

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.

blood dyscrasias Ñ 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

Classes of Drugs

5-lipoxygenase Inhibitor Adrenergic Stimulants, Central

Alcohol Abuse Reduction Preparations

Analgesics Anesthetics, Inhalation

Antiandrogen 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

Cholelitholytic Agents Diabetes Agents, Oral

Diuretics * Fungal Medications, Intravaginal,

Systemic * Gastric Acidity and Peptic

Ulcer Agents * Gastrointestinal

Prokinetic Agents Ulcerative Colitis Agents

Gout Treatment Agents Hemorrheologic Agents

Hepatotoxic Drugs Hyperglycemic Agents

Hypertensive Emergency Agents Hypnotics *

Hypolipidemics * Bile Acid-Binding Resins *

Fibric Acid Derivatives

HMG-CoA Reductase Inhibitors *

Leukotriene Receptor Antagonist 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

atorvastatin * azithromycin

capecitabine cefamandole

cefazolin cefoperazone

cefotetan cefoxitin

ceftriaxone celecoxib

cerivastatin chenodiol

chloramphenicol chloral hydrate *

chlorpropamide cholestyramine *

cimetidine ciprofloxacin

cisapride clarithromycin

clofibrate COUMADIN overdose

cyclophosphamide * danazol

dextran dextrothyroxine

diazoxide diclofenac

dicumarol diflunisal

disulfiram doxycycline

erythromycin ethacrynic acid

fenofibrate fenoprofen

fluconazole fluorouracil

fluoxetine flutamide

fluvastatin fluvoxamine

gemfibrozil glucagon

halothane heparin

ibuprofen ifosfamide

indomethacin influenza virus vaccine

itraconazole ketoprofen

ketorolac levamisole

levofloxacin levothyroxine

liothyronine lovastatin

mefenamic acid methimazole *

methyldopa methylphenidate

methylsalicylate ointment (topical)

metronidazole miconazole

(intravaginal, systemic) moricizine hydrochloride *

nalidixic acid naproxen

neomycin norfloxacin

ofloxacin olsalazine

omeprazole oxaprozin

oxymetholone paroxetine

penicillin G, intravenous pentoxifylline

phenylbutazone phenytoin *

piperacillin piroxicam

pravastatin * prednisone *

propafenone propoxyphene

propranolol propylthiouracil *

quinidine quinine

ranitidine * rofecoxib

sertraline simvastatin

stanozolol streptokinase

sulfamethizole sulfamethoxazole

sulfinpyrazone sulfisoxazole

sulindac tamoxifen

tetracycline thyroid

ticarcillin ticlopidine

tissue plasminogen activator (t-PA)

tolbutamide tramadol

trimethoprim/ sulfamethoxazole urokinase

valproate vitamin E

zafirlukast zileuton

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

ENDOGENOUS FACTORS:

EXOGENOUS FACTORS: Potential drug interactions with COUMADIN (Warfarin Sodium) are listed below by drug class and by specific

drugs.

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 COUMADIN 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 con-comitantly with COUMADIN. Few adequate, well-controlled studies exist evaluating the potential for metabolic and/ or pharmacologic interactions between botanicals and COUMADIN. Due to a lack of manufacturing standardi-zation 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 COUMADIN therapy include the following:

° Bromelains, danshen, dong quai (Angelica sinensis), garlic, Ginkgo biloba, and ginseng are associated most often with an INCREASE in the effects of COUMADIN.

° Coenzyme Q 10 (ubidecarenone) and St. John's wort are associated most often with a DECREASE in the effects of COUMADIN.

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 COUMADIN. Conversely, other botanicals may have coagulant properties when taken alone or may decrease the effects of COUMADIN.

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 recog-nized common botanical names are listed.

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.

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:

COUMADIN (Warfarin Sodium) 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 COUMADIN (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 COUMADIN 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 effective-ly 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), other over-the-counter medications, and botanical (herbal) products (e. g., bromelains, coenzyme Q 10 , danshen, dong quai, garlic, Ginkgo biloba, ginseng, and St. John's wort) except on advice of the physician. Avoid alcohol con-sumption.

Do not take COUMADIN during pregnancy and do not become pregnant while taking it (see CON-TRAINDICATIONS). 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 COUMADIN is being taken. If the prescribed dose of COUMADIN 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 COUMADIN the next day to make up for missed doses.

The amount of vitamin K in food may affect therapy with COUMADIN. 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 COUMADIN is discontinued, patients should be cautioned that the anticoagulant effects of COUMADIN may persist for about 2 to 5 days. Patients should be informed that all warfarin sodium, USP, products represent the same medication, and should not be taken concomitantly, as

overdosage may result.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Carcinogenicity and mutagenicity studies have not been performed with COUMADIN. The reproductive effects of COUMADIN 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 ran-domized, controlled clinical trials. However, the use of COUMADIN 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.

Geriatric Use:

Patients 60 years or older appear to exhibit greater than expected PT/ INR response to the anticoag-ulant effects of warfarin (see CLINICAL PHARMACOLOGY). COUMADIN is contraindicated in any unsupervised patient with senility. Caution should be observed with administration of warfarin sodium to elderly patients in any situation or physical condition where added risk of hemorrhage is present. Lower initiation and maintenance doses of COUMADIN are recommended for elderly patients (see DOSAGE AND ADMINISTRATION).