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Coumadin Side Effects, and Drug Interactions - Warfarin Sodium

DRUG INTERACTIONS

Drugs may interact with COUMADIN through pharmacodynamic or pharmacokinetic mechanisms. Pharmacodynamic mechanisms for drug interactions with COUMADIN 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 COUMADIN 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 COUMADIN are listed below by drug class and by specific drugs.

Classes of Drugs
5-lipoxygenase Inhibitor	Antiparasitic/Antimicrobials	HMG-CoA Reductase
Adrenergic Stimulants, Central	Antiplatelet Drugs/Effects	Inhibitors^†
Alcohol Abuse Reduction	Antithyroid Drugs^†	Leukotriene Receptor Antagonist
Preparations	Beta-Adrenergic Blockers	Monoamine Oxidase Inhibitors
Analgesics	Cholelitholytic Agents	Narcotics,prolonged
Anesthetics, Inhalation	Diabetes Agents, Oral	Nonsteroidal Anti-Inflammatory
Antiandrogen	Diuretics^†	Agents
Antiarrhythmics^†	Fungal Medications, Intravaginal,	Psychostimulants
Antibiotics^†	Systemic^†	Pyrazolones
Aminoglycosides (oral)	Gastric Acidity and Peptic	Salicylates
Cephalosporins, parenteral	Ulcer Agents^†	Selective Serotonin
Macrolides	Gastrointestinal	Reuptake Inhibitors
Miscellaneous	Prokinetic Agents	Steroids, Adrenocortical^†
Penicillins, intravenous,	Ulcerative Colitis Agents	Steroids, Anabolic (17-Alkyl
high dose	Gout Treatment Agents	Testosterone Derivatives)
Quinolones (fluoroquinolones)	Hemorrheologic Agents	Thrombolytics
Sulfonamides, long acting	Hepatotoxic Drugs	Thyroid Drugs
Tetracyclines	Hyperglycemic Agents	Tuberculosis Agents^†
Anticoagulants	Hypertensive Emergency Agents	Uricosuric Agents
Anticonvulsants^†	Hypnotics^†	Vaccines
Antidepressants^†	Hypolipidemics^†	Vitamins^†
Antimalarial Agents	Bile Acid-Binding Resins^†
Antineoplastics^†	Fibric Acid Derivatives

Specific Drugs Reported
acetaminophen	fluconazole	penicillin G,intravenous
alcohol^†	fluorouracil	pentoxifylline
allopurinol	fluoxetine	phenylbutazone
aminosalicylic acid	flutamide	phenytoin^†
amiodarone HCl	fluvastatin	piperacillin
aspirin	fluvoxamine	piroxicam
atorvastatin^†	gemfibrozil	pravastatin^†
azithromycin	glucagon	prednisone^†
capecitabine	halothane	propafenone
cefamandole	heparin	propoxyphene
cefazolin	ibuprofen	propranolol
cefoperazone	ifosfamide	propylthiouracil^†
cefotetan	indomethacin	quinidine
cefoxitin	influenza virus vaccine	quinine
ceftriaxone	itraconazole	ranitidine^†
celecoxib	ketoprofen	rofecoxib
cerivastatin	ketorolac	sertraline
chenodiol	levamisole	simvastatin
chloramphenicol	levofloxacin	stanozolol
chloral hydrate^†	levothyroxine	streptokinase
chlorpropamide	liothyronine	sulfamethizole
cholestyramine^†	lovastatin	sulfamethoxazole
cimetidine	mefenamic acid	sulfinpyrazone
ciprofloxacin	methimazole^†	sulfisoxazole
cisapride	methyldopa	sulindac
clarithromycin	methylphenidate	tamoxifen
clofibrate	methylsalicylate ointment	tetracycline
COUMADIN overdose	(topical)	thyroid
cyclophosphamide^†	metronidazole	ticarcillin
danazol	miconazole	ticlopidine
dextran	(intravaginal,systemic)	tissue plasminogen
dextrothyroxine	moricizine hydrochloride^†	activator (t-PA)
diazoxide	nalidixic acid	tolbutamide
diclofenac	naproxen	tramadol
dicumarol	neomycin	trimethoprim/sulfamethoxazole
diflunisal	norfloxacin	urokinase
disulfiram	ofloxacin	valproate
doxycycline	olsalazine	vitamin E
erythromycin	omeprazole	zafirlukast
ethacrynic acid	oxaprozin	zileuton
fenofibrate	oxymetholone
fenoprofen	paroxetine

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	hypothyroidism
hereditary coumarin resistance	nephrotic syndrome
hyperlipemia

EXOGENOUS FACTORS

Potential drug interactions with COUMADIN (Warfarin Sodium) are listed below by drug class and by specific drugs.

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

Specific Drugs Reported
alcohol^†	COUMADIN 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

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 concomitantly 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 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 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 Q₁₀ (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 anti-coagulant, 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 recognized common botanical names are listed.

Botanticals that contain coumarins with potential anticoagulant effects:
Alfalfa	Celery	Parsley
Angelica (Dong Quai)	Chamomile	Passion Flower
Aniseed	(German and Roman)	Prickly Ash (Northern)
Arnica	Dandelion³	Quassia
Asa Foetida	Fenugreek	Red Clover
Bogbean¹	Horse Chestnut	Sweet Clover
Boldo	Horseradish	Sweet Woodruff
Buchu	Licorice³	Tonka Beans
Capsicum²	Meadowsweet¹	Wild Carrot
Cassia³	Nettle	Wild Lettuce

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

Botanicals that contain salicylate and/or have antiplatelet properties:
Agrimony⁴	Dandelion³	Meadowsweet¹
Aloe Gel	Feverfew	Onion⁵
Aspen	Garlic⁵	Policosanol
Black Cohosh	German Sarsaparilla	Poplar
Black Haw	Ginger	Senega
Bogbean¹	Ginkgo Biloba	Tamarind
Cassia³	Ginseng (Panax)⁵	Willow
Clove	Licorice³	Wintergreen

Botanticals with fibrinolytic properties:
Bromelains	Garlic⁵	Inositol Nicotinate
Capsicum²	Ginseng (Panax)⁵	Onion⁵

Botanticals with coagulant properties:
Agrimony⁴Mistletoe	Yarrow
Goldenseal
¹Contains coumarins and salicylate.
²Contains coumarins and has fibrinolytic properties.
³Contains coumarins and has antiplatelet properties.
⁴Contains salicylate and has coagulant properties.
⁵Has 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 antiinflammatory 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.

SIDE EFFECTS

Potential adverse reactions to COUMADIN 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.

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