Pharmacokinetics

Warfarin sodium is a racemic mixture of the R- and S-enantiomers. The S-enantiomer exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer in humans, but generally has a more rapid clearance.

Absorption

Warfarin sodium is essentially completely absorbed after oral administration with peak concentration generally attained within the first 4 hours.

Distribution

There are no differences in the apparent volumes of distribution after intravenous and oral administration of single doses of warfarin solution. Warfarin distributes into a relatively small apparent volume of distribution of about 0.14 liter/kg. A distribution phase lasting 6 to 12 hours is distinguishable after rapid intravenous or oral administration of an aqueous solution. Using a one compartment model, and assuming complete bioavailability, estimates of the volumes of distribution of R- and S-warfarin are similar to each other and to that of the racemate. Concentrations in fetal plasma approach the maternal values, but warfarin has not been found in human milk (see WARNINGS: Lactation). Approximately 99% of the drug is bound to plasma proteins.

Metabolism

The elimination of warfarin is almost entirely by metabolism. Warfarin sodium is stereoselectively metabolized by hepatic microsomal enzymes (cytochrome P-450) to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolites (warfarin alcohols). The warfarin alcohols have minimal anticoagulant activity. The metabolites are principally excreted into the urine; and to a lesser extent into the bile. The metabolites of warfarin that have been identified include dehydrowarfarin, two diastereoisomer alcohols, 4'-, 6-, 7-, 8- and 10-hydroxywarfarin. The Cytochrome P-450 isozymes involved in the metabolism of warfarin include 2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. 2C9 is likely to be the principal form of human liver P-450 which modulates the in vivo anticoagulant activity of warfarin.

Excretion

The terminal half-life of warfarin after a single dose is approximately one week; however, the effective half-life ranges from 20 to 60 hours, with a mean of about 40 hours. The clearance of R-warfarin is generally half that of S-warfarin, thus as the volumes of distribution are similar, the half-life of R-warfarin is longer than that of S-warfarin. The half-life of R-warfarin ranges from 37 to 89 hours, while that of S-warfarin ranges from 21 to 43 hours. Studies with radiolabeled drug have demonstrated that up to 92% of the orally administered dose is recovered in urine. Very little warfarin is excreted unchanged in urine. Urinary excretion is in the form of metabolites.

Elderly

Patients 60 years or older appear to exhibit greater than expected PT/INR response to the anticoagulant effects of warfarin. The cause of the increased sensitivity to the anticoagulant effects of warfarin in this age group is unknown. This increased anticoagulant effect from warfarin may be due to a combination of pharmacokinetic and pharmacodynamic factors. Racemic warfarin clearance may be unchanged or reduced with increasing age. Limited information suggests there is no difference in the clearance of S-warfarin in the elderly versus young subjects. However, there may be a slight decrease in the clearance of R-warfarin in the elderly as compared to the young. Therefore, as patient age increases, a lower dose of warfarin is usually required to produce a therapeutic level of anticoagulation.

Asians

Asian patients may require lower initiation and maintenance doses of warfarin. One non-controlled study conducted in 151 Chinese outpatients reported a mean daily warfarin requirement of 3.3 ± 1.4 mg to achieve an INR of 2 to 2.5. These patients were stabilized on warfarin for various indications. Patient age was the most important determinant of warfarin requirement in Chinese patients with a progressively lower warfarin requirement with increasing age.

Renal Dysfunction

Renal clearance is considered to be a minor determinant of anticoagulant response to warfarin. No dosage adjustment is necessary for patients with renal failure.

Hepatic Dysfunction

Hepatic dysfunction can potentiate the response to warfarin through impaired synthesis of clotting factors and decreased metabolism of warfarin.

The administration of warfarin sodium via the intravenous (I.V.) route should provide the patient with the same concentration of an equal oral dose, but maximum plasma concentration will be reached earlier. However, the full anticoagulant effect of a dose of warfarin may not be achieved until 72 to 96 hours after dosing, indicating that the administration of I.V. warfarin sodium should not provide any increased biological effect or earlier onset of action.

Clinical Trials

ATRIAL FIBRILLATION (AF)

In five prospective randomized controlled clinical trials involving 3711 patients with non-rheumatic AF, warfarin significantly reduced the risk of systemic thromboembolism including stroke (See Table 1). The risk reduction ranged from 60% to 86% in all except one trial (CAFA: 45%) which stopped early due to published positive results from two of these trials. The incidence of major bleeding in these trials ranged from 0.6 to 2.7% (see Table 1). Meta-analysis findings of these studies revealed that the effects of warfarin in reducing thromboembolic events including stroke were similar at either moderately high INR (2.0 to 4.5) or low INR (1.4 to 3.0). There was a significant reduction in minor bleeds at the low INR. Similar data from clinical studies in valvular atrial fibrillation patients are not available.

TABLE 1
CLINICAL STUDIES OF WARFARIN IN NON-RHEUMATIC AF PATIENTS*
Study	N		PT Ratio	INR	Thromboembolism		% Major Bleeding
	Warfarin-	Control			% Risk	p- value	Warfarin-	Control
	Treated	Patients			Reduction		Treated	Patients
	Patients						Patients
AFASAK	335	336	1.5-2.0	2.8-4.2	60	0.027	0.6	0.0
SPAF	210	211	1.3-1.8	2.0-4.5	67	0.01	1.9	1.9
BAATAF	212	208	1.2-1.5	1.5-2.7	86	<0.05	0.9	0.5
CAFA	187	191	1.3-1.6	2.0-3.0	45	0.25	2.7	0.5
SPINAF	260	265	1.2-1.5	1.4-2.8	79	0.001	2.3	1.5

*All study results of warfarin vs. control are based on intention-to-treat analysis and include ischemic stroke and systemic thromboembolism, excluding hemorrhage and transient ischemic attacks.

MYOCARDIAL INFARCTION

WARIS (The Warfarin Re-Infarction Study) was a double-blind, randomized study of 1214 patients 2 to 4 weeks postinfarction treated with warfarin to a target INR of 2.8 to 4.8. [But note that a lower INR was achieved and increased bleeding was associated with INR's above 4.0; (see DOSAGE AND ADMINISTRATION)]. The primary endpoint was a combination of total mortality and recurrent infarction. A secondary endpoint of cerebrovascular events was assessed. Mean follow-up of the patients was 37 months. The results for each endpoint separately, including an analysis of vascular death, are provided in the following table:

TABLE 2
				%Risk
Event	Warfarin	Placebo		Reduction
	(N=607)	(N=607)	RR(95%CI)	(p-value)
Total Patient Years of Follow-up	2018	1944
Total Mortality	94 (4.7/100 py)	123 (6.3/100 py)	0.76 (0.60, 0.97)	24 (p=0.030)
Vascular Death	82 (4.1/100 py)	105 (5.4/100 py)	0.78 (0.60, 1.02)	22 (p=0.068)
Recurrent MI	82 (4.1/100 py)	124 (6.4/100 py)	0.66 (0.51, 0.85)	34 (p=0.001)
Cerebrovascular Event	20 (1.0/100 py)	44 (2.3/100 py)	0.46 (0.28, 0.75)	54 (p=0.002)

RR=Relative risk; Risk reduction=(I-RR); CI=Confidence interval; MI=Myocardial infarction; py=patient years

WARIS II (The Warfarin, Aspirin, Re-Infarction Study) was an open-label randomized study of 3630 patients hospitalized for acute myocardial infarction treated with warfarin target INR 2.8 to 4.2, aspirin 160 mg/day, or warfarin target INR 2.0 to 2.5 plus aspirin 75 mg/day prior to hospital discharge. There were approximately four times as many major bleeding episodes in the two groups receiving warfarin than in the group receiving aspirin alone. Major bleeding episodes were not more frequent among patients receiving aspirin plus warfarin than among those receiving warfarin alone, but the incidence of minor bleeding episodes was higher in the combined therapy group. The primary endpoint was a composite of death, nonfatal reinfarction, or thromboembolic stroke. The mean duration of observation was approximately 4 years. The results for WARIS II are provided in the following table1:

Table 3: WARIS II - Distribution of Separate Events According to Treatment Group*
Event	Aspirin	Warfarin	Aspirin Plus Warfarin	Rate Ratio	p-value
	(N=1206)	(N=1216)	(N=1208)	(95% CI)
		No.of Events
Reinfarction	117	90	69	0.56 (0.41-0.78)a	<0.001
				0.74 (0.55-0.98)b	0.03
Thromboembolic stroke	32	17	17	0.52 (0.28-0.98)a	0.03
				0.52 (0.28-0.97)b	0.03
Major Bleeding c	8	33	28	3.35a (ND)	ND
				4.00b (ND)	ND
Minor Bleeding d	39	103	133	3.21a (ND)	ND
				2.55b (ND)	ND
Death	92	96	95		0.82

* CI denotes confidence interval.

a The rate ratio is for aspirin plus warfarin as compared with aspirin.

b The rate ratio is for warfarin as compared with aspirin.

cMajor bleeding episodes were defined as nonfatal cerebral hemorrhage or bleeding necessitating

surgical intervention.

d Minor bleeding episodes were defined as non-cerebral hemorrhage not necessitating surgical intervention of blood transfusion.

ND =not determined.

MECHANICAL AND BIOPROSTHETIC HEART VALVES

In a prospective, randomized, open label, positive-controlled study2 in 254 patients, the thromboembolic-free interval was found to be significantly greater in patients with mechanical prosthetic heart valves treated with warfarin alone compared with dipyridamole-aspirin (p<0.005) and pentoxifylline-aspirin (p<0.05) treated patients. Rates of hromboembolic events in these groups were 2.2, 8.6, and 7.9/100 patient years, respectively. Major bleeding rates were 2.5, 0.0, and 0.9/100 patient years, respectively.

In a prospective, open label, clinical trial comparing moderate (INR 2.65) vs. high intensity (INR 9.0) warfarin therapies in 258 patients with mechanical prosthetic heart valves, thromboembolism occurred with similar frequency in the two groups (4.0 and 3.7 events/100 patient years, respectively). Major bleeding was more common in the high intensity group (2.1 events/100 patient years) vs. 0.95 events/100 patient years in the moderate intensity group3.

In a randomized trial in 210 patients comparing two intensities of warfarin therapy (INR 2.0 to 2.25 vs. INR 2.5 to 4.0) for a three month period following tissue heart valve replacement, thromboembolism occurred with similar frequency in the two groups (major embolic events 2.0% vs. 1.9%, respectively and minor embolic events 10.8% vs. 10.2%, respectively). Major bleeding complications were more frequent with the higher intensity (major hemorrhages 4.6%) vs. none in the lower intensity4.

Drug-Drug and Drug-Disease Interactions

Numerous factors, alone or in combination, including changes in diet, and medications, includingbotanicals, may influence response of the patient to anticoagulants. It is generally good practice tomonitor the patient’s response with additional PT/INR determinations in the period immediately afterdischarge 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 mayalso 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 controlloop for vitamin K metabolism (hereditary resistance). Pharmacokinetic mechanisms for drug interactionswith warfarin sodium are mainly enzyme induction, enzyme inhibition, and reduced plasma protein binding. It isimportant 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 Wild Lettuce

 

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 Wintergreen

Botanicals with fibrinolytic proper
Bromeleins Capsicum2	Garlic5 Ginseng (Panax)5	Inositol Nicotinate Onion5

Botanicals with coagultant properties
Agrimony4 Goldenseal	Mistletoe  Yarrow

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

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 warfarin sodium 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 warfarin sodium are required to maintain a patient’s PT/INR within a normal therapeutic range.

Carcinogenesis, mutagenesis, impairment of fertility

Carcinogenicity and mutagenicity studies have not been performed with warfarin sodium. The reproductive effects of warfarin sodium 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 randomized, controlled clinical trials. However, the use of warfarin sodium 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 anticoagulant effects of warfarin (see CLINICAL PHARMACOLOGY). Warfarin sodium 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 warfarin are recommended for elderly patients (see DOSAGE AND ADMINISTRATION).

Signs and Symptoms

Suspected or overt abnormal bleeding (e.g., appearance of blood in stools or urine, hematuria, excessive menstrual bleeding, melena, petechiae, excessive bruising or persistent oozing from superficial injuries) are early manifestations of anticoagulation beyond a safe and satisfactory level.

Treatment

Excessive anticoagulation, with or without bleeding, may be controlled by discontinuing warfarin sodium therapy and if necessary, by administration of oral or parenteral vitamin K1. (Please see recommendations accompanying vitamin K1 preparations prior to use).8,9

Such use of vitamin K1 reduces response to subsequent warfarin sodium therapy. Patients may return to a pretreatment thrombotic status following the rapid reversal of a prolonged PT/INR. Resumption of warfarin sodium administration reverses the effect of vitamin K, and a therapeutic PT/INR can again be obtained by careful dosage adjustment. If rapid anticoagulation is indicated, heparin may be preferable for initial therapy.

If minor bleeding progresses to major bleeding, give 5 to 25 mg (rarely up to 50 mg) parenteral vitamin K1. In emergency situations of severe hemorrhage, clotting factors can be returned to normal by administering 200 to 500 mL of fresh whole blood or fresh frozen plasma, or by giving commercial Factor IX complex.

A risk of hepatitis and other viral diseases is associated with the use of these blood products; Factor IX complex is also associated with an increased risk of thrombosis. Therefore, these preparations should be used only in exceptional or life-threatening bleeding episodes secondary to warfarin sodium overdosage.

Purified Factor IX preparations should not be used because they cannot increase the levels of prothrombin, Factor VII and Factor X which are also depressed along with the levels of Factor IX as a result of warfarin sodium treatment. Packed red blood cells may also be given if significant blood loss has occurred. Infusions of blood or plasma should be monitored carefully to avoid precipitating pulmonary edema in elderly patients or patients with heart disease.

Venous Thromboembolism (including deep venous thrombosis [DVT] and pulmonary embolism [PE])

For patients with a first episode of DVT or PE secondary to a transient (reversible) risk factor, treatment with warfarin for 3 months is recommended. For patients with a first episode of idiopathic DVT or PE, warfarin is recommended for at least 6 to 12 months. For patients with two or more episodes of documented DVT or PE, indefinite treatment with warfarin is suggested. For patients with a first episode of DVT or PE who have documented antiphospholipid antibodies or who have two or more thrombophilic conditions, treatment for 12 months is recommended and indefinite therapy is suggested. For patients with a first episode of DVT or PE who have documented deficiency of antithrombin, deficiency of Protein C or Protein S, or the Factor V Leiden or prothrombin 20210 gene mutation, homocystinemia, or high Factor VIII levels (>90th percentile of normal), treatment for 6 to 12 months is recommended and indefinite therapy is suggested for idiopathic thrombosis. The risk-benefit should be reassessed periodically in patients who receive indefinite anticoagulant treatment.5,13 The dose of warfarin should be adjusted to maintain a target INR of 2.5 (INR range, 2.0 to 3.0) for all treatment durations. These recommendations are supported by the 7th ACCP guidelines.8,10,14,15

Atrial Fibrillation

Five recent clinical trials evaluated the effects of warfarin in patients with non-valvular atrial fibrillation (AF). Meta analysis findings of these studies revealed that the effects of warfarin in reducing thromboembolic events including stroke were similar at either moderately high INR (2.0 to 4.5) or low INR (1.4 to 3.0). There was a significant reduction in minor bleeds at the low INR. There are no adequate and well controlled studies in populations with atrial fibrillation and valvular heart disease. Similar data from clinical studies in valvular atrial fibrillation patients are not available. The trials in non-valvular atrial fibrillation support the American College of Chest Physicians' (7th ACCP) recommendation that an INR of 2.0 to 3.0 be used for warfarin therapy in appropriate AF patients10.

Oral anticoagulation therapy with warfarin is recommended in patients with persistent or paroxysmal AF (PAF) (intermittent AF) at high risk of stroke (i.e., having any of the following features: prior ischemic stroke, transient ischemic attack, or systemic embolism, age >75 years, moderately or severely impaired left ventricular systolic function and/or congestive heart failure, history of hypertension, or diabetes mellitus). In patients with persistent AF or PAF, age 65 to 75 years, in the absence of other risk factors, but who are at intermediate risk of stroke, antithrombotic therapy with either oral warfarin or aspirin, 325 mg/day, is recommended. For patients with AF and mitral stenosis, anticoagulation with oral warfarin is recommended (7th ACCP). For patients with AF and prosthetic heart valves, anticoagulation with oral warfarin should be used; the target INR may be increased and aspirin added depending on valve type and position, and on patient factors.10

Post-Myocardial Infarction

The results of the WARIS II study and 7th ACCP guidelines suggest that in most healthcare settings, moderate- and lowrisk patients with a myocardial infarction should be treated with aspirin alone over oral vitamin-K antagonist (VKA) therapy plus aspirin. In healthcare settings in which meticulous INR monitoring is standard and routinely accessible, for both high- and low-risk patients after myocardial infarction (MI), long-term (up to 4 years) high-intensity oral warfarin (target INR, 3.5; range, 3.0 to 4.0) without concomitant aspirin or moderate-intensity oral warfarin (target INR, 2.5; range, 2.0 to 3.0) with aspirin is recommended. For high-risk patients with MI, including those with large anterior MI, those with significant heart failure, those with intracardiac thrombus visible on echocardiography, and those with a history of a thromboembolic event, therapy with combined moderate-intensity (INR, 2.0 to 3.0) oral warfarin plus low-dose aspirin (≤100mg/day) for 3 months after the MI is suggested.16

Mechanical and Bioprosthetic Heart Valves

For all patients with mechanical prosthetic heart valves, warfarin is recommended. For patients with a St. Jude Medical (St. Paul, MN) bileaflet valve in the aortic position, a target INR of 2.5 (range, 2.0 to 3.0) is recommended. For patients with tilting disk valves and bilealet mechanical valves in the mitral position, the 7th ACCP recommends a target INR of 3.0 (range, 2.5 to 3.5). For patients with caged ball or caged disk valves, a target INR of 3.0 (range, 2.5 to 3.5) in combination with aspirin, 75 to 100 mg/day is recommended. For patients with bioprosthetic valves, warfarin therapy with a target INR of 2.5 (range, 2.0 to 3.0) is recommended for valves in the mitral position and is suggested for valves in the aortic position for the first 3 months after valve insertion.8

Recurrent Systemic Embolism

Oral anticoagulation therapy has not been evaluated by properly designed clinical trials in patients with valvular disease associated with atrial fibrillation, patients with mitral stenosis, and patients with recurrent systemic embolism of unknown etiology. A moderate dose regimen (INR 2.0 to 3.0) is recommended for these patients.10

An INR of greater than 4.0 appears to provide no additional therapeutic benefit in most patients and isassociated with a higher risk of bleeding.

Initial Dosage

The dosing of warfarin sodium must be individualized according to patient’s sensitivity to the drug as indicated by the PT/INR. Use of a large loading dose may increase the incidence of hemorrhagic and other complications, does not offer more rapid protection against thrombi formation, and is not recommended. Lower initiation and maintenance doses are recommended for elderly and/or debilitated patients and patients with potential to exhibit greater than expected PT/INR response to warfarin sodium (see PRECAUTIONS). Based on limited data, Asian patients may also require lower initiation and maintenance doses of warfarin sodium (see CLINICAL PHARMACOLOGY). It is recommended that warfarin sodium therapy be initiated with a dose of 2 to 5 mg per day with dosage adjustments based on the results of PT/INR determinations.10,11

Maintenance

Most patients are satisfactorily maintained at a dose of 2 to 10 mg daily. Flexibility of dosage is provided by breaking scored tablets in half. The individual dose and interval should be gauged by the patient’s prothrombin response.

Duration of Therapy

The duration of therapy in each patient should be individualized. In general, anticoagulant therapy should be continued until the danger of thrombosis and embolism has passed.7,8,10,11,14,15

Missed Dose

The anticoagulant effect of warfarin sodium persists beyond 24 hours. If the patient forgets to take the prescribed dose of warfarin sodium at the scheduled time, the dose should be taken as soon as possible on the same day. The patient should not take the missed dose by doubling the daily dose to make up for missed doses, but should refer back to his or her physician.

Intravenous Route of Administration

Warfarin sodium for injection provides an alternate administration route for patients who cannot receive oral drugs. The IV osage would be the same as those that would be used orally if the patient could take the drug by oral route.

LABORATORY CONTROL: The PT reflects the depression of vitamin K dependent Factors VII, X and II. A system of standardizing the PT in oral anticoagulant control was introduced by the World Health Organization in 1983. It is based upon the determination of an International Normalized Ratio (INR) which provides a common basis for communication of PT results and interpretations of therapeutic ranges.17 The PT should be determined daily after the administration of the initial dose until PT/INR results stabilize in the therapeutic range. Intervals between subsequent PT/INR determinations should be based upon the physician’s judgment of the patient's reliability and response to warfarin sodium in order to maintain the individual within the therapeutic range. Acceptable intervals for PT/INR determinations are normally within the range of one to four weeks after a stable dosage has been determined. To ensure adequate control, it is recommended that additional PT tests be done when other warfarin products are interchanged with warfarin sodium tablets, USP, as well as whenever other medications are initiated, discontinued, or taken irregularly (see PRECAUTIONS). Safety and efficacy of warfarin therapy can be improved by increasing the quality of laboratory control. Reports suggest that in usual care monitoring, patients are in therapeutic range only 33%-64% of the time. Time in therapeutic range is significantly greater (56%-93%) in patients managed by anticoagulation clinics, among self-testing and self-monitoring patients, and in patients managed with the help of computer programs.18 Self-testing patients had fewer bleeding events than patients in usual care.18

TREATMENT DURING DENTISTRY AND SURGERY: The management of patients who undergo dental and surgical procedures requires close liaison between attending physicians, surgeons and dentists.8,12 PT/INR determination is recommended just prior to any dental or surgical procedure. In patients undergoing minimal invasive procedures who must be anticoagulated prior to, during, or immediately following these procedures, adjusting the dosage of warfarin sodium to maintain the PT /INR at the low end of the therapeutic range may safely allow for continued anticoagulation. The operative site should be sufficiently limited and accessible to permit the effective use of local procedures for hemostasis. Under these conditions, dental and minor surgical procedures may be performed without undue risk of hemorrhage. Some dental or surgical procedures may necessitate the interruption of warfarin sodium therapy. When discontinuing warfarin sodium even for a short period of time, the benefits and risks should be strongly considered.

CONVERSION FROM HEPARIN THERAPY: Since the anticoagulant effect of warfarin sodium is delayed, heparin is preferred initially for rapid anticoagulation. Conversion to warfarin sodium may begin concomitantly with heparin therapy or may be delayed 3 to 6 days. To ensure continuous anticoagulation, it is advisable to continue full dose heparin therapy and that warfarin sodium therapy be overlapped with heparin for 4 to 5 days, until warfarin has produced the desired therapeutic response as determined by PT/INR. When warfarin sodium has produced the desired PT/INR or prothrombin activity, heparin may be discontinued.

Warfarin sodium may increase the aPTT test, even in the absence of heparin. During initial therapy with warfarin sodium, the interference with heparin anticoagulation is of minimal clinical significance.

As heparin may affect the PT/INR, patients receiving both heparin and warfarin sodium should have blood for PT/INR determination drawn at least:

• 5 hours after the last IV bolus dose of heparin, or

• 4 hours after cessation of a continuous IV infusion of heparin, or

• 24 hours after the last subcutaneous heparin injection.

What is WARFARIN?

WARFARIN is an anticoagulant medicine. It is used to lower the chance of blood clots forming in your body. Blood clots can cause a stroke, heart attack, or other serious conditions such as blood clots in the legs or lungs.

Who should not take WARFARIN?

Do not take WARFARIN if:

•your chance of having bleeding problems is higher than the possible

benefit of treatment.

Your healthcare provider will decide if WARFARIN is right for you.

Talk to your healthcare provider about all of your health conditions.

•you are pregnant or plan to become pregnant.

WARFARIN can cause death or birth defects to an unborn baby. Use

effective birth control if you can get pregnant.

•you are allergic to warfarin or to anything else in WARFARIN.

What should I tell my healthcare provider before starting WARFARIN?

Tell your healthcare provider about all of your health conditions, including ifyou:

•have bleeding problems

•fall often

•have liver or kidney problems

•have high blood pressure

•have a heart problem called congestive heart failure

•have diabetes

•drink alcohol or have problems with alcohol abuse. Alcohol can affect your WARFARIN dose and should be avoided.

•are pregnant or planning to become pregnant. See “Who should not

take WARFARIN?”

•are breastfeeding. WARFARIN may increase bleeding in your baby. Talk to your doctor about the best way to feed your baby. If you choose to breastfeed while taking WARFARIN, both you and your baby should be carefully monitored for bleeding problems.

Tell your healthcare provider about all the medicines you take includingprescription and non-prescription medicines, vitamins, and herbalsupplements. See “What is the most important information I should knowabout WARFARIN?”

How should I take WARFARIN?

•Take WARFARIN exactly as prescribed. Your healthcare provider will adjust your dose from time to time depending on your response to WARFARIN.

•You must have regular blood tests and visits with your healthcare provider to monitor your condition.

•Take WARFARIN at the same time every day. You can take WARFARIN either with food or on an empty stomach.

•If you miss a dose of WARFARIN, call your healthcare provider. Take the dose as soon as possible on the same day. Do not take a double dose of WARFARIN the next day to make up for a missed dose.

•Call your healthcare provider right away if you take too much WARFARIN.

•Call your healthcare provider if you are sick with diarrhea, an infection, or have a fever.

•Tell your healthcare provider about any planned surgeries, medical or dental procedures. Your WARFARIN may have to be stopped for a short time or you may need your dose adjusted.

•Call your healthcare provider right away if you fall or injure yourself,especially if you hit your head. Your healthcare provider may need to check you.

What should I avoid while taking WARFARIN?

• Do not start, stop, or change any medicine without talking with your healthcare provider.

• Do not make changes in your diet, such as eating large amounts of green, leafy vegetables.

• Do not change your weight by dieting, without first checking with your

healthcare provider.

• Avoid drinking alcohol.

• Do not do any activity or sport that may cause a serious injury.

What are the possible side effects of WARFARIN?

• WARFARIN is very important for your health, but it can cause serious and lifethreatening bleeding problems. See “What is the most important information

I should know about WARFARIN?”

•Serious side effects of WARFARIN also include:

•death of skin tissue (skin necrosis or gangrene). This can happen soon after starting WARFARIN. It happens because blood clots form and block blood flow to an area of your body. Call your healthcare provider right away if you have pain, color, or temperature change to any area of your body. You may need medical care right away to prevent death or loss (amputation) of your affected body part.

•“purple toes syndrome.”Call your healthcare provider right away if you

have pain in your toes and they look purple in color or dark in color.

Other side effects with WARFARIN include allergic reactions, liver problems, low blood pressure, swelling, low red blood cells, paleness, fever, and rash. Call your healthcare provider if you have any side effect that bothers you.

These are not all of the side effects of WARFARIN. For more information, ask your healthcare provider or pharmacist.

How should I store WARFARIN?

• Store WARFARIN at room temperature between 59° and 86° F. Protect from light.

•Keep WARFARIN and all medicines out of the reach of children.

General Information about WARFARIN

Medicines are sometimes prescribed for purposes not mentioned in a Medication Guide. Do not use WARFARIN for a condition for which it was not prescribed. Do not give WARFARIN to other people, even if they have the same condition. It may harm them.

This Medication Guide summarizes the most important information about WARFARIN. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about WARFARIN that was written for healthcare professionals.

If you would like more information, call

1-866-436-9155

Rx only

WARFARIN is distributed by:

Genpharm, L.P.

Napa, CA 94558

This Medication Guide has been approved by the U.S. Food and Drug Administration.

This leaflet was prepared by:

Genpharm Inc.

85 Advance Road

Etobicoke, OntarioM8Z 2S6

Issue date: November 2006