Coumadin

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Hemorrhage

COUMADIN can cause major or fatal bleeding. Bleeding is more likely to occur within the first month. Risk factors for bleeding include high intensity of anticoagulation (INR >4.0), age greater than or equal to 65, history of highly variable INRs, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, anemia, malignancy, trauma, renal impairment, certain genetic factors [see CLINICAL PHARMACOLOGY], certain concomitant drugs [see DRUG INTERACTIONS], and long duration of warfarin therapy.

Perform regular monitoring of INR in all treated patients. Those at high risk of bleeding may benefit from more frequent INR monitoring, careful dose adjustment to desired INR, and a shortest duration of therapy appropriate for the clinical condition. However, maintenance of INR in the therapeutic range does not eliminate the risk of bleeding.

Drugs, dietary changes, and other factors affect INR levels achieved with COUMADIN therapy. Perform more frequent INR monitoring when starting or stopping other drugs, including botanicals, or when changing dosages of other drugs [see DRUG INTERACTIONS].

Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding [see PATIENT INFORMATION].

Tissue Necrosis

Necrosis and/or gangrene of skin and other tissues is an uncommon but serious risk (<0.1%). Necrosis may be associated with local thrombosis and usually appears within a few days of the start of COUMADIN therapy. In severe cases of necrosis, treatment through debridement or amputation of the affected tissue, limb, breast, or penis has been reported.

Careful clinical evaluation is required to determine whether necrosis is caused by an underlying disease. Although various treatments have been attempted, no treatment for necrosis has been considered uniformly effective. Discontinue COUMADIN therapy if necrosis occurs. Consider alternative drugs if continued anticoagulation therapy is necessary.

Calciphylaxis

Fatal and serious calciphylaxis or calcium uremic arteriolopathy has been reported in patients with and without end-stage renal disease. When calciphylaxis is diagnosed in these patients, discontinue COUMADIN and treat calciphylaxis as appropriate. Consider alternative anticoagulation therapy.

Acute Kidney Injury

In patients with altered glomerular integrity or with a history of kidney disease, acute kidney injury may occur with COUMADIN, possibly in relation to episodes of excessive anticoagulation and hematuria [see Use In Specific Populations]. More frequent monitoring of anticoagulation is advised in patients with compromised renal function.

Systemic Atheroemboli And Cholesterol Microemboli

Anticoagulation therapy with COUMADIN may enhance the release of atheromatous plaque emboli. Systemic atheroemboli and cholesterol microemboli can present with a variety of signs and symptoms depending on the site of embolization. The most commonly involved visceral organs are the kidneys followed by the pancreas, spleen, and liver. Some cases have progressed to necrosis or death. A distinct syndrome resulting from microemboli to the feet is known as “purple toes syndrome.” Discontinue COUMADIN therapy if such phenomena are observed. Consider alternative drugs if continued anticoagulation therapy is necessary.

Limb Ischemia, Necrosis, And Gangrene In Patients With HIT And HITTS

Do not use COUMADIN as initial therapy in patients with heparin-induced thrombocytopenia (HIT) and with heparin-induced thrombocytopenia with thrombosis syndrome (HITTS). Cases of limb ischemia, necrosis, and gangrene have occurred in patients with HIT and HITTS when heparin treatment was discontinued and warfarin therapy was started or continued. In some patients, sequelae have included amputation of the involved area and/or death. Treatment with COUMADIN may be considered after the platelet count has normalized.

Use In Pregnant Women With Mechanical Heart Valves

COUMADIN can cause fetal harm when administered to a pregnant woman. While COUMADIN is contraindicated during pregnancy, the potential benefits of using COUMADIN may outweigh the risks for pregnant women with mechanical heart valves at high risk of thromboembolism. In those individual situations, the decision to initiate or continue COUMADIN should be reviewed with the patient, taking into consideration the specific risks and benefits pertaining to the individual patient’s medical situation, as well as the most current medical guidelines. COUMADIN exposure during pregnancy causes a recognized pattern of major congenital malformations (warfarin embryopathy and fetotoxicity), fatal fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use In Specific Populations].

Other Clinical Settings With Increased Risks

In the following clinical settings, the risks of COUMADIN therapy may be increased:

• Moderate to severe hepatic impairment
• Infectious diseases or disturbances of intestinal flora (e.g., sprue, antibiotic therapy)
• Use of an indwelling catheter
• Severe to moderate hypertension
• Deficiency in protein C-mediated anticoagulant response: COUMADIN reduces the synthesis of the naturally occurring anticoagulants, protein C and protein S. Hereditary or acquired deficiencies of protein C or its cofactor, protein S, have been associated with tissue necrosis following warfarin administration. Concomitant anticoagulation therapy with heparin for 5 to 7 days during initiation of therapy with COUMADIN may minimize the incidence of tissue necrosis in these patients.
• Eye surgery: In cataract surgery, COUMADIN use was associated with a significant increase in minor complications of sharp needle and local anesthesia block but not associated with potentially sightthreatening operative hemorrhagic complications. As COUMADIN cessation or reduction may lead to serious thromboembolic complications, the decision to discontinue COUMADIN before a relatively less invasive and complex eye surgery, such as lens surgery, should be based upon the risks of anticoagulant therapy weighed against the benefits.
• Polycythemia vera
• Vasculitis
• Diabetes mellitus

Endogenous Factors Affecting INR

The following factors may be responsible for increased INR response: diarrhea, hepatic disorders, poor nutritional state, steatorrhea, or vitamin K deficiency.

The following factors may be responsible for decreased INR response: increased vitamin K intake or hereditary warfarin resistance.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Instructions For Patients

Advise patients to:

• Strictly adhere to the prescribed dosage schedule [see DOSAGE AND ADMINISTRATION].
• If the prescribed dose of COUMADIN is missed, 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 [see DOSAGE AND ADMINISTRATION].
• Obtain prothrombin time tests and make regular visits to their physician or clinic to monitor therapy [see DOSAGE AND ADMINISTRATION] .
• Be aware that if therapy with COUMADIN is discontinued, the anticoagulant effects of COUMADIN may persist for about 2 to 5 days [see CLINICAL PHARMACOLOGY].
• Avoid any activity or sport that may result in traumatic injury [see Use In Specific Populations]. And to tell their physician if they fall often as this may increase their risk for complications.
• Eat a normal, balanced diet to maintain a consistent intake of vitamin K. Avoid drastic changes in dietary habits, such as eating large amounts of leafy, green vegetables [see DRUG INTERACTIONS].
• Contact their physician to report any serious illness, such as severe diarrhea, infection, or fever [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].
• Carry identification stating that they are taking COUMADIN.

Bleeding Risks

Advise patients to

• Notify their 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 [see BOX WARNING and WARNINGS AND PRECAUTIONS].

Concomitant Medications And Botanicals (Herbals )

Advise patients to:

• Not take or discontinue any other drug, including salicylates (e.g., aspirin and topical analgesics), other over-the-counter drugs, and botanical (herbal) products except on advice of your physician [see DRUG INTERACTIONS].

Pregnancy And Nursing

Advise patients to:

• Contact their doctor
  • immediately if they think they are pregnant [see Use In Specific Populations],
  • to discuss pregnancy planning [see Use In Specific Populations],
  • if they are considering breastfeeding [see Use In Specific Populations].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity, mutagenicity, or fertility studies have not been performed with warfarin.

Use In Specific Populations

Pregnancy

Risk Summary

COUMADIN is contraindicated in women who are pregnant except in pregnant women with mechanical heart valves, who are at high risk of thromboembolism, and for whom the benefits of COUMADIN may outweigh the risks [see WARNINGS AND PRECAUTIONS]. COUMADIN can cause fetal harm. Exposure to warfarin during the first trimester of pregnancy caused a pattern of congenital malformations in about 5% of exposed offspring. Because these data were not collected in adequate and well-controlled studies, this incidence of major birth defects is not an adequate basis for comparison to the estimated incidences in the control group or the U.S. general population and may not reflect the incidences observed in practice. Consider the benefits and risks of COUMADIN and possible risks to the fetus when prescribing COUMADIN to a pregnant woman.

Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

In humans, warfarin crosses the placenta, and concentrations in fetal plasma approach the maternal values. Exposure to warfarin during the first trimester of pregnancy caused a pattern of congenital malformations in about 5% of exposed offspring. Warfarin embryopathy is characterized by nasal hypoplasia with or without stippled epiphyses (chondrodysplasia punctata) and growth retardation (including low birth weight). Central nervous system and eye abnormalities have also been reported, including dorsal midline dysplasia characterized by agenesis of the corpus callosum, Dandy-Walker malformation, midline cerebellar atrophy, and ventral midline dysplasia characterized by optic atrophy. Mental retardation, blindness, schizencephaly, microcephaly, hydrocephalus, and other adverse pregnancy outcomes have been reported following warfarin exposure during the second and third trimesters of pregnancy [see CONTRAINDICATIONS].

Lactation

Risk Summary

Warfarin was not present in human milk from mothers treated with warfarin from a limited published study. Because of the potential for serious adverse reactions, including bleeding in a breastfed infant, consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for COUMADIN and any potential adverse effects on the breastfed infant from COUMADIN or from the underlying maternal condition before prescribing COUMADIN to a lactating woman.

Clinical Considerations

Monitor breastfeeding infants for bruising or bleeding.

Data

Human Data

Based on published data in 15 nursing mothers, warfarin was not detected in human milk. Among the 15 full-term newborns, 6 nursing infants had documented prothrombin times within the expected range. Prothrombin times were not obtained for the other 9 nursing infants. Effects in premature infants have not been evaluated.

Females And Males Of Reproductive Potential

Pregnancy Testing

COUMADIN can cause fetal harm [see Use In Specific Populations].

Verify the pregnancy status of females of reproductive potential prior to initiating COUMADIN therapy.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after the final dose of COUMADIN.

Pediatric Use

Adequate and well-controlled studies with COUMADIN have not been conducted in any pediatric population, and the optimum dosing, safety, and efficacy in pediatric patients is unknown. Pediatric use of COUMADIN is based on adult data and recommendations, and available limited pediatric data from observational studies and patient registries. Pediatric patients administered COUMADIN should avoid any activity or sport that may result in traumatic injury.

The developing hemostatic system in infants and children results in a changing physiology of thrombosis and response to anticoagulants. Dosing of warfarin in the pediatric population varies by patient age, with infants generally having the highest, and adolescents having the lowest milligram per kilogram dose requirements to maintain target INRs. Because of changing warfarin requirements due to age, concomitant medications, diet, and existing medical condition, target INR ranges may be difficult to achieve and maintain in pediatric patients, and more frequent INR determinations are recommended.

Bleeding rates varied by patient population and clinical care center in pediatric observational studies and patient registries.

Infants and children receiving vitamin K-supplemented nutrition, including infant formulas, may be resistant to warfarin therapy, while human milk-fed infants may be sensitive to warfarin therapy.

Geriatric Use

Of the total number of patients receiving warfarin sodium in controlled clinical trials for which data were available for analysis, 1885 patients (24.4%) were 65 years and older, while 185 patients (2.4%) were 75 years and older. No overall differences in effectiveness or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients 60 years or older appear to exhibit greater than expected INR response to the anticoagulant effects of warfarin [see CLINICAL PHARMACOLOGY]. COUMADIN is contraindicated in any unsupervised patient with senility. Observe caution with administration of COUMADIN to elderly patients in any situation or with any physical condition where added risk of hemorrhage is present. Consider lower initiation and maintenance doses of COUMADIN in elderly patients [see DOSAGE AND ADMINISTRATION].

Renal Impairment

Renal clearance is considered to be a minor determinant of anticoagulant response to warfarin. No dosage adjustment is necessary for patients with renal impairment. Instruct patients with renal impairment taking warfarin to monitor their INR more frequently [see WARNINGS AND PRECAUTIONS].

Hepatic Impairment

Hepatic impairment can potentiate the response to warfarin through impaired synthesis of clotting factors and decreased metabolism of warfarin. Use caution when using COUMADIN in these patients.

OVERDOSE

Signs And Symptoms

Bleeding (e.g., appearance of blood in stools or urine, hematuria, excessive menstrual bleeding, melena, petechiae, excessive bruising or persistent oozing from superficial injuries, unexplained fall in hemoglobin) is a manifestation of excessive anticoagulation.

Treatment

The treatment of excessive anticoagulation is based on the level of the INR, the presence or absence of bleeding, and clinical circumstances. Reversal of COUMADIN anticoagulation may be obtained by discontinuing COUMADIN therapy and, if necessary, by administration of oral or parenteral vitamin K₁ .

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

Prothrombin complex concentrate (PCC), fresh frozen plasma, or activated Factor VII treatment may be considered if the requirement to reverse the effects of COUMADIN is urgent. A risk of hepatitis and other viral diseases is associated with the use of blood products; PCC and activated Factor VII are also associated with an increased risk of thrombosis. Therefore, these preparations should be used only in exceptional or life-threatening bleeding episodes secondary to COUMADIN overdosage.

CONTRAINDICATIONS

COUMADIN is contraindicated in:

• Pregnancy

COUMADIN is contraindicated in women who are pregnant except in pregnant women with mechanical heart valves, who are at high risk of thromboembolism [see WARNINGS AND PRECAUTIONS and Use In Specific Populations]. COUMADIN can cause fetal harm when administered to a pregnant woman. COUMADIN exposure during pregnancy causes a recognized pattern of major congenital malformations (warfarin embryopathy and fetotoxicity), fatal fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality. If COUMADIN is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use In Specific Populations].

COUMADIN is contraindicated in patients with:

• Hemorrhagic tendencies or blood dyscrasias
• Recent or contemplated surgery of the central nervous system or eye, or traumatic surgery resulting in large open surfaces [see WARNINGS AND PRECAUTIONS]
• Bleeding tendencies associated with:
  • Active ulceration or overt bleeding of the gastrointestinal, genitourinary, or respiratory tract
  • Central nervous system hemorrhage
  • Cerebral aneurysms, dissecting aorta
  • Pericarditis and pericardial effusions
  • Bacterial endocarditis
• Threatened abortion, eclampsia, and preeclampsia
• Unsupervised patients with conditions associated with potential high level of non-compliance
• Spinal puncture and other diagnostic or therapeutic procedures with potential for uncontrollable bleeding
• Hypersensitivity to warfarin or to any other components of this product (e.g., anaphylaxis) [see ADVERSE REACTIONS]
• Major regional or lumbar block anesthesia
• Malignant hypertension

CLINICAL PHARMACOLOGY

Mechanism Of Action

Warfarin acts by inhibiting the synthesis of vitamin K-dependent clotting factors, which include Factors II, VII, IX, and X, and the anticoagulant proteins C and S. Vitamin K is an essential cofactor for the post ribosomal synthesis of the vitamin K-dependent clotting factors. Vitamin K promotes the biosynthesis of γ-carboxyglutamic acid residues in the proteins that are essential for biological activity. Warfarin is thought to interfere with clotting factor synthesis by inhibition of the C1 subunit of vitamin K epoxide reductase (VKORC1) enzyme complex, thereby reducing the regeneration of vitamin K₁ epoxide [see Pharmacogenomics].

Pharmacodynamics

An anticoagulation effect generally occurs within 24 hours after warfarin administration. However, peak anticoagulant effect may be delayed 72 to 96 hours. The duration of action of a single dose of racemic warfarin is 2 to 5 days. The effects of COUMADIN may become more pronounced as effects of daily maintenance doses overlap. This is consistent with the half-lives of the affected vitamin Kdependent clotting factors and anticoagulation proteins: Factor II - 60 hours, VII - 4 to 6 hours, IX - 24 hours, X - 48 to 72 hours, and proteins C and S are approximately 8 hours and 30 hours, respectively.

Pharmacokinetics

COUMADIN is a racemic mixture of the R- and S-enantiomers of warfarin. 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 is essentially completely absorbed after oral administration, with peak concentration generally attained within the first 4 hours.

Distribution

Warfarin distributes into a relatively small apparent volume of distribution of about 0.14 L/kg. A distribution phase lasting 6 to 12 hours is distinguishable after rapid intravenous or oral administration of an aqueous solution. Approximately 99% of the drug is bound to plasma proteins.

Metabolism

The elimination of warfarin is almost entirely by metabolism. Warfarin is stereoselectively metabolized by hepatic cytochrome P-450 (CYP450) microsomal enzymes to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolites (warfarin alcohols) with minimal anticoagulant activity. Identified metabolites of warfarin include dehydrowarfarin, two diastereoisomer alcohols, and 4’-, 6-, 7-, 8-, and 10-hydroxywarfarin. The CYP450 isozymes involved in the metabolism of warfarin include CYP2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. CYP2C9, a polymorphic enzyme, is likely to be the principal form of human liver CYP450 that modulates the in vivo anticoagulant activity of warfarin. Patients with one or more variant CYP2C9 alleles have decreased S-warfarin clearance [see Pharmacogenomics].

Excretion

The terminal half-life of warfarin after a single dose is approximately 1 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 Rwarfarin 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.

Geriatric Patients

Patients 60 years or older appear to exhibit greater than expected 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 but may be due to a combination of pharmacokinetic and pharmacodynamic factors. Limited information suggests there is no difference in the clearance of S-warfarin; 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 [see DOSAGE AND ADMINISTRATION].

Asian Patients

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

Pharmacogenomics

CYP2C9 And VKORC1 Polymorphisms

The S-enantiomer of warfarin is mainly metabolized to 7-hydroxywarfarin by CYP2C9, a polymorphic enzyme. The variant alleles, CYP2C9*2 and CYP2C9*3, result in decreased in vitro CYP2C9 enzymatic 7-hydroxylation of S-warfarin. The frequencies of these alleles in Caucasians are approximately 11% and 7% for CYP2C9*2 and CYP2C9*3, respectively.

Other CYP2C9 alleles associated with reduced enzymatic activity occur at lower frequencies, including *5, *6, and *11 alleles in populations of African ancestry and *5, *9, and *11 alleles in Caucasians.

Warfarin reduces the regeneration of vitamin K from vitamin K epoxide in the vitamin K cycle through inhibition of VKOR, a multiprotein enzyme complex. Certain single nucleotide polymorphisms in the VKORC1 gene (e.g., .1639G>A) have been associated with variable warfarin dose requirements.

VKORC1 and CYP2C9 gene variants generally explain the largest proportion of known variability in warfarin dose requirements.

CYP2C9 and VKORC1 genotype information, when available, can assist in selection of the initial dose of warfarin [see DOSAGE AND ADMINISTRATION].

Clinical Studies

Atrial Fibrillation

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 4). The risk reduction ranged from 60% to 86% in all except one trial (CAFA: 45%), which was 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 4).

Table 4: Clinical Studies of Warfarin in Non-Rheumatic AF Patients *

Study	N				Thromboembolism		% Major Bleeding
	Warfarin- Treated Patients	Control Patients	PT Ratio	INR	% Risk Reduction	p-value	Warfarin- Treated Patients	Control 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 hemorrhagic stroke and transient ischemic attacks.

Trials in patients with both AF and mitral stenosis suggest a benefit from anticoagulation with COUMADIN [see DOSAGE AND ADMINISTRATION].

Mechanical And Bioprosthetic Heart Valves

In a prospective, randomized, open-label, positive-controlled study in 254 patients with mechanical prosthetic heart valves, the thromboembolic-free interval was found to be significantly greater in patients treated with warfarin alone compared with dipyridamole/aspirin-treated patients (p<0.005) and pentoxifylline/aspirin-treated patients (p<0.05). The results of this study are presented in Table 5.

Table 5: Prospective, Randomized, Open-Label, Positive-Controlled Clinical Study of Warfarin in Patients with Mechanical Prosthetic Heart Valves

Event	Patients Treated With
	Warfarin	Dipyridamole/ Aspirin	Pentoxifylline/ Aspirin
Thromboembolism	2.2/100 py	8.6/100 py	7.9/100 py
Major Bleeding	2.5/100 py	0.0/100 py	0.9/100 py
py=patient years

In a prospective, open-label, clinical study comparing moderate (INR 2.65) versus 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 per 100 patient years, respectively). Major bleeding was more common in the high intensity group. The results of this study are presented in Table 6.

Table 6: Prospective, Open-Label Clinical Study of Warfarin in Patients with Mechanical Prosthetic Heart Valves

Event	Moderate Warfarin Therapy INR 2.65	High Intens ity Warfarin Therapy INR 9.0
Thromboembolism	4.0/100 py	3.7/100 py
Major Bleeding	0.95/100 py	2.1/100 py
py=patient years

In a randomized trial in 210 patients comparing two intensities of warfarin therapy (INR 2.0-2.25 vs. INR 2.5-4.0) 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 hemorrhages occurred in 4.6% of patients in the higher intensity INR group compared to zero in the lower intensity INR group.

Myocardial Infarction

WARIS (The Warfarin Re-Infarction Study) was a double-blind, randomized study of 1214 patients 2 to 4 weeks post-infarction treated with warfarin to a target INR of 2.8 to 4.8. The primary endpoint was a composite 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 Table 7.

Table 7: WARIS . Endpoint Analys is of Separate Events

Event	Warfarin (N=607)	Placebo (N=607)	RR (95% CI)	% Risk Reduction (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=(1 - RR); CI=Confidence interval; MI=Myocardial infarction; py=patient year

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 to a target INR 2.8 to 4.2, aspirin 160 mg per day, or warfarin to a target INR 2.0 to 2.5 plus aspirin 75 mg per day prior to hospital discharge. 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 Table 8.

Table 8: WARIS II . Distribution of Events According to Treatment Group

Event	Aspirin (N=1206)	Warfarin (N=1216)	Aspirin plus Warfarin (N=1208)	Rate Ratio (95% CI)	p-value
	No. of Events
Major Bleedinga	8	33	28	3.35b (ND)	ND
				4.00 c (ND)	ND
Minor Bleedingd	39	103	133	3.21b (ND)	ND
				2.55c (ND)	ND
Composite Endpointse	241	203	181	0.81 (0.69-0.95)b	0.03
				0.71 (0.60-0.83)c	0.001
Reinfarction	117	90	69	0.56 (0.41-0.78)b	<0.001
				0.74 (0.55-0.98)c	0.03
Thromboembolic Stroke	32	17	17	0.52 (0.28-0.98)b	0.03
				0.52 (0.28-0.97)c	0.03
Death	92	96	95		0.82
aMajor bleeding episodes were defined as nonfatal cerebral hemorrhage or bleeding necessitating surgical intervention or blood transfusion. bThe rate ratio is for aspirin plus warfarin as compared with aspirin. cThe rate ratio is for warfarin as compared with aspirin. dMinor bleeding episodes were defined as non-cerebral hemorrhage not necessitating surgical intervention or blood transfusion. eIncludes death, nonfatal reinfarction, and thromboembolic cerebral stroke. CI=confidence interval ND=not determined

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.

PATIENT INFORMATION

COUMADIN^®
(COU-ma-din)
(warfarin sodium)

What is the most important information I should know about COUMADIN?

COUMADIN can cause bleeding which can be serious and sometimes lead to death. This is because COUMADIN is a blood thinner medicine that lowers the chance of blood clots forming in your body.

• You may have a higher risk of bleeding if you take COUMADIN and:
  • are 65 years of age or older
  • have a history of stomach or intestinal bleeding
  • have high blood pressure (hypertension)
  • have a history of stroke, or “mini-stroke” (transient ischemic attack or TIA)
  • have serious heart disease
  • have a low blood count or cancer
  • have had trauma, such as an accident or surgery
  • have kidney problems
  • take other medicines that increase your risk of bleeding, including:
    • a medicine that contains heparin
    • other medicines to prevent or treat blood clots
    • nonsteroidal anti-inflammatory drugs (NSAIDs)
  • take warfarin sodium for a long time. Warfarin sodium is the active ingredient in COUMADIN.

Tell your healthcare provider if you take any of these medicines . Ask your healthcare provider if you are not sure if your medicine is one listed above.

Many other medicines can interact with COUMADIN and affect the dose you need or increase COUMADIN side effects. Do not change or stop any of your medicines or start any new medicines before you talk to your healthcare provider.

Do not take other medicines that contain warfarin sodium while taking COUMADIN.

• Get your regular blood test to check for your response to COUMADIN. This blood test is called an INR test. The INR test checks to see how fast your blood clots. Your healthcare provider will decide what INR numbers are best for you. Your dose of COUMADIN will be adjusted to keep your INR in a target range for you.
• Call your healthcare provider right away if you get any of the following signs or symptoms of bleeding problems :
  • pain, swelling, or discomfort
  • headaches, dizziness, or weakness
  • unusual bruising (bruises that develop without known cause or grow in size)
  • nosebleeds
  • bleeding gums
  • bleeding from cuts takes a long time to stop
  • menstrual bleeding or vaginal bleeding that is heavier than normal
  • pink or brown urine
  • red or black stools
  • coughing up blood
  • vomiting blood or material that looks like coffee grounds
• Some foods and beverages can interact with COUMADIN and affect your treatment and dose.
  • Eat a normal, balanced diet. Talk to your healthcare provider before you make any diet changes. Do not eat large amounts of leafy, green vegetables. Leafy, green vegetables contain vitamin K. Certain vegetable oils also contain large amounts of vitamin K. Too much vitamin K can lower the effect of COUMADIN.
• Always tell all of your healthcare providers that you take COUMADIN.
• Wear or carry information that you take COUMADIN.

See “What are the possible side effects of COUMADIN?” for more information about side effects .

What is COUMADIN?

COUMADIN is prescription medicine used to treat blood clots and to lower the chance of blood clots forming in your body. Blood clots can cause a stroke, heart attack, or other serious conditions if they form in the legs or lungs.

Who should not take COUMADIN?

Do not take COUMADIN if:

• your risk of having bleeding problems is higher than the possible benefit of treatment. Your healthcare provider will decide if COUMADIN is right for you.
• you are pregnant unless you have a mechanical heart valve. COUMADIN may cause birth defects, miscarriage, or death of your unborn baby.
• you are allergic to warfarin or any of the other ingredients in COUMADIN. See the end of this leaflet for a complete lis t of ingredients in COUMADIN.

Before taking COUMADIN

Tell your healthcare provider about all of your medical conditions, including if you:

• have bleeding problems
• fall often
• have liver problems
• have kidney problems or are undergoing dialysis
• have high blood pressure
• have a heart problem called congestive heart failure
• have diabetes
• plan to have any surgery or a dental procedure
• have any other medical conditions
• are pregnant or plan to become pregnant. See “Who should not take COUMADIN?”
  Your healthcare provider will do a pregnancy test before you start treatment with COUMADIN. Females who can become pregnant should use effective birth control during treatment, and for at least 1 month after the last dose of COUMADIN.
• are breastfeeding. You and your healthcare provider should decide if you will take COUMADIN and breastfeed. Check your baby for bruising or bleeding if you take COUMADIN and breastfeed.

Tell all of your healthcare providers and dentists that you are taking COUMADIN. They should talk to the healthcare provider who prescribed COUMADIN for you before you have any surgery or dental procedure. Your COUMADIN may need to be stopped for a short time or you may need your dose adjusted.

Tell your healthcare provider about all the medicines you take, including prescription and over-thecounter medicines, vitamins, and herbal supplements. Some of your other medicines may affect the way COUMADIN works. Certain medicines may increase your risk of bleeding. See “What is the most important information I should know about COUMADIN?”

How should I take COUMADIN?

• Take COUMADIN exactly as prescribed. Your healthcare provider will adjust your dose from time to time depending on your response to COUMADIN.
• You must have regular blood tess and vis its with your healthcare provider to monitor your condition.
• If you miss a dose of COUMADIN, call your healthcare provider. Take the dose as soon as possible on the same day. Do not take a double dose of COUMADIN the next day to make up for a missed dose.
• Call your healthcare provider right away if you:
  • take too much COUMADIN
  • are sick with diarrhea, an infection, or have a fever
  • fall or injure yourself, especially if you hit your head. Your healthcare provider may need to check you.

What should I avoid while taking COUMADIN?

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

What are the possible side effects of COUMADIN?

COUMADIN may cause serious side effects including:

• See “What is the most important information I should know about COUMADIN?”
• Death of skin tissue (skin necros is or gangrene). This can happen soon after starting COUMADIN. 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.
• Kidney problems. Kidney injury may happen in people who take COUMADIN. Tell your healthcare provider right away if develop blood in your urine.Your healthcare provider may do tests more often during treatment with COUMADIN to check for bleeding if you already have kidney problems.
• “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.

These are not all of the side effects of COUMADIN. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1..800-FDA-1088.

How should I store COUMADIN?

• Store COUMADIN at 59°F to 86°F (15°C to 30°C).
• Keep COUMADIN in a tightly closed container
• Keep COUMADIN out of the light and moisture.
• Follow your healthcare provider or pharmacist instructions about the right way to throw away outdated or unused COUMADIN.
• Females who are pregnant should not handle crushed or broken COUMADIN tablets.

Keep COUMADIN and all medicines out of the reach of children.

General information about the safe and effective use of COUMADIN.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use COUMADIN for a condition for which it was not prescribed. Do not give COUMADIN to other people, even if they have the same symptoms that you have. It may harm them.

You can ask your healthcare provider or pharmacist for information about COUMADIN that is written for health professionals.

What are the ingredients in COUMADIN tablets?

Active ingredient: warfarin sodium

Inactive ingredients : lactose, starch, and magnesium stearate, in addition:

1 mg: D&C Red No. 6 Barium Lake

2 mg: FD&C Blue No. 2 Aluminum Lake and FD&C Red No. 40 Aluminum Lake

2.5 mg: D&C Yellow No. 10 Aluminum Lake and FD&C Blue No. 1 Aluminum Lake

3 mg: FD&C Yellow No. 6 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, and FD&C Red No. 40 Aluminum Lake

4 mg: FD&C Blue No. 1 Aluminum Lake

5 mg: FD&C Yellow No. 6 Aluminum Lake

6 mg: FD&C Yellow No. 6 Aluminum Lake and FD&C Blue No. 1 Aluminum Lake

7.5 mg: D&C Yellow No. 10 Aluminum Lake and FD&C Yellow No. 6 Aluminum Lake

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