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COUMADIN (warfarin sodium 2.5 mg) Dailymed

  1. Human Prescription
  2. Archived
  3. Lake Erie Medical & Surgical Supply DBA Quality Care Products LLC

Generic: warfarin sodium

COUMADIN tablet - (warfarin sodium 2.5 mg) image
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IMPRINT: 2 1 2 COUMADIN     SHAPE: round
    COLOR: green    SCORE: 2

All Imprints

warfarin sodium 2.5 mg - 2 1 2 coumadin round green

warfarin sodium 2 mg - 2 coumadin round purple

warfarin sodium 1 mg - 1 coumadin round pink

warfarin sodium 4 mg - 4 coumadin round blue

warfarin sodium 3 mg - 3 coumadin round brown

warfarin sodium 10 mg - 10 coumadin round white

warfarin sodium 6 mg - 6 coumadin round turquoise

warfarin sodium 5 mg - 5 coumadin round orange

warfarin sodium 7.5 mg - 7 1 2 coumadin round yellow

Boxed Warning

Warning: Bleeding Risk

WARNING: BLEEDING RISK See full prescribing information for complete boxed warning.
  • COUMADIN can cause major or fatal bleeding. (5.1)
  • Perform regular monitoring of INR in all treated patients. (2.1)
  • Drugs, dietary changes, and other factors affect INR levels achieved with COUMADIN therapy. (7)
  • Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding. (17)

  1. FDA Adverse Reactions

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Warning: Bleeding Risk



WARNING: BLEEDING RISK

See full prescribing information for complete boxed warning.
  • COUMADIN can cause major or fatal bleeding. (5.1)
  • Perform regular monitoring of INR in all treated patients. (2.1)
  • Drugs, dietary changes, and other factors affect INR levels achieved with COUMADIN therapy. (7)
  • Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding. (17)

Recent Major Changes Section



Contraindications (4)   10/2011

Warnings and Precautions, Use in Pregnant Women with Mechanical Heart Valves (5.5)   10/2011

1 Indications And Usage


COUMADIN® is indicated for:
  • Prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism (PE).
  • Prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation (AF) and/or cardiac valve replacement.
  • Reduction in the risk of death, recurrent myocardial infarction (MI), and thromboembolic events such as stroke or systemic embolization after myocardial infarction.

Limitations of Use

COUMADIN has no direct effect on an established thrombus, nor does it reverse ischemic tissue damage. Once a thrombus has occurred, however, the goals of anticoagulant treatment are to prevent further extension of the formed clot and to prevent secondary thromboembolic complications that may result in serious and possibly fatal sequelae.


COUMADIN is a vitamin K antagonist indicated for:
  • Prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism (1)
  • Prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement (1)
  • Reduction in the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic embolization after myocardial infarction (1)

Limitation of Use

COUMADIN has no direct effect on an established thrombus, nor does it reverse ischemic tissue damage. (1)

3 Dosage Forms And Strengths


COUMADIN tablets are single scored with one face imprinted numerically with 1, 2, 2-1/2, 3, 4, 5, 6, 7-1/2, or 10 superimposed and inscribed with “COUMADIN” and with the opposite face plain.

COUMADIN tablets are supplied in the following strengths:
COUMADIN Tablets
Strength Color
1 mg pink
2 mg lavender
2-1/2 mg green
3 mg tan
4 mg blue
5 mg peach
6 mg teal
7-1/2 mg yellow
10 mg white (dye-free)

COUMADIN for injection is available in a vial containing 5 mg of lyophilized powder.

  • Scored tablets: 1, 2, 2-1/2, 3, 4, 5, 6, 7-1/2, or 10 mg (3)
  • For injection: Vial containing 5 mg lyophilized powder (3)

4 Contraindications

  • 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 (5.5) and Use in Specific Populations (8.1) ]. 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 Warnings and Precautions (5.6) and Use in Specific Populations (8.1) ].
  • 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 (5.7) ]
  • 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 (6) ]
  • Major regional or lumbar block anesthesia
  • Malignant hypertension

  • Pregnancy, except in women with mechanical heart valves (4)
  • Hemorrhagic tendencies or blood dyscrasias (4)
  • Recent or contemplated surgery of the central nervous system (CNS) or eye, or traumatic surgery resulting in large open surfaces (4, 5.7)
  • Bleeding tendencies associated with certain conditions (4)
  • Threatened abortion, eclampsia, and preeclampsia (4)
  • Unsupervised patients with potential high levels of non-compliance (4)
  • Spinal puncture and other diagnostic or therapeutic procedures with potential for uncontrollable bleeding (4)
  • Hypersensitivity to warfarin or any component of the product (4)
  • Major regional or lumbar block anesthesia (4)
  • Malignant hypertension (4)

5 Warnings And Precautions


  • Tissue necrosis: Necrosis or gangrene of skin or other tissues can occur, with severe cases requiring debridement or amputation. Discontinue COUMADIN and consider alternative anticoagulants if necessary. (5.2)
  • Systemic atheroemboli and cholesterol microemboli: Some cases have progressed to necrosis or death. Discontinue COUMADIN if such emboli occur. (5.3)
  • Heparin-induced thrombocytopenia (HIT): Initial therapy with COUMADIN in HIT has resulted in cases of amputation and death. COUMADIN may be considered after platelet count has normalized. (5.4)
  • Pregnant women with mechanical heart valves: COUMADIN may cause fetal harm; however, the benefits may outweigh the risks. (5.5)

5.1 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 (12.5) ], certain concomitant drugs [see Drug Interactions (7) ], 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 (7) ].

Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding [see Patient Counseling Information (17) ].

5.2 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.

5.3 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.

5.4 Heparin-Induced Thrombocytopenia


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.

5.5 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 (8.1) ].

5.6 Females of Reproductive Potential


COUMADIN exposure during pregnancy can cause pregnancy loss, birth defects, or fetal death. Discuss pregnancy planning with females of reproductive potential who are on COUMADIN therapy [see Contraindications (4) and Use in Specific Populations (8.8) ].

5.7 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 sight-threatening 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

5.8 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.

6 Adverse Reactions


The following serious adverse reactions to COUMADIN are discussed in greater detail in other sections of the labeling:

Other adverse reactions to COUMADIN include:
  • Immune system disorders: hypersensitivity/allergic reactions (including urticaria and anaphylactic reactions)
  • Vascular disorders: vasculitis
  • Hepatobiliary disorders: hepatitis, elevated liver enzymes. Cholestatic hepatitis has been associated with concomitant administration of COUMADIN and ticlopidine.
  • Gastrointestinal disorders: nausea, vomiting, diarrhea, taste perversion, abdominal pain, flatulence, bloating
  • Skin disorders: rash, dermatitis (including bullous eruptions), pruritus, alopecia
  • Respiratory disorders: tracheal or tracheobronchial calcification
  • General disorders: chills


Most common adverse reactions to COUMADIN are fatal and nonfatal hemorrhage from any tissue or organ. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 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 alteration of the 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.

More frequent INR monitoring should be performed when starting or stopping other drugs, including botanicals, or when changing dosages of other drugs, including drugs intended for short-term use (e.g., antibiotics, antifungals, corticosteroids) [see Boxed Warning ].

Consult the labeling of all concurrently used drugs to obtain further information about interactions with COUMADIN or adverse reactions pertaining to bleeding.

  • Consult labeling of all concurrently used drugs for complete information about interactions with COUMADIN or increased risks for bleeding. (7)
  • Inhibitors and inducers of CYP2C9, 1A2, or 3A4: May alter warfarin exposure. Monitor INR closely when any such drug is used with COUMADIN. (7.1)
  • Drugs that increase bleeding risk: Closely monitor patients receiving any such drug (e.g., other anticoagulants, antiplatelet agents, nonsteroidal anti-inflammatory drugs, serotonin reuptake inhibitors). (7.2)
  • Antibiotics and antifungals: Closely monitor INR when initiating or stopping an antibiotic or antifungal course of therapy. (7.3)
  • Botanical (herbal) products: Some may influence patient response to COUMADIN necessitating close INR monitoring. (7.4)

7.1 CYP450 Interactions


CYP450 isozymes involved in the metabolism of warfarin include CYP2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. The more potent warfarin S-enantiomer is metabolized by CYP2C9 while the R-enantiomer is metabolized by CYP1A2 and 3A4.
  • Inhibitors of CYP2C9, 1A2, and/or 3A4 have the potential to increase the effect (increase INR) of warfarin by increasing the exposure of warfarin.
  • Inducers of CYP2C9, 1A2, and/or 3A4 have the potential to decrease the effect (decrease INR) of warfarin by decreasing the exposure of warfarin.

Examples of inhibitors and inducers of CYP2C9, 1A2, and 3A4 are below in Table 2; however, this ul should not be considered all-inclusive. Consult the labeling of all concurrently used drugs to obtain further information about CYP450 interaction potential. The CYP450 inhibition and induction potential should be considered when starting, stopping, or changing dose of concomitant mediations. Closely monitor INR if a concomitant drug is a CYP2C9, 1A2, and/or 3A4 inhibitor or inducer.
Table 2:   Examples of CYP450 Interactions with Warfarin
Enzyme Inhibitors Inducers
CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

7.2 Drugs that Increase Bleeding Risk


Examples of drugs known to increase the risk of bleeding are presented in Table 3. Because bleeding risk is increased when these drugs are used concomitantly with warfarin, closely monitor patients receiving any such drug with warfarin.
Table 3:   Drugs that Can Increase the Risk of Bleeding
Drug Class Specific Drugs
Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

7.3 Antibiotics and Antifungals


There have been reports of changes in INR in patients taking warfarin and antibiotics or antifungals, but clinical pharmacokinetic studies have not shown consistent effects of these agents on plasma concentrations of warfarin.

Closely monitor INR when starting or stopping any antibiotic or antifungal in patients taking warfarin.

7.4 Botanical (Herbal) Products and Foods


Exercise caution when botanical (herbal) products are taken concomitantly with COUMADIN. Few adequate, well-controlled studies evaluating the potential for metabolic and/or pharmacologic interactions between botanicals and COUMADIN exist. 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.

Some botanicals may cause bleeding events when taken alone (e.g., garlic and Ginkgo biloba) and may have anticoagulant, antiplatelet, and/or fibrinolytic properties. These effects would be expected to be additive to the anticoagulant effects of COUMADIN. Conversely, some botanicals may decrease the effects of COUMADIN (e.g., co-enzyme Q10, St. John’s wort, ginseng). Some botanicals and foods can interact with COUMADIN through CYP450 interactions (e.g., echinacea, grapefruit juice, ginkgo, goldenseal, St. John’s wort).

Monitor the patient’s response with additional INR determinations when initiating or discontinuing any botanicals.

10 Overdosage


10.1 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.

10.2 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.

11 Description


COUMADIN (warfarin sodium) is an anticoagulant that acts by inhibiting vitamin K-dependent coagulation factors. Chemically, it is 3-(α-acetonylbenzyl)-4-hydroxycoumarin and is a racemic mixture of the R- and S-enantiomers. Crystalline warfarin sodium is an isopropanol clathrate. Its empirical formula is C19H15NaO4, and its structural formula is represented by the following:

Crystalline warfarin sodium occurs as a white, odorless, crystalline powder that is discolored by light. It is very soluble in water, freely soluble in alcohol, and very slightly soluble in chloroform and ether.

COUMADIN tablets for oral use also contain:
All strengths: Lactose, starch, and magnesium stearate
1 mg: D&C Red No. 6 Barium Lake
2 mg: FD&C Blue No. 2 Aluminum Lake andFD&C Red No. 40 Aluminum Lake
2-1/2 mg: D&C Yellow No. 10 Aluminum Lake andFD&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 andFD&C Blue No. 1 Aluminum Lake
7-1/2 mg: D&C Yellow No. 10 Aluminum Lake andFD&C Yellow No. 6 Aluminum Lake
10 mg: Dye-free

COUMADIN for injection for intravenous use is supplied as a sterile, lyophilized powder, which, after reconstitution with 2.7 mL Sterile Water for Injection, contains:
Warfarin sodium 2 mg per mL
Sodium phosphate, dibasic, heptahydrate 4.98 mg per mL
Sodium phosphate, monobasic, monohydrate 0.194 mg per mL
Sodium chloride 0.1 mg per mL
Mannitol 38.0 mg per mL
Sodium hydroxide, as needed for pH adjustment to 8.1 to 8.3

13 Nonclinical Toxicology


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility


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

14 Clinical Studies


14.1 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*
N Thromboembolism % Major Bleeding
Study Warfarin-Treated Patients Control Patients PT Ratio INR % Risk Reduction p-value Warfarin-Treated Patients Control Patients
*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.
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

Trials in patients with both AF and mitral stenosis suggest a benefit from anticoagulation with COUMADIN [see Dosage and Administration (2.2) ].

14.2 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
Patients Treated With
Warfarin Dipyridamole/Aspirin Pentoxifylline/Aspirin
Event
py=patient years
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

In a prospective, open-label, clinical study 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 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 TherapyINR 2.65 High Intensity Warfarin TherapyINR 9.0
py=patient years
Thromboembolism 4.0/100 py 3.7/100 py
Major Bleeding 0.95/100 py 2.1/100 py

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.

14.3 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 Analysis of Separate Events
Event Warfarin(N=607) Placebo(N=607) RR(95% CI) % RiskReduction(p-value)
RR=Relative risk; Risk reduction=(1 - RR); CI=Confidence interval; MI=Myocardial infarction; py=patient years
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)

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
a  Major bleeding episodes were defined as nonfatal cerebral hemorrhage or bleeding necessitating surgical intervention or blood transfusion.
b  The rate ratio is for aspirin plus warfarin as compared with aspirin.
c  The rate ratio is for warfarin as compared with aspirin.
d  Minor bleeding episodes were defined as non-cerebral hemorrhage not necessitating surgical intervention or blood transfusion.
e  Includes death, nonfatal reinfarction, and thromboembolic cerebral stroke.
CI=confidence interval
ND=not determined
No. of Events
Major Bleedinga 8 33 28 3.35b (ND) 4.00c (ND) NDND
Minor Bleedingd 39 103 133 3.21b (ND)2.55c (ND) NDND
Composite Endpointse 241 203 181 0.81 (0.69-0.95)b 0.71 (0.60-0.83)c 0.030.001
     Reinfarction 117 90 69 0.56 (0.41-0.78)b 0.74 (0.55-0.98)c <0.0010.03
     Thromboembolic Stroke 32 17 17 0.52 (0.28-0.98)b 0.52 (0.28-0.97)c 0.030.03
     Death 92 96 95 0.82

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.

15 References

  • Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K antagonists. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. 8th Ed. Chest. 2008;133:160S-198S.
  • Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ. Antithrombotic therapy for venous thromboembolic disease. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. 8th Ed. Chest. 2008;133:454S-545S.
  • Singer DE, Albers GW, Dalen JE, et al. Antithrombotic therapy in atrial fibrillation. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. 8th Ed. Chest. 2008;133:546S-592S.
  • Becker RC, Meade TW, Berger PB, et al. The primary and secondary prevention of coronary artery disease. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. 8th Ed. Chest. 2008;133:776S-814S.
  • Salem DN, O'Gara PT, Madias C, Pauker SG. Valvular and structural heart disease. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. 8th Ed. Chest. 2008;133:593S-629S.
  • Monagle P, Chalmers E, Chan A, et al. Antithrombotic therapy in neonates and children. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. 8th Ed. Chest. 2008;133:887S-968S.

17 Patient Counseling Information


See FDA-approved patient labeling (Medication Guide).

Advise patients to:
  • Tell their physician if they fall often as this may increase their risk for complications.
  • Strictly adhere to the prescribed dosage schedule. Do 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.
  • 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.
  • Contact their doctor
    • –immediately if they think they are pregnant
    • –to discuss pregnancy planning
    • –if they are considering breast-feeding
  • Avoid any activity or sport that may result in traumatic injury.
  • Obtain prothrombin time tests and make regular visits to their physician or clinic to monitor therapy.
  • Carry identification stating that they are taking COUMADIN.
  • 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.
  • 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.
  • Contact their physician to report any serious illness, such as severe diarrhea, infection, or fever.
  • Be aware that if therapy with COUMADIN is discontinued, the anticoagulant effects of COUMADIN may persist for about 2 to 5 days.


Distributed by: Bristol-Myers Squibb Company Princeton, New Jersey 08543 USA

COUMADIN® is a trademark of Bristol-Myers Squibb Pharma Company.

Copyright © Bristol-Myers Squibb Company 2011

Printed in USA1274054A0 / 1274029A0 / 1274055A0 / 1274053A0Rev October 2011

Spl Medguide Section


MEDICATION GUIDE

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

Read this Medication Guide before you start taking COUMADIN (warfarin sodium) and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. You and your healthcare provider should talk about COUMADIN when you start taking it and at regular checkups.

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 uled 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.

It is not known if COUMADIN is safe and effective in children.

Who should not take COUMADIN?

Do not take COUMADIN if:
  • your chance of having bleeding problems is higher than the possible benefit of treatment. Your healthcare provider will decide if COUMADIN is right for you. Talk to your healthcare provider about all of your health conditions.
  • 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 ul of ingredients in COUMADIN.

What should I tell my healthcare provider before taking COUMADIN?

Before you take COUMADIN, tell your healthcare provider if you:
  • have bleeding problems
  • fall often
  • have liver or kidney problems
  • 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?"
  • are breast-feeding. You and your healthcare provider should decide if you will take COUMADIN and breast-feed.

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 non-prescription 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?"

Know the medicines you take. Keep a ul of them to show your healthcare provider and pharmacist when you get a new medicine.

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 tests and visits 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 necrosis 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.
    • "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.

Tell your healthcare provider if you have any side effect that bothers you or does not go away.

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, and keep COUMADIN out of the light.

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

General Information about COUMADIN.

Medicines are sometimes prescribed for purposes other than those uled 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.

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

If you would like more information, go to www.coumadin.com or call 1-800-321-1335.

What are the ingredients in COUMADIN?

Active ingredient: Warfarin Sodium

Inactive ingredients: Lactose, starch, and magnesium stearate. The following tablets contain:
1 mg: D&C Red No. 6 Barium Lake
2 mg: FD&C Blue No. 2 Aluminum Lake andFD&C Red No. 40 Aluminum Lake
2-1/2 mg: D&C Yellow No. 10 Aluminum Lake andFD&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 andFD&C Blue No. 1 Aluminum Lake
7-1/2 mg: D&C Yellow No. 10 Aluminum Lake andFD&C Yellow No. 6 Aluminum Lake

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

COUMADIN is distributed by: Bristol-Myers Squibb Company Princeton, New Jersey 08543 USA

COUMADIN® is a registered trademark of Bristol-Myers Squibb Pharma Company.

**The brands uled (other than COUMADIN®) are registered trademarks of their respective owners and are not trademarks of Bristol-Myers Squibb Company.

1258498A3 / 1215385A4 / 1205734A4 / 1205736A4Rev October 2011

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