Coumadin

Take the missed dose as soon as you remember it, if it is the same day that you were to take the dose. Do not take a double dose the next day to make up for a missed one. Call your doctor if you miss a dose of warfarin.

Warfarin may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• gas
• abdominal pain
• bloating
• change in the way things taste
• loss of hair
• feeling cold or having chills

If you experience any of the following symptoms, or those listed in the IMPORTANT WARNING section, call your doctor immediately:

• hives
• rash
• itching
• difficulty breathing or swallowing
• swelling of the face, throat, tongue, lips, or eyes
• hoarseness
• chest pain or pressure
• swelling of the hands, feet, ankles, or lower legs
• fever
• infection
• nausea
• vomiting
• diarrhea
• extreme tiredness
• lack of energy
• loss of appetite
• pain in the upper right part of the stomach
• yellowing of the skin or eyes
• flu-like symptoms

You should know that warfarin may cause necrosis or gangrene (death of skin or other body tissues). Call your doctor immediately if you notice a purplish or darkened color to your skin, skin changes, ulcers, or an unusual problem in any area of your skin or body, or if you have a severe pain that occurs suddenly, or color or temperature change in any area of your body. Call your doctor immediately if your toes become painful or become purple or dark in color. You may need medical care right away to prevent amputation (removal) of your affected body part.

Warfarin may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

To decrease your risk for bleeding, your doctor or other health care provider will monitor you closely and check your lab results (INR test) to make sure you are not taking too much warfarin. Keep all medical and laboratory appointments. Tell your doctor right away if you notice any signs of serious bleeding. See also Side Effects section.

Dosage Forms And Strengths

COUMADIN Single-Scored Tablets

For injection: 5 mg, lyophilized powder in a single-dose vial.

Storage And Handling

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 is available in bottles and hospital unit-dose blister packages with potencies and colors as follows:

Protect from light and moisture. Store at controlled room temperature (59°-86°F, 15°-30°C). Dispense in a tight, light-resistant container as defined in the USP.

Store the hospital unit-dose blister packages in the carton until contents have been used.

COUMADIN for injection vials yield 5 mg of warfarin after reconstitution with 2.7 mL of Sterile Water for Injection (maximum yield is 2.5 mL of a 2 mg/mL solution). Net content of vial is 5.4 mg lyophilized powder.

5-mg vial (box of 6) - NDC 0590-0324-35

Protect from light. Keep vial in box until used. Store at controlled room temperature (59°-86°F, 15°- 30°C).

After reconstitution, store at controlled room temperature (59°-86°F, 15°-30°C) and use within 4 hours.

Do not refrigerate. Discard any unused solution.

Procedures for proper handling and disposal of potentially hazardous drugs should be considered.

Guidelines on this subject have been published [see REFERENCES].

Pharmacy and clinical personnel who are pregnant should avoid exposure to crushed or broken tablets [see Use In Specific Populations].

REFERENCES

OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

Distributed by: Bristol-Myers Squibb Company, Princeton, New Jersey 08543 USA. Revised: June 2017

• Bristol-Myers Squibb Co.

Take Coumadin exactly as your doctor prescribes it. Follow the directions on your prescription label carefully.

Your doctor will adjust your dose from time to time depending on your response to Coumadin based upon your PT/INR.

• Importance of providing patient a copy of manufacturer’s patient medication guide.211 330 445 453

• Importance of strict adherence to prescribed dosage and schedule.211 330 Importance of taking tablets at the same time each day.453 If a dose is missed, take as soon as possible on the same day; do not take a double dose the next day to make up for the missed dose.453

• Importance of informing clinician if a dose is missed or an extra dose is taken.453

• Importance of close laboratory monitoring to determine INR and regular visits to clinician.211 330

• Importance of informing clinician of coexisting conditions such as hepatic or renal dysfunction, high BP, CHF, diabetes mellitus, propensity for falling, and alcohol abuse.453

• Importance of informing clinician if diarrhea, infections, or fever occurs during therapy.453

• Importance of patients carrying a notice stating that they are undergoing anticoagulant therapy.211 330

• Importance of avoiding alcohol211 330 445 453 485 486 or limiting use to small amounts; consult and inform clinician about alcohol use and abuse.211 330 445 453 (See Interactions.)

• Importance of avoiding drastic changes in diet and of eating a balanced diet with a constant amount of vitamin K.211 330 Avoid ingestion of large quantities of foods that contain a large amount of vitamin K (e.g., leafy green vegetables, certain vegetable oils).453 Importance of informing clinician before attempting to diet during warfarin therapy.453

• Importance of avoiding211 330 445 453 or using only small amounts488 of cranberry products and of informing clinician if these products are part of the diet.211 330 445 453

• Importance of avoiding activities or sports that could cause traumatic injury.211 330 Importance of informing clinician about falls or injuries, especially head injuries, during therapy.453

• Importance of patients reporting any signs of bleeding (e.g., 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) to clinicians immediately.211 330 418

• Importance of patients reporting symptoms of blood clots (e.g., pain, color, or temperature changes to any area of the body).453 Importance of reporting symptoms of purple toes syndrome (e.g., pain in toes, purple or dark toes) to clinician immediately.453

• Importance of patients informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements.211 330 418 Importance of not taking OTC drugs or drugs prescribed by other clinicians without first informing primary clinician or pharmacist.211 330

• Importance of women informing clinician if they are or plan to become pregnant or plan to breast-feed.211 330

• Importance of informing patients of other important precautionary information.211 330 (See Cautions.)

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Bleeding gums
• blood in the urine
• bloody stools
• blurred vision
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• chest pain or discomfort
• confusion
• coughing up blood
• difficulty with breathing or swallowing
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• excessive bruising
• headache
• increased menstrual flow or vaginal bleeding
• nosebleeds
• paralysis
• peeling of the skin
• prolonged bleeding from cuts
• red or black, tarry stools
• red or dark brown urine
• stomach pain with cramping
• sweating
• unexplained swelling
• unusual tiredness or weakness

• Arm, back, or jaw pain
• blue-green to black skin discoloration
• blue or purple toes
• change in consciousness
• chest tightness or heaviness
• chills
• clay-colored stools
• diarrhea
• dizziness
• fainting or loss of consciousness
• fast or irregular breathing
• fast or irregular heartbeat
• fever
• itching or skin rash
• light-colored stools
• loss of appetite
• nausea and vomiting
• pain in the toes
• pain, redness, or sloughing of the skin
• pale skin
• purplish red, net-like, blotchy spots on the skin
• skin blisters
• small red or purple spots on the skin
• stomach pain
• swelling of the eyes or eyelids
• troubled breathing with exertion
• unpleasant breath odor
• unusual bleeding or bruising
• upper right stomach pain
• vomiting of blood
• yellow eyes and skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Joint pain
• muscle pain

• Bloated
• change in taste, or bad, unusual, or unpleasant (after) taste
• cold intolerance
• excess air or gas in the stomach or intestines
• full feeling
• general feeling of discomfort or illness
• hair loss or thinning of the hair
• hives or welts
• lack or loss of strength
• pain
• passing gas
• red, sore, or itching skin
• sores, welting, or blisters
• unusual drowsiness, dullness, or feeling of sluggishness

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Coumadin® is indicated for:

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.

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

• Hemorrhage [see Boxed Warning, Warnings and Precautions(5.1), and Overdosage(10)]
• Tissue Necrosis [see Warnings and Precautions(5.2)]
• Calciphylaxis [see Warnings and Precautions(5.3)]
• Acute Kidney Injury [see Warnings and Precautions (5.4)]
• Systemic Atheroemboli and Cholesterol Microemboli [see Warnings and Precautions(5.5)]
• Limb Ischemia, Necrosis, and Gangrene in Patients with HIT and HITTS [see Warnings and Precautions(5.6)]
• Other Clinical Settings with Increased Risks [see Warnings and Precautions(5.8)]

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

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.

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 list 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 medications. Closely monitor INR if a concomitant drug is a CYP2C9, 1A2, and/or 3A4 inhibitor or inducer.

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.

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.

Botanical (Herbal) Products and Foods

More frequent INR monitoring should be performed when starting or stopping botanicals.

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).

The amount of vitamin K in food may affect therapy with Coumadin. Advise patients taking Coumadin to eat a normal, balanced diet maintaining a consistent amount of vitamin K. Patients taking Coumadin should avoid drastic changes in dietary habits, such as eating large amounts of green leafy vegetables.

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 Clinical Pharmacology (12.5)].

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 K-dependent 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.

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

Warfarin shows a volume of distribution of about 0.14 L/kg. Approximately 99% of the drug is bound to plasma proteins.

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 Clinical Pharmacology (12.5)].

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 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.

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 (2.3, 2.4)].

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

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 (2.3)].

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

NDC 0056-0176-70
2½ mg Rx only
Coumadin®
(Warfarin Sodium Tablets, USP)
Crystalline*
DISPENSE WITH MEDICATION GUIDE
HIGHLY POTENT ANTICOAGULANT
WARNING: Serious bleeding results from overdosage. Do not use or dispense before reading directions and warnings in accompanying product information.
DOSAGE: See package insert.
100 TABLETS

NDC 0056-0168-70
4 mg Rx only
Coumadin®
(Warfarin Sodium Tablets, USP)
Crystalline*
DISPENSE WITH MEDICATION GUIDE
HIGHLY POTENT ANTICOAGULANT
WARNING: Serious bleeding results from overdosage. Do not use or dispense before reading directions and warnings in accompanying product information.
DOSAGE: See package insert.
100 TABLETS

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

• Some slowing of the blood's ability to clot may be noticed within 24 hours; however, it can take from 72 to 96 hours for the full effects to be seen. One dose of Coumadin lasts for 2 to 5 days; however, daily dosing is needed to keep blood levels consistent. Effects are likely to accumulate with repeated dosing because of the time it takes for the affected vitamin K-dependent clotting factors to replenish. Desired INR range varies depending on the condition being treated and specific guidelines; however, the majority of guidelines aim for a target INR of 2.5 (range 2-3).
• Treatment duration also varies, from three months to life-long depending on the condition and other patient factors; generally, until the danger of thrombosis or embolism has passed.
• INR readings greater than 4 are associated with a higher risk of bleeding with no additional therapeutic benefit in most people.

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Substance Name

Warfarin

CAS Registry Number

81-81-2

Drug Class

Anticoagulants

• It is used to treat blood clots.
• It is used to thin the blood so that clots will not form.
• It is used to lower the chance of heart attack, stroke, and death in some people.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if you have any side effects that bother you or do not go away.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.