Warfarin (oral)

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# Black Box Warning

# Overview
Warfarin (oral) is an anticoagulant that is FDA approved for the treatment of venous thromboembolism, pulmonary embolism, thromboembolic complications associated with atrial fibrillation, cardiac valve replacement, and/or myocardial infarction. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include hemorrhage, necrosis of skin and other tissues, systemic atheroemboli, and cholesterol microemboli.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Individualized Dosing
- The dosage and administration of Coumadin must be individualized for each patient according to the patients INR response to the drug. Adjust the dose based on the patients INR and the condition being treated. Consult the latest evidence-based clinical practice guidelines from the American College of Chest Physicians (ACCP) to assist in the determination of the duration and intensity of anticoagulation with Coumadin.
- An INR of greater than 4.0 appears to provide no additional therapeutic benefit in most patients and is associated with a higher risk of bleeding.
- Dosing Information
- Adjust the warfarin dose to maintain a target INR of 2.5 (INR range, 2.0-3.0) for all treatment durations. The duration of treatment is based on the indication as follows:
- For patients with a DVT or PE secondary to a transient (reversible) risk factor, treatment with warfarin for 3 months is recommended.
- For patients with an unprovoked DVT or PE, treatment with warfarin is recommended for at least 3 months. After 3 months of therapy, evaluate the risk-benefit ratio of long-term treatment for the individual patient.
- For patients with two episodes of unprovoked DVT or PE, long-term treatment with warfarin is recommended. For a patient receiving long-term anticoagulant treatment, periodically reassess the risk-benefit ratio of continuing such treatment in the individual patient.
- Dosing Information
- In patients with non-valvular AF, anticoagulate with warfarin to target INR of 2.5 (range, 2.0-3.0).
- In patients with non-valvular AF that is persistent or paroxysmal and at high risk of stroke (i.e., having any of the following features: prior ischemic stroke, transient ischemic attack, or systemic embolism, or 2 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended.
- In patients with non-valvular AF that is persistent or paroxysmal and at an intermediate risk of ischemic stroke (i.e., having 1 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended.
- For patients with AF and mitral stenosis, long-term anticoagulation with warfarin is recommended.
- For patients with AF and prosthetic heart valves, long-term anticoagulation with warfarin is recommended; the target INR may be increased and aspirin added depending on valve type and position, and on patient factors.
- Dosing Information
- For patients with a bileaflet mechanical valve or a Medtronic Hall (Minneapolis, MN) tilting disk valve in the aortic position who are in sinus rhythm and without left atrial enlargement, therapy with warfarin to a target INR of 2.5 (range, 2.0-3.0) is recommended.
- For patients with tilting disk valves and bileaflet mechanical valves in the mitral position, therapy with warfarin to a target INR of 3.0 (range, 2.5-3.5) is recommended.
- For patients with caged ball or caged disk valves, therapy with warfarin to a target INR of 3.0 (range, 2.5-3.5) is recommended.
- For patients with a bioprosthetic valve in the mitral position, therapy with warfarin to a target INR of 2.5 (range, 2.0-3.0) for the first 3 months after valve insertion is recommended. If additional risk factors for thromboembolism are present (AF, previous thromboembolism, left ventricular dysfunction), a target INR of 2.5 (range, 2.0-3.0) is recommended.
- Dosing Information
- For high-risk patients with MI (e.g., those with a large anterior MI, those with significant heart failure, those with intracardiac thrombus visible on transthoracic echocardiography, those with AF, and those with a history of a thromboembolic event), therapy with combined moderate-intensity (INR, 2.0-3.0) warfarin plus low-dose aspirin (100 mg/day) for at least 3 months after the MI is recommended.
- Dosing Information
- Oral anticoagulation therapy with warfarin has not been fully evaluated by clinical trials in patients with valvular disease associated with AF, patients with mitral stenosis, and patients with recurrent systemic embolism of unknown etiology. However, a moderate dose regimen (INR 2.0-3.0) may be used for these patients.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
- Developed by: American College of Chest Physicians (ACCP)
- Class of Recommendation: Class IIa
- Strength of Evidence: Category B
- Dosing Information
- In patients with antiphospholipid syndrome with previous arterial or VTE, vitamin K antagonists, such as warfarin, should be titrated to a moderate-intensity INR range (INR 2 to 3), rather than higher intensity (INR 3 to 4.5).

### NonGuideline-Supported Use
- Dosing Information
- Warfarin, dosed at an average of 4.1 mg daily to achieve a goal INR of 1.5, with or without aspirin significantly reduced overall ischemic heart disease events in a primary prevention study.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
- 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.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Warfarin (oral) in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Warfarin (oral) in pediatric patients.

# 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. 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.
- Hemorrhagic tendencies or blood dyscrasias
- Recent or contemplated surgery of the central nervous system or eye, or traumatic surgery resulting in large open surfaces.
- 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)
- Major regional or lumbar block anesthesia
- Malignant hypertension

# Warnings
- 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, certain concomitant drugs, 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.
- Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding.
- 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.
- 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.
- 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.
- 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 patients 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.
- 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.
- 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
- 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.

# Adverse Reactions

## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Warfarin (oral) in the drug label.

## Postmarketing Experience
- The following serious adverse reactions to Coumadin are discussed in greater detail in other sections of the labeling:
- Hemorrhage.
- Necrosis of skin and other tissues.
- Systemic atheroembolism and cholesterol microemboli.
Chills
Nausea, vomiting, diarrhea, taste alteration, abdominal pain, flatulence, bloating, hepatitis, elevated liver enzymes. Cholestatic hepatitis has been associated with concomitant administration of Coumadin and ticlopidine.
Tracheal or tracheobronchial calcification
Rash, dermatitis (including bullous eruptions), pruritus, alopecia, hypersensitivity/allergic reactions (including urticaria and anaphylactic reactions), vasculitis

# 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).
- Consult the labeling of all concurrently used drugs to obtain further information about interactions with Coumadin or adverse reactions pertaining to bleeding.
- 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 mediations. Closely monitor INR if a concomitant drug is a CYP2C9, 1A2, and/or 3A4 inhibitor or inducer.
- 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.
- 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.
- 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. Johns wort, ginseng). Some botanicals and foods can interact with Coumadin through CYP450 interactions (e.g., echinacea, grapefruit juice, ginkgo, goldenseal, St. Johns wort).
- Monitor the patients response with additional INR determinations when initiating or discontinuing any botanicals.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category:
- Pregnancy Category D for women with mechanical heart valves and Pregnancy Category X for other pregnant populations.
- 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. 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), fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality. The reproductive and developmental effects of Coumadin have not been evaluated in animals. 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 the fetus.
- 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.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Warfarin (oral) in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Warfarin (oral) during labor and delivery.

### Nursing Mothers
- 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. Monitor breast-feeding infants for bruising or bleeding. Effects in premature infants have not been evaluated. Caution should be exercised when Coumadin is administered to a nursing woman.

### 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.

### Geriatic 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. 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.

### Gender
There is no FDA guidance on the use of Warfarin (oral) with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Warfarin (oral) with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Warfarin (oral) in patients with renal impairment.

### 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.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Warfarin (oral) in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Warfarin (oral) in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Oral
- Intravenous

### Monitoring
- Perform regular monitoring of INR in all treated patients. Click here for more details about Warfarin monitoring.

# IV Compatibility
There is limited information regarding IV Compatibility of Warfarin (oral) in the drug label.

# Overdosage

## Acute 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.

### Management
- 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.

## Chronic Overdose
There is limited information regarding Chronic Overdose of Warfarin (oral) in the drug label.

# 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 -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.

## Structure
- Coumadin (warfarin sodium) is an anticoagulant that acts by inhibiting vitamin K-dependent coagulation factors. Chemically, it is 3-(-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 for injection for intravenous use is supplied as a sterile, lyophilized powder, which, after reconstitution with 2.7 mL Sterile Water for Injection, contains:

## 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.
- 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.

## 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 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.
- 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.
- 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.
- 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.

## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- Carcinogenicity, mutagenicity, or fertility studies have not been performed with warfarin.

# Clinical Studies
- 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).
- Trials in patients with both AF and mitral stenosis suggest a benefit from anticoagulation with Coumadin.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.

# How Supplied
- Tablets
- 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 (59-86F, 15-30C). 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.
- Injection
- 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.
- Protect from light. Keep vial in box until used. Store at controlled room temperature (59-86F, 15-30C).
- After reconstitution, store at controlled room temperature (59-86F, 15-30C) and use within 4 hours. Do not refrigerate. Discard any unused solution.

## Storage
There is limited information regarding Warfarin (oral) Storage in the drug label.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information

# Precautions with Alcohol
- Alcohol-Warfarin (oral) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- Coumadin
- Jantoven

# Look-Alike Drug Names
- Coumadin - Avandia
- Coumadin - Cardura
- Jantoven - Janumet
- Jantoven - Januvia

# Drug Shortage Status

# Price