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Warfarin Sodium Tablet and Injection

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING

 


WARNING: BLEEDING RISK

• Warfarin sodium can cause major or fatal bleeding [see Warnings and Precautions].

• Perform regular monitoring of INR in all treated patients [see Dosage and Administration].

• Drugs, dietary changes, and other factors affect INR levels achieved with warfarin sodium therapy [see Drug Interactions].

• Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding.



1. DESCRIPTION

Crystalline warfarin sodium is an anticoagulant which 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. The crystallization of warfarin sodium virtually eliminates trace impurities present in amorphous warfarin. Its empirical formula is C19H15NaO4, and its structural formula may be represented by the following:

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

Warfarin sodium tablets for oral use also contain:

Warfarin sodium for injection is supplied as a sterile, lyophilized powder, which, after reconstitution with 2.7 mL sterile Water for Injection, contains:

2. INDICATIONS AND USAGE

Warfarin sodium is indicated for:

1) The prophylaxis and/or treatment of venous thrombosis and its extension, and pulmonary embolism.

2) The prophylaxis and/or treatment of the thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement.

3) To reduce the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic embolization after myocardial infarction.

Limitations of Use

Warfarin sodium 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.

3. DOSAGE AND ADMINISTRATION

3.1 Individualized Dosing

The dosage and administration of warfarin must be individualized for each patient according to the patient’s INR response to the drug. Adjust the dose based on the patient’s 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 warfarin.

3.2 Recommended Target INR Ranges and Durations for Individual Indications

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.

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

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.

Atrial Fibrillation

In patients with non-valvular AF, anticoagulate with warfarin to target INR of 2.5 (range, 2.03.0).

• 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.

Mechanical and Bioprosthetic Heart Valves

• 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.

Post-Myocardial Infarction

• 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.

Recurrent Systemic Embolism and Other Indications

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.

3.3 Initial and Maintenance Dosing

The appropriate initial dosing of warfarin varies widely for different patients. Not all factors responsible for warfarin dose variability are known, and the initial dose is influenced by:

• Clinical factors including age, race, body weight, sex, concomitant medications, and comorbidities

• Genetic factors (CYP2C9 and VKORC1 genotypes)

Select the initial dose based on the expected maintenance dose, taking into account the above factors. Modify this dose based on consideration of patient-specific clinical factors. Consider lower initial and maintenance doses for elderly and/or debilitated patients and in Asian patients [see Use in Specific Populations]. Routine use of loading doses is not recommended as this practice may increase hemorrhagic and other complications and does not offer more rapid protection against clot formation.

Individualize the duration of therapy for each patient. In general, anticoagulant therapy should be continued until the danger of thrombosis and embolism has passed [see Dosage and Administration].

Dosing Recommendations without Consideration of Genotype

If the patient’s CYP2C9 and VKORC1 genotypes are not known, the initial dose of warfarin is usually 2 to 5 mg once daily. Determine each patient’s dosing needs by close monitoring of the INR response and consideration of the indication being treated. Typical maintenance doses are 2 to 10 mg once daily.

Dosing Recommendations with Consideration of Genotype

Table 1 displays three ranges of expected maintenance warfarin doses observed in subgroups of patients having different combinations of CYP2C9 and VKORC1 gene variants. If the patient’s CYP2C9 and/or VKORC1 genotype are known, consider these ranges in choosing the initial dose. Patients with CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3 may require more prolonged time (>2 to 4 weeks) to achieve maximum INR effect for a given dosage regimen than patients without these CYP variants.

Table 1: Three Ranges of Expected Maintenance Warfarin Daily Doses Based on CYP2C9 and VKORC1 Genotypes†

† Ranges are derived from multiple published clinical studies. VKORC1 −1639G>A (rs9923231) variant is used in this table. Other co-inherited VKORC1 variants may also be important determinants of warfarin dose.

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3.4 Monitoring to Achieve Optimal Anticoagulation

Warfarin is a narrow therapeutic range (index) drug, and its action may be affected by factors such as other drugs and dietary vitamin K. Therefore, anticoagulation must be carefully monitored during warfarin therapy. Determine the INR daily after the administration of the initial dose until INR results stabilize in the therapeutic range. After stabilization, maintain dosing within the therapeutic range by performing periodic INRs. The frequency of performing INR should be based on the clinical situation but generally acceptable intervals for INR determinations are 1 to 4 weeks. Perform additional INR tests when other warfarin products are interchanged with warfarin, as well as whenever other medications are initiated, discontinued, or taken irregularly. Heparin, a common concomitant drug, increases the INR [see Dosage and Administration and Drug Interactions].

Determinations of whole blood clotting and bleeding times are not effective measures for monitoring of warfarin therapy.

3.5 Missed Dose

The anticoagulant effect of warfarin persists beyond 24 hours. If a patient misses a dose of warfarin at the intended time of day, the patient should take the dose as soon as possible on the same day. The patient should not double the dose the next day to make up for a missed dose.

3.6 Intravenous Route of Administration

The intravenous dose of warfarin is the same as the oral dose. After reconstitution, warfarin for injection should be administered as a slow bolus injection into a peripheral vein over 1 to 2 minutes. Warfarin for injection is not recommended for intramuscular administration.

Reconstitute the vial with 2.7 mL of Sterile Water for Injection. The resulting yield is 2.5 mL of a 2 mg per mL solution (5 mg total). Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use if particulate matter or discoloration is noted.

After reconstitution, warfarin for injection is stable for 4 hours at room temperature. It does not contain any antimicrobial preservative and, thus, care must be taken to assure the sterility of the prepared solution. The vial is for single use only, and any unused solution should be discarded.

3.7 Treatment During Dentistry and Surgery

Some dental or surgical procedures may necessitate the interruption or change in the dose of warfarin therapy. Consider the benefits and risks when discontinuing warfarin even for a short period of time. Determine the INR immediately prior to any dental or surgical procedure. In patients undergoing minimally invasive procedures who must be anticoagulated prior to, during, or immediately following these procedures, adjusting the dosage of warfarin to maintain the INR at the low end of the therapeutic range may safely allow for continued anticoagulation.

3.8 Conversion From Other Anticoagulants

Heparin

Since the full anticoagulant effect of warfarin is not achieved for several days, heparin is preferred for initial rapid anticoagulation. During initial therapy with warfarin, the interference with heparin anticoagulation is of minimal clinical significance. Conversion to warfarin may begin concomitantly with heparin therapy or may be delayed 3 to 6 days. To ensure therapeutic anticoagulation, continue full dose heparin therapy and overlap warfarin therapy with heparin for 4 to 5 days and until warfarin has produced the desired therapeutic response as determined by INR, at which point heparin may be discontinued.

As heparin may affect the INR, patients receiving both heparin and warfarin should have INR monitoring at least:

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

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

• 24 hours after the last subcutaneous heparin injection.

Warfarin may increase the activated partial thromboplastin time (aPTT) test, even in the absence of heparin. A severe elevation (>50 seconds) in aPTT with an INR in the desired range has been identified as an indication of increased risk of postoperative hemorrhage.

Other Anticoagulants

Consult the labeling of other anticoagulants for instructions on conversion to warfarin.

4. CONTRAINDICATIONS

• Pregnancy

Warfarin is contraindicated in women who are pregnant except in pregnant women with mechanical heart valves, who are at high risk of thromboembolism [see Warnings and Precautions and Use in Specific Populations]. Warfarin can cause fetal harm when administered to a pregnant woman. Warfarin 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 warfarin 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 and Use in Specific Populations].

• Hemorrhagic tendencies or blood dyscrasias

• Recent or contemplated surgery of the central nervous system or eye, or traumatic surgery resulting in large open surfaces [see Warnings and Precautions]

• Bleeding tendencies associated with:

− Active ulceration or overt bleeding of the gastrointestinal, genitourinary, or respiratory tract

− Central nervous system hemorrhage

− Cerebral aneurysms, dissecting aorta

− Pericarditis and pericardial effusions

− Bacterial endocarditis

• Threatened abortion, eclampsia, and preeclampsia

• Unsupervised patients with conditions associated with potential high level of non-compliance

• Spinal puncture and other diagnostic or therapeutic procedures with potential for uncontrollable bleeding

• Hypersensitivity to warfarin or to any other components of this product (e.g., anaphylaxis) [see Adverse Reactions]

• Major regional or lumbar block anesthesia

• Malignant hypertension

5. 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.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category D for women with mechanical heart valves [see Warnings and Precautions] and Pregnancy Category X for other pregnant populations [see Contraindications].

Warfarin 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 warfarin may outweigh the risks. Warfarin can cause fetal harm when administered to a pregnant woman. Warfarin 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 warfarin 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 [see Contraindications and Warnings and Precautions].

6.2 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 warfarin is administered to a nursing woman.

6.3 Pediatric Use

Adequate and well-controlled studies with warfarin have not been conducted in any pediatric population, and the optimum dosing, safety, and efficacy in pediatric patients is unknown. Pediatric use of warfarin is based on adult data and recommendations, and available limited pediatric data from observational studies and patient registries. Pediatric patients administered warfarin 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.

6.4 Geriatric Use

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

Patients 60 years or older appear to exhibit greater than expected INR response to the anticoagulant effects of warfarin. Warfarin is contraindicated in any unsupervised patient with senility. Observe caution with administration of warfarin 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 warfarin in elderly patients [see Dosage and Administration].

6.5 Renal Impairment

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

6.6 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 warfarin in these patients.

6.7 Females of Reproductive Potential

Warfarin exposure during pregnancy can cause spontaneous abortion, birth defects, or fetal death. Females of reproductive potential who are candidates for warfarin therapy should be counseled regarding the benefits of therapy and potential reproductive risks. Discuss pregnancy planning with females of reproductive potential who are on warfarin therapy. If the patient becomes pregnant while taking warfarin, she should be apprised of the potential risks to the fetus.

7. WARNINGS AND PRECAUTIONS

7.1 Hemorrhage

Warfarin 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 [see Drug Interactions], and long duration of warfarin therapy.

Perform regular monitoring of INR in all treated patients. Those at high risk of bleeding may benefit from more frequent INR monitoring, careful dose adjustment to desired INR, and a shortest duration of therapy appropriate for the clinical condition. However, maintenance of INR in the therapeutic range does not eliminate the risk of bleeding. Drugs, dietary changes, and other factors affect INR levels achieved with warfarin therapy. Perform more frequent INR monitoring when starting or stopping other drugs, including botanicals, or when changing dosages of other drugs [see Drug Interactions].

Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding.

7.2 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 warfarin 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 warfarin therapy if necrosis occurs. Consider alternative drugs if continued anticoagulation therapy is necessary.

7.3 Systemic Atheroemboli and Cholesterol Microemboli

Anticoagulation therapy with warfarin 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 warfarin therapy if such phenomena are observed. Consider alternative drugs if continued anticoagulation therapy is necessary.

7.4 Heparin-Induced Thrombocytopenia

Do not use warfarin 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 warfarin may be considered after the platelet count has normalized.

7.5 Use in Pregnant Women with Mechanical Heart Valves

Warfarin can cause fetal harm when administered to a pregnant woman. While warfarin is contraindicated during pregnancy, the potential benefits of using warfarin 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 warfarin 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. Warfarin 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].

7.6 Females of Reproductive Potential

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

7.7 Other Clinical Settings with Increased Risks

In the following clinical settings, the risks of warfarin 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: Warfarin 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 warfarin may minimize the incidence of tissue necrosis in these patients.

• Eye surgery: In cataract surgery, warfarin 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 warfarin cessation or reduction may lead to serious thromboembolic complications, the decision to discontinue warfarin 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

7.8 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.

8. ADVERSE REACTIONS

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

• Hemorrhage [see Boxed Warning, Warnings and Precautions, and Overdosage]

• Necrosis of skin and other tissues [see Warnings and Precautions]

• Systemic atheroemboli and cholesterol microemboli [see Warnings and Precautions]

Other adverse reactions to warfarin 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 warfarin 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

9. OVERDOSAGE

9.1 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.

9.2 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 warfarin anticoagulation may be obtained by discontinuing warfarin therapy and, if necessary, by administration of oral or parenteral vitamin K1.

The use of vitamin K1 reduces response to subsequent warfarin therapy and patients may return to a pretreatment thrombotic status following the rapid reversal of a prolonged INR. Resumption of warfarin 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 warfarin 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 warfarin overdosage.

10. DRUG INTERACTIONS

Drugs may interact with warfarin through pharmacodynamic or pharmacokinetic mechanisms. Pharmacodynamic mechanisms for drug interactions with warfarin 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 warfarin 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 warfarin or adverse reactions pertaining to bleeding.

10.1 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 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.

Table 2: Examples of CYP450 Interactions with Warfarin

10.2 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

10.3 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.

10.4 Botanical (Herbal) Products and Foods

Exercise caution when botanical (herbal) products are taken concomitantly with warfarin. Few adequate, well-controlled studies evaluating the potential for metabolic and/or pharmacologic interactions between botanicals and warfarin 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 warfarin. Conversely, some botanicals may decrease the effects of warfarin (e.g., co-enzyme Q10, St. John’s wort ginseng). Some botanicals and foods can interact with warfarin 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.

11. PHARMACOKINETICS

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

Absorption

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

Distribution

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

Metabolism

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

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 allelles in Caucasians are approximately 11% and 7% for CYP2C9*2 and CYP2C9*3, respectively. Patients with one or more of these variant CYP2C9 alleles have decreased S-warfarin clearance.

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.

Excretion

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

Elderly

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

Asians

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

Renal Dysfunction

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

Hepatic Dysfunction

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

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

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand name: COUMADIN, by BRISTOL MYERS SQUIBB.

b) Generic drugs:

Tablets: JANTOVEN (by USL PHARMA), warfarin sodium (by various manufacturers).

Injection: No generic drugs available.

2) How Supplied:

Tablets

Warfarin Sodium Tablets, USP (by Mylan Pharms) are available containing 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7.5 mg or 10 mg of warfarin sodium, USP.

The 1 mg tablet is a dark pink round, scored tablet with "WF" above the score and "1" below the score on one side and "G" on the other side. They are available as follows:

NDC 0378-8801-01 bottles of 100 tablets

NDC 0378-8801-10 bottles of 1000 tablets

The 2 mg tablet is a lavender round, scored tablet with "WF" above the score and "2" below the score on one side and "G" on the other side. They are available as follows:

NDC 0378-8802-01 bottles of 100 tablets

NDC 0378-8802-10 bottles of 1000 tablets

The 2.5 mg tablet is a green round, scored tablet with "WF" above the score and "2.5" below the score on one side and "G" on the other side. They are available as follows:

NDC 0378-8825-01 bottles of 100 tablets

NDC 0378-8825-10 bottles of 1000 tablets

The 3 mg tablet is a beige round, scored tablet with "WF" above the score and "3" below the score on one side and "G" on the other side. They are available as follows:

NDC 0378-8803-01 bottles of 100 tablets

NDC 0378-8803-10 bottles of 1000 tablets

The 4 mg tablet is a blue round, scored tablet with "WF" above the score and "4" below the score on one side and "G" on the other side. They are available as follows:

NDC 0378-8804-01 bottles of 100 tablets

NDC 0378-8804-10 bottles of 1000 tablets

The 5 mg tablet is a peach round, scored tablet with "WF" above the score and "5" below the score on one side and "G" on the other side. They are available as follows:

NDC 0378-8805-01 bottles of 100 tablets

NDC 0378-8805-10 bottles of 1000 tablets

The 6 mg tablet is a greenish-blue round, scored tablet with "WF" above the score and "6" below the score on one side and "G" on the other side. They are available as follows:

NDC 0378-8806-01 bottles of 100 tablets

NDC 0378-8806-10 bottles of 1000 tablets

The 7.5 mg tablet is a yellow round, scored tablet with "WF" above the score and "7.5" below the score on one side and "G" on the other side. They are available as follows:

NDC 0378-8875-01 bottles of 100 tablets

NDC 0378-8875-10 bottles of 1000 tablets

The 10 mg tablet is a white to off-white round, scored tablet with "WF" above the score and "10" below the score on one side and "G" on the other side. They are available as follows:

NDC 0378-8810-01 bottles of 100 tablets

NDC 0378-8810-10 bottles of 1000 tablets

COUMADIN Injection

Available for intravenous use only. Not recommended for intramuscular administration. Reconstitute with 2.7 mL of sterile Water for Injection to yield 2 mg/mL. Net contents 5.4 mg lyophilized powder. Maximum yield 2.5 mL.

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

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.

3) Storage:

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Protect from light.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

PHARMACIST: Dispense a Medication Guide with each prescription.

Rx only

Rev 10/11