Warfarin Sodium

WARFARIN SODIUM- warfarin sodium tablet
RedPharm Drug, Inc.

WARNING: BLEEDING RISK

Warfarin sodium can cause major or fatal bleeding [see WARNINGS AND PRECAUTIONS (5.1)].
Perform regular monitoring of INR in all treated patients [see DOSAGE AND ADMINISTRATION (2.1)].
Drugs, dietary changes, and other factors affect INR levels achieved with warfarin sodium therapy [see DRUG INTERACTIONS (7)].
Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding [see PATIENT COUNSELING INFORMATION (17)].

HIGHLIGHTS OF PRESCRIBING INFORMATION


HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use WARFARIN SODIUM TABLETS safely and effectively. See full prescribing information for WARFARIN SODIUM TABLETS.
WARFARIN SODIUM Tablets (Crystalline), for oral use
Initial U.S. Approval: 1954

WARNING: BLEEDING RISK
SEE FULL PRESCRIBING INFORMATION FOR COMPLETE BOXED WARNING.

Warfarin sodium can cause major or fatal bleeding. (5.1)
Perform regular monitoring of INR in all treated patients. (2.1)
Drugs, dietary changes, and other factors affect INR levels achieved with warfarin sodium therapy. (7)
Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding. (17)

INDICATIONS AND USAGE

Warfarin sodium is indicated for:

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

Limitations of Use

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

DOSAGE AND ADMINISTRATION

Individualize dosing regimen for each patient, and adjust based on INR response. (2.1,2.2)
Knowledge of genotype can inform initial dose selection. (2.3)
Monitoring: Obtain daily INR determinations upon initiation until stable in the therapeutic range. Obtain subsequent INR determinations every 1 to 4 weeks. (2.4)
Review conversion instructions from other anticoagulants. (2.8)

DOSAGE FORMS AND STRENGTHS

Scored tablets: 1, 2, 2-1/2, 3, 4, 5, 6, 7-1/2, or 10 mg (3)

CONTRAINDICATIONS

Pregnancy, except in women with mechanical heart valves (4, 5.5, 8.1)
Hemorrhagic tendencies or blood dyscrasias (4)
Recent or contemplated surgery of the central nervous system (CNS) or eye, or traumatic surgery resulting in large open surfaces (4,5.7)
Bleeding tendencies associated with certain conditions (4)
Threatened abortion, eclampsia, and preeclampsia (4)
Unsupervised patients with potential high levels of non-compliance (4)
Spinal puncture and other diagnostic or therapeutic procedures with potential for uncontrollable bleeding (4)
Hypersensitivity to warfarin or any component of the product (4)
Major regional or lumbar block anesthesia (4)
Malignant hypertension (4)

WARNINGS AND PRECAUTIONS

Tissue necrosis: Necrosis or gangrene of skin or other tissues can occur, with severe cases requiring debridement or amputation. Discontinue warfarin sodium and consider alternative anticoagulants if necessary. (5.2)
Calciphylaxis: Fatal and serious cases have occurred. Discontinue warfarin and consider alternative anticoagulation therapy. (5.3)
Systemic atheroemboli and cholesterol microemboli: Some cases have progressed to necrosis or death. Discontinue warfarin sodium if such emboli occur. (5.4)
Heparin-induced thrombocytopenia (HIT): Initial therapy with warfarin sodium in HIT has resulted in cases of amputation and death. Warfarin sodium may be considered after platelet count has normalized. (5.5)
Pregnant women with mechanical heart valves: Warfarin sodium may cause fetal harm; however, the benefits may outweigh the risks.(5.6)

ADVERSE REACTIONS

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

To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Concomitant use of drugs that increase bleeding risk, antibiotics, antifungals, botanical (herbal) products, and inhibitors and inducers of CYP2C9, 1A2, or 3A4 (7).
Consult labeling of all concurrently used drugs for complete information about interactions with warfarin sodium or increased risks for bleeding. (7)

USE IN SPECIFIC POPULATIONS

Pregnant womenwith mechanical heart valves: warfarin sodium may cause fetal harm; however, the benefits may outweigh the risks. (8.1)
Lactation. Monitor breastfeeding infants for bruising or bleeding. (8.2)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 9/2016

FULL PRESCRIBING INFORMATION: CONTENTS*

RECENT MAJOR CHANGES
WARNING: BLEEDING RISK
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Individualized Dosing
2.2 Recommended Target INR Ranges and Durations for Individual Indications
2.3 Initial and Maintenance Dosing
2.4 Monitoring to Achieve Optimal Anticoagulation
2.5 Missed Dose
2.7 Treatment During Dentistry and Surgery
2.8 Conversion From Other Anticoagulants
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Hemorrhage
5.2 Tissue Necrosis
5.3 Calciphylaxis
5.4 Systemic Atheroemboli and Cholesterol Microemboli
5.5 Limb Ischemia, Necrosis, and Gangrene in Patients with HIT and HITTS
5.6 Use in Pregnant Women with Mechanical Heart Valves
5.7 Other Clinical Settings with Increased Risks
5.8 Endogenous Factors Affecting INR
6 ADVERSE REACTIONS
7 DRUG INTERACTIONS
7.1 CYP450 Interactions
7.2 Drugs that Increase Bleeding Risk
7.3 Antibiotics and Antifungals
7.4 Botanical (Herbal) Products and Foods
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
10 OVERDOSAGE
10.1 Signs and Symptoms
10.2 Treatment
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
12.5 Pharmacogenomics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Atrial Fibrillation
14.2 Mechanical and Bioprosthetic Heart Valves
14.3 Myocardial Infarction
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION

*
Sections or subsections omitted from the full prescribing information are not listed.

1 INDICATIONS AND USAGE

Warfarin sodium is indicated for:

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

Limitations of Use

Warfarin sodium tablets have 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.

2 DOSAGE AND ADMINISTRATION

2.1 Individualized Dosing

The dosage and administration of warfarin sodium tablets must be individualized for each patient according to the patient’s International Normalized Ratio (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 regarding the duration and intensity of anticoagulation for the indicated conditions.

2.2 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 to 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, 2.0 to 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.

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 to 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 to 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 to 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 to 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 to 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 to 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 to 3.0) may be used for these patients.

2.3 Initial and Maintenance Dosing

The appropriate initial dosing of warfarin sodium tablets 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) [see CLINICAL PHARMACOLOGY (12.5)]

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 (8.5) and CLINICAL PHARMACOLOGY (12.3)]. 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 (2.2)].

Dosing Recommendations without Consideration of Genotype

If the patient’s CYP2C9 and VKORC1 genotypes are not known, the initial dose of warfarin sodium tablets 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 sodium tablets doses observed in subgroups of patients having different combinations of CYP2C9 and VKORC1 gene variants [see CLINICAL PHARMACOLOGY (12.5)]. 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 Sodium Tablets Daily Doses Based on CYP2C9 and VKORC1 Genotypes†
VKORC1 CYP2C9
†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.
*1/*1 *1/*2 *1/*3 *2/*2 *2/*3 *3/*3
GG 5 to 7 mg 5 to 7 mg 3 to 4 mg 3 to 4 mg 3 to 4 mg 0.5 to 2 mg
AG 5 to 7 mg 3 to 4 mg 3 to 4 mg 3 to 4 mg 0.5 to 2 mg 0.5 to 2 mg
AA 3 to 4 mg 3 to 4 mg 0.5 to 2 mg 0.5 to 2 mg 0.5 to 2 mg 0.5 to 2 mg

2.4 Monitoring to Achieve Optimal Anticoagulation

Warfarin sodium tablets have a narrow therapeutic range (index), and its action may be affected by factors such as other drugs and dietary vitamin K. Therefore, anticoagulation must be carefully monitored during warfarin sodium tablets 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 sodium tablets as well as whenever other medications are initiated, discontinued, or taken irregularly. Heparin, a common concomitant drug, increases the INR [see DOSAGE AND ADMINISTRATION (2.8) and DRUG INTERACTIONS (7)].

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

2.5 Missed Dose

The anticoagulant effect of warfarin sodium tablets persists beyond 24 hours. If a patient misses a dose of warfarin sodium tablets 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.

2.7 Treatment During Dentistry and Surgery

Some dental or surgical procedures may necessitate the interruption or change in the dose of warfarin sodium tablets therapy. Consider the benefits and risks when discontinuing warfarin sodium tablets 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 sodium tablets to maintain the INR at the low end of the therapeutic range may safely allow for continued anticoagulation.

2.8 Conversion From Other Anticoagulants

Heparin

Since the full anticoagulant effect of warfarin sodium tablets is not achieved for several days, heparin is preferred for initial rapid anticoagulation. During initial therapy with warfarin sodium tablets, the interference with heparin anticoagulation is of minimal clinical significance. Conversion to warfarin sodium tablets 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 sodium tablets therapy with heparin for 4 to 5 days and until warfarin sodium tablets 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 sodium tablets 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 sodium tablets 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 sodium tablets.

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