WARFARIN SODIUM tablet

United States - English - NLM (National Library of Medicine)

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Active ingredient:
WARFARIN SODIUM (UNII: 6153CWM0CL) (WARFARIN - UNII:5Q7ZVV76EI)
Available from:
NuCare Pharmaceuticals,Inc.
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Warfarin sodium tablets are 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. Warfarin Sodium is contraindicated in: - Pregnancy Warfarin sodium tablets are contraindicated in women who are pregnant except in pregnant women with mechanical heart valves, who are at high risk of thromboembo
Product summary:
Warfarin sodium tablets, USP are supplied as follows: • 1 mg Tablets: Light pink, Round, Flat Beveled edge tablets debossed "I" on the left side of bisect and "G" on the right side of bisect on one side and "W" on the top and "1" on the bottom of other side, supplied in bottles of 90's count ( NDC 57237-119-90), 100's count ( NDC 57237-119-01) and 1000's count ( NDC 57237-119-99) • 2 mg Tablets: Lavender, Round, Flat Beveled edge tablets debossed "I" on the left side of bisect and "G" on the right side of bisect on one side and "W" on the top and "2" on the bottom of other side, supplied in bottles of 90's count ( NDC 57237-120-90), 100's count ( NDC 57237-120-01) and 1000's count ( NDC 57237-120-99) • 2.5 mg Tablets: Green, Round, Flat Beveled edge tablets debossed "I" on the left side of bisect and "G" on the right side of bisect on one side and "W" on the top and "21/2" on the bottom of other side, supplied in bottles of 90's count ( NDC 57237-121-90) 100's count ( NDC 57237-121-01) and 1000's count ( NDC 57237-121-99) • 3 mg Tablets: Tan, Round, Flat Beveled edge tablets debossed "I" on the left side of bisect and "G" on the right side of bisect on one side and "W" on the top and "3" on the bottom of other side, supplied in bottles of 90's count ( NDC 57237-122-90) 100's count ( NDC 57237-122-01) and 1000's count ( NDC 57237-122-99) • 4 mg Tablets: Blue, Round, Flat Beveled edge tablets debossed "I" on the left side of bisect and "G" on the right side of bisect on one side and "W" on the top and "4" on the bottom of other side, supplied in bottles of 90's count ( NDC 57237-123-90) 100's count ( NDC 57237-123-01) and 1000's count ( NDC 57237-123-99) • 5 mg Tablets: Peach, Round, Flat Beveled edge tablets debossed "I" on the left side of bisect and "G" on the right side of bisect on one side and "W" on the top and "5" on the bottom of other side, supplied in bottles of 90's count ( NDC 57237-124-90), 100's count ( NDC 57237-124-01) and 1000's count ( NDC 57237-124-99) • 6 mg Tablets: Teal, Round, Flat Beveled edge tablets de-bossed "I" on the left side of bisect and "G" on the right side of bisect on one side and "W" on the top and "6" on the bottom of other side, supplied in bottles of 90's count ( NDC 57237-125-90), 100's count ( NDC 57237-125-01) and 1000's count ( NDC 57237-125-99) • 7.5 mg Tablets: Yellow, Round, Flat Beveled edge tablets debossed "I" on the left side of bisect and "G" on the right side of bisect on one side and "W" on the top and "71/2" on the bottom of other side, supplied in bottles of 90's count ( NDC 57237-126-90), 100's count ( NDC 57237-126-01) and 1000's count ( NDC 57237-126-99) • 10 mg Tablets: White, Round, Flat Beveled edge tablets debossed "I" on the left side of bisect and "G" on the right side of bisect on one side and "W" on the top and "10" on the bottom of other side, supplied in bottles of 90's count ( NDC 57237-127-90), 100's count ( NDC 57237-127-01) and 1000's count ( NDC 57237-127-99) Storage: Store at 20° to 25°C (68° F to 77° F). [see USP Controlled Room Temperature]. Protect from light and moisture. Dispense in a tight, light-resistant container as defined in the USP. Special Handling Procedures for proper handling and disposal of potentially hazardous drugs should be considered. Guidelines on this subject have been published [see References (15)]. Pharmacy and clinical personnel who are pregnant should avoid exposure to crushed or broken tablets [see Use in Specific Populations (8.1)].
Authorization status:
Abbreviated New Drug Application
Authorization number:
68071-5004-3

NuCare Pharmaceuticals,Inc.

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MEDICATION GUIDE

Warfarin Sodium Tablets, USP ( (war' far in soe' dee um)

What is the most important information I should know about warfarin sodium?

Warfarin sodium can cause bleeding which can be serious and sometimes lead to death. This is because

warfarin sodium is a blood thinner medicine that lowers the chance of blood clots forming in your body.

You may have a higher risk of bleeding if you take warfarin sodium and:

are 65 years of age or older

have a history of stomach or intestinal bleeding

have high blood pressure (hypertension)

have a history of stroke, or “mini-stroke” (transient ischemic attack or TIA)

have serious heart disease

have a low blood count or cancer

have had trauma, such as an accident or surgery

have kidney problems

take other medicines that increase your risk of bleeding, including:

a medicine that contains heparin

other medicines to prevent or treat blood clots

nonsteroidal anti-inflammatory drugs (NSAIDs)

take warfarin sodium for a long time. Warfarin sodium is the active ingredient in warfarin sodium

tablets.

Tell your healthcare provider if you take any of these medicines. Ask your healthcare provider if you are not

sure if your medicine is one listed above.

Many other medicines can interact with warfarin sodium and affect the dose you need or increase warfarin

sodium side effects. Do not change or stop any of your medicines or start any new medicines before you talk

to your healthcare provider.

Do not take other medicines that contain warfarin sodium while taking warfarin sodium tablets.

Get your regular blood test to check for your response to warfarin sodium. This blood test is called an

INR test. The INR test checks to see how fast your blood clots. Your healthcare provider will decide

what INR numbers are best for you. Your dose of warfarin sodium will be adjusted to keep your INR

in a target range for you.

Call your healthcare provider right away if you get any of the following signs or symptoms of

bleeding problems:

pain, swelling, or discomfort

headaches, dizziness, or weakness

unusual bruising (bruises that develop without known cause or grow in size)

nosebleeds

bleeding gums

bleeding from cuts takes a long time to stop

menstrual bleeding or vaginal bleeding that is heavier than normal

pink or brown urine

red or black stools

coughing up blood

vomiting blood or material that looks like coffee grounds

Some foods and beverages can interact with warfarin sodium and affect your treatment and dose.

Eat a normal, balanced diet. Talk to your healthcare provider before you make any diet changes. Do

not eat large amounts of leafy, green vegetables. Leafy, green vegetables contain vitamin K. Certain

vegetable oils also contain large amounts of vitamin K. Too much vitamin K can lower the effect of

warfarin sodium.

Always tell all of your healthcare providers that you take warfarin sodium.

Wear or carry information that you take warfarin sodium.

See “What are the possible side effects of warfarin sodium?” for more information about side effects.

What is warfarin sodium?

Warfarin sodium is prescription medicine used to treat blood clots and to lower the chance of blood clots

forming in your body. Blood clots can cause a stroke, heart attack, or other serious conditions if they form in

the legs or lungs.

Who should not take warfarin sodium?

Do not take warfarin sodium if:

your risk of having bleeding problems is higher than the possible benefit of treatment. Your

healthcare provider will decide if warfarin sodium is right for you.

you are pregnant unless you have a mechanical heart valve. Warfarin sodium may cause birth defects,

miscarriage, or death of your unborn baby.

you are allergic to warfarin or any of the other ingredients in warfarin sodium tablets. See the end of

this leaflet for a complete list of ingredients in warfarin sodium tablets.

Before taking warfarin sodium, tell your healthcare provider about all of your medical conditions, including

if you:

have bleeding problems

fall often

have liver problems

have kidney problems or are undergoing dialysis

have high blood pressure

have a heart problem called congestive heart failure

have diabetes

plan to have any surgery or a dental procedure

are pregnant or plan to become pregnant. See “ Who should not take warfarin sodium?”

Your healthcare provider will do a pregnancy test before you start treatment with warfarin sodium.

Females who can become pregnant should use effective birth control during treatment, and for at least

1 month after the last dose of warfarin sodium.

are breastfeeding. You and your healthcare provider should decide if you will take warfarin sodium

and breastfeed. Check your baby for bruising or bleeding if you take warfarin sodium and breastfeed.

Tell all of your healthcare providers and dentists that you are taking warfarin sodium. They should talk to the

healthcare provider who prescribed warfarin sodium for you before you have any surgery or dental

procedure. Your warfarin sodium may need to be stopped for a short time or you may need your dose

adjusted.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-

counter medicines, vitamins, and herbal supplements. Some of your other medicines may affect the way

warfarin sodium works. Certain medicines may increase your risk of bleeding. See “ What is the most

important information I should know about warfarin sodium?”

How should I take warfarin sodium?

Take warfarin sodium exactly as prescribed. Your healthcare provider will adjust your dose from time

to time depending on your response to warfarin sodium.

You must have regular blood tests and visits with your healthcare provider to monitor your condition.

If you miss a dose of warfarin sodium, call your healthcare provider. Take the dose as soon as

possible on the same day. Do not take a double dose of warfarin sodium the next day to make up for a

missed dose.

Call your healthcare provider right away if you:

take too much warfarin sodium

are sick with diarrhea, an infection, or have a fever

fall or injure yourself, especially if you hit your head. Your healthcare provider may need to check

you.

What should I avoid while taking warfarin sodium?

Do not do any activity or sport that may cause a serious injury.

What are the possible side effects of warfarin sodium?

Warfarin sodium may cause serious side effects, including:

See “ What is the most important information I should know about warfarin sodium?”

Death of skin tissue (skin necrosis or gangrene). This can happen soon after starting warfarin sodium.

It happens because blood clots form and block blood flow to an area of your body. Call your

healthcare provider right away if you have pain, color, or temperature change to any area of your

body. You may need medical care right away to prevent death or loss (amputation) of your affected

body part.

Kidney problems. Kidney injury may happen in people who take warfarin sodium. Tell your

healthcare provider right away if you develop blood in your urine. Your healthcare provider may do

tests more often during treatment with warfarin sodium to check for bleeding if you already have

kidney problems.

“Purple toes syndrome.” Call your healthcare provider right away if you have pain in your toes and

they look purple in color or dark in color.

These are not all of the side effects of warfarin sodium. For more information, ask your healthcare provider

or pharmacist.

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

1088.

How should I store warfarin sodium tablets?

Store warfarin sodium tablets at 20°C to 25°C (68°F to 77°F)

Keep warfarin sodium tablets in a tightly closed container, and keep warfarin sodium tablets out of

the light and moisture.

Follow your healthcare provider or pharmacist instructions about the right way to throw away

outdated or unused warfarin sodium.

Females who are pregnant should not handle crushed or broken warfarin sodium tablets.

Keep warfarin sodium tablets and all medicines out of the reach of children.

General information about the safe and effective use of warfarin sodium.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use

warfarin sodium for a condition for which it was not prescribed. Do not give warfarin sodium to other

people, even if they have the same symptoms that you have. It may harm them.

You can ask your healthcare provider or pharmacist for information about warfarin sodium that is written for

health professionals.

If you would like more information, talk to your healthcare provider or call Rising Health, LLC at 1-833-

395-6928

What are the ingredients in warfarin sodium tablets, USP?

Active ingredient: Warfarin Sodium, USP

Inactive ingredients: Lactose monohydrate, starch, pregelatinised starch, hydroxypropyl cellulose, starlac and

magnesium stearate. Additionally each:

1 mg tablet contains: D&C Red #30 aluminum lake

2 mg tablet contains: FD&C Red #40 aluminum lake and FD&C Blue#2

2.5 mg tablet contains: D&C Yellow # 10 aluminum lake and FD&C Blue#2

3 mg tablet contains: FD&C Yellow # 6 aluminum lake, FD&C Blue#2 and FD&C Red # 40 aluminum lake

4 mg tablet contains: FD&C Blue#2

5 mg tablet contains: FD&C Yellow # 6 aluminum lake

6 mg tablet contains: FD&C Yellow # 6 aluminum lake and FD&C Blue #2

7.5 mg tablet contains: D&C Yellow # 10 aluminum lake and FD&C Yellow # 6 aluminum lake

10 mg tablet is dye free.

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

Distributed by:

Rising Health, LLC

Saddle Brook, NJ 07663

Made in USA

Revised: 06/2018

Rx only

Revised: 4/2020

Document Id: a4891b18-503b-7808-e053-2995a90a5db3

34391-3

Set id: 8ed46bb1-9f7d-4418-e053-2a95a90abd4b

Version: 2

Effective Time: 20200430

NuCare Pharmaceuticals,Inc.

WARFARIN SODIUM- warfarin sodium tablet

NuCare Pharmaceuticals,Inc.

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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, 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)

RECENT MAJOR CHANGES

Dosage and Administration, Renal Impairment (2.5) 5/2017

Warnings and Precautions, Calciphylaxis (5.3) 9/2016

Warnings and Precautions, Acute kidney injury (5.4) 5/2017

INDICATIONS AND USAGE

Warfarin sodium tablets are vitamin K antagonist indicated for:

Prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism. (1)

Prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation and/or cardiac valve

replacement. (1)

Reduction in the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic

embolization after myocardial infarction. (1)

Limitations of Use

Warfarin sodium tablets have 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, 2.5, 3, 4, 5, 6, 7.5, or 10 mg (3)

CONTRAINDICATIONS

Pregnancy, except in women with mechanical heart valves. ( 4, 5.7, 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. ( 4,5.8)

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 sodium and consider alternative

anticoagulation therapy. ( 5.3)

Acute kidney injury may occur during episodes of excessive anticoagulation and hematuria. ( 5.4)

Systemic atheroemboli and cholesterol microemboli: Some cases have progressed to necrosis or death. Discontinue

warfarin sodium if such emboli occur. ( 5.5)

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. ( 5.6)

Pregnant women with mechanical heart valves: Warfarin sodium may cause fetal harm; however, the benefits may

outweigh the risks.( 5.7)

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 Rising Health, LLC at 1-833-395-6928 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 women with 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)

Renal Impairment: Instruct patients with renal impairment to frequently monitor their INR. ( 8.6)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 6/2018

FULL PRESCRIBING INFORMATION: CONTENTS*

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 Renal Impairment

2.6 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 Acute Kidney Injury

5.5 Systemic Atheroemboli and Cholesterol Microemboli

5.6 Limb Ischemia, Necrosis, and Gangrene in Patients with HIT and HITTS

5.7 Use in Pregnant Women with Mechanical Heart Valves

5.8 Other Clinical Settings with Increased Risks

5.9 Endogenous Factors Affecting INR

6 ADVERSE REACTIONS

7 DRUG INTERACTIONS

7.1 General Information

7.2 CYP450 Interactions

7.3 Drugs that Increase Bleeding Risk

7.4 Antibiotics and Antifungals

7.5 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

FULL PRESCRIBING INFORMATION

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)].

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

1 INDICATIONS AND USAGE

Warfarin sodium tablets are 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 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 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) [ seeClinical 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 [seeUse 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 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 doses observed in subgroups

of patients having different combinations of CYP2C9 and VKORC1 gene variants [ seeClinical

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 Daily Doses Based on

CYP2C9 and VKORC1 Genotypes†

VKORC1

CYP2C9

*1/*1

*1/*2

*1/*3

*2/*2

*2/*3

*3/*3

5-7 mg

5-7 mg

3-4 mg

3-4 mg

3-4 mg

0.5-2 mg

5-7 mg

3-4 mg

3-4 mg

3-4 mg

0.5-2 mg

0.5-2 mg

3-4 mg

3-4 mg

0.5-2 mg

0.5-2 mg

0.5-2 mg

0.5-2 mg

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.

2.4 Monitoring to Achieve Optimal Anticoagulation

Warfarin sodium is 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 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 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 therapy.

2.5 Renal Impairment

No dosage adjustment is necessary for patients with renal failure. Monitor INR more frequently in

patients with compromised renal function to maintain INR within the therapeutic range [see Warnings and

Precautions (5.4)and Use in Specific Populations (8.6)].

2.6 Missed Dose

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

warfarin sodium 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 therapy. Consider the benefits and risks when discontinuing warfarin sodium 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 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 is not achieved for several days, heparin is

preferred for initial rapid anticoagulation. During initial therapy with warfarin sodium, the interference

with heparin anticoagulation is of minimal clinical significance. Conversion to warfarin sodium 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 therapy with heparin

for 4 to 5 days and until warfarin sodium 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 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 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.

3 DOSAGE FORMS AND STRENGTHS

Warfarin sodium tablets, USP are supplied as follows:

1 mg Tablets: Light pink, Round, Flat Beveled edge tablets debossed " I" on the left side of bisect

and " G" on the right side of bisect on one side and " W" on the top and " 1" on the bottom of other side

2 mg Tablets: Lavender, Round, Flat Beveled edge tablets debossed " I" on the left side of bisect and

" G" on the right side of bisect on one side and " W" on the top and " 2" on the bottom of other side

2.5 mg Tablets: Green, Round, Flat Beveled edge tablets debossed " I" on the left side of bisect and "

G" on the right side of bisect on one side and " W" on the top and " 2

/

" on the bottom of other side

3 mg Tablets: Tan, Round, Flat Beveled edge tablets debossed " I" on the left side of bisect and " G"

on the right side of bisect on one side and " W" on the top and " 3" on the bottom of other side

4 mg Tablets: Blue, Round, Flat Beveled edge tablets debossed " I" on the left side of bisect and "

G" on the right side of bisect on one side and " W" on the top and " 4" on the bottom of other side

5 mg Tablets: Peach, Round, Flat Beveled edge tablets debossed " I" on the left side of bisect and "

G" on the right side of bisect on one side and " W" on the top and " 5" on the bottom of other side

6 mg Tablets: Teal, Round, Flat Beveled edge tablets de-bossed " I" on the left side of bisect and "

G" on the right side of bisect on one side and " W" on the top and " 6" on the bottom of other side

7.5 mg Tablets: Yellow, Round, Flat Beveled edge tablets debossed " I" on the left side of bisect

and " G" on the right side of bisect on one side and " W" on the top and " 7

/

" on the bottom of other

side

10 mg Tablets: White, Round, Flat Beveled edge tablets debossed " I" on the left side of bisect and "

G" on the right side of bisect on one side and " W" on the top and " 10" on the bottom of other side

4 CONTRAINDICATIONS

Warfarin Sodium is contraindicated in:

Pregnancy

1

2

1

2

Warfarin sodium tablets are contraindicated in women who are pregnant except in pregnant women with

mechanical heart valves, who are at high risk of thromboembolism [ see Warnings and Precautions (5.7)

and Use in Specific Populations (8.1) ]. Warfarin sodium can cause fetal harm when administered to a

pregnant woman. Warfarin sodium 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 sodium is used during pregnancy

or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential

hazard to a fetus [ see Use in Specific Populations (8.1)].

Warfarin Sodium is contraindicated in patients with:

Hemorrhagic tendencies or blood dyscrasias

Recent or contemplated surgery of the central nervous system or eye, or traumatic surgery resulting

in large open surfaces [ seeWarnings and Precautions (5.8)]

Bleeding tendencies associated with: − Active ulceration or overt bleeding of the gastrointestinal,

genitourinary, or respiratory tract− Central nervous system hemorrhage− Cerebral aneurysms,

dissecting aorta− Pericarditis and pericardial effusions− Bacterial endocarditis

Threatened abortion, eclampsia, and preeclampsia

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

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

bleeding

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

Adverse Reactions (6)]

Major regional or lumbar block anesthesia

Malignant hypertension

5 WARNINGS AND PRECAUTIONS

5.1 Hemorrhage

Warfarin sodium 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 [

seeClinical Pharmacology (12.5)], certain concomitant drugs [ seeDrug Interactions (7)], and long duration

of warfarin therapy.

Perform regular monitoring of INR in all treated patients. Those at high risk of bleeding may benefit

from more frequent INR monitoring, careful dose adjustment to desired INR, and a shortest duration of

therapy appropriate for the clinical condition. However, maintenance of INR in the therapeutic range

does not eliminate the risk of bleeding.

Drugs, dietary changes, and other factors affect INR levels achieved with warfarin sodium therapy.

Perform more frequent INR monitoring when starting or stopping other drugs, including botanicals, or

when changing dosages of other drugs [ see Drug Interactions (7)].

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

symptoms of bleeding [ seePatient Counseling Information (17)].

5.2 Tissue Necrosis

Warfarin sodium can cause necrosis and/or gangrene of skin and other tissues, which 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 sodium 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 sodium therapy if necrosis occurs. Consider

alternative drugs if continued anticoagulation therapy is necessary.

5.3 Calciphylaxis

Warfarin sodium can cause fatal and serious calciphylaxis or calcium uremic arteriolopathy, which has

been reported in patients with and without end-stage renal disease. When calciphylaxis is diagnosed in

these patients, discontinue Warfarin sodium and treat calciphylaxis as appropriate. Consider alternative

anticoagulation therapy.

5.4 Acute Kidney Injury

In patients with altered glomerular integrity or with a history of kidney disease, acute kidney injury may

occur with Warfarin sodium, possibly in relation to episodes of excessive anticoagulation and

hematuria [see Use in Specific Populations (8.6)] . More frequent monitoring of anticoagulation is advised

in patients with compromised renal function.

5.5 Systemic Atheroemboli and Cholesterol Microemboli

Anticoagulation therapy with warfarin sodium 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 sodium therapy if such phenomena are observed. Consider alternative drugs if

continued anticoagulation therapy is necessary.

5.6 Limb Ischemia, Necrosis, and Gangrene in Patients with HIT and HITTS

Do not use warfarin sodium 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 sodium may be

considered after the platelet count has normalized.

5.7 Use in Pregnant Women with Mechanical Heart Valves

Warfarin sodium can cause fetal harm when administered to a pregnant woman. While warfarin sodium is

contraindicated during pregnancy, the potential benefits of using warfarin sodium 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 sodium 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 sodium 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 [ seeUse in Specific Populations (8.1)].

5.8 Other Clinical Settings with Increased Risks

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

Eye surgery: In cataract surgery, warfarin sodium 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 sodium cessation or reduction

may lead to serious thromboembolic complications, the decision to discontinue warfarin sodium

before a relatively less invasive and complex eye surgery, such as lens surgery, should be based

upon the risks of anticoagulant therapy weighed against the benefits.

Polycythemia vera

Vasculitis

Diabetes mellitus

5.9 Endogenous Factors Affecting INR

The following factors may be responsible for increased INR response: diarrhea, hepatic disorders,

poor nutritional state, steatorrhea, or vitamin K deficiency.

The following factors may be responsible for decreased INR response: increased vitamin K intake or

hereditary warfarin resistance.

6 ADVERSE REACTIONS

The following serious adverse reactions to warfarin sodium are discussed in greater detail in other

sections of the labeling:

Hemorrhage [see Boxed Warning, Warnings and Precautions (5.1), and Overdosage (10)]

Tissue Necrosis [see Warnings and Precautions (5.2)]

Calciphylaxis [see Warnings and Precautions (5.3)]

Acute Kidney Injury [see Warnings and Precautions (5.4)]

Systemic Atheroemboli and Cholesterol Microemboli [see Warnings and Precautions (5.5)]

Limb Ischemia, Necrosis, and Gangrene in Patients with HIT and HITTS [see Warnings and

Precautions (5.6)]

Other Clinical Settings with Increased Risks [see Warnings and Precautions (5.8)]

Other adverse reactions to warfarin sodium 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 sodium 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

7 DRUG INTERACTIONS

7.1 General Information

Drugs may interact with warfarin sodium through pharmacodynamic or pharmacokinetic mechanisms.

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