Warfarin Sodium

• Warfarin sodium can cause major or fatal bleeding [see
  
  
  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 [see

  Clinical Pharmacology (12.5)

  ], certain concomitant drugs [see

  Drug 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 [see

  Patient Counseling Information (17)

  ].
  ].
  
• Perform regular monitoring of INR in all treated patients [see
  
  
  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.
  ].
  
• Drugs, dietary changes, and other factors affect INR levels achieved with warfarin sodium therapy [see
  
  
  7 DRUG INTERACTIONS

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

  7.1 General Information

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

  7.2 CYP450 Interactions

  CYP450 isozymes involved in the metabolism of warfarin include CYP2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. The more potent warfarin

  S

  -enantiomer is metabolized by CYP2C9 while the

  R

  -enantiomer is metabolized by CYP1A2 and 3A4.

  • Inhibitors of CYP2C9, 1A2, and/or 3A4 have the potential to increase the effect (increase INR) of warfarin by increasing the exposure of warfarin.
  • Inducers of CYP2C9, 1A2, and/or 3A4 have the potential to decrease the effect (decrease INR) of warfarin by decreasing the exposure of warfarin.

  Examples of inhibitors and inducers of CYP2C9, 1A2, and 3A4 are below in Table 2; however, this list should not be considered all-inclusive. Consult the labeling of all concurrently used drugs to obtain further information about CYP450 interaction potential. The CYP450 inhibition and induction potential should be considered when starting, stopping, or changing dose of concomitant medications. Closely monitor INR if a concomitant drug is a CYP2C9, 1A2, and/or 3A4 inhibitor or inducer.

  Table 2: Examples of CYP450 Interactions with Warfarin

  Enzyme	Inhibitors	Inducers
  CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
  CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
  CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

  7.3 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

  Drug Class	Specific Drugs
  Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
  Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
  Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
  Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

  7.4 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.

  7.5 Botanical (Herbal) Products and Foods

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

  Few adequate, well-controlled studies evaluating the potential for metabolic and/or pharmacologic interactions between botanicals and warfarin sodium 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 sodium. Conversely, some botanicals may decrease the effects of warfarin sodium (e.g., co-enzyme Q₁₀, St. John's wort, ginseng). Some botanicals and foods can interact with warfarin sodium through CYP450 interactions (e.g., echinacea, grapefruit juice, ginkgo, goldenseal, St. John's wort).

  The amount of vitamin K in food may affect therapy with warfarin sodium. Advise patients taking warfarin sodium to eat a normal, balanced diet maintaining a consistent amount of vitamin K. Patients taking warfarin sodium should avoid drastic changes in dietary habits, such as eating large amounts of green leafy vegetables.
  ].
  
• Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding [see
  
  
  17 PATIENT COUNSELING INFORMATION

  Advise the patient to read the FDA-approved patient labeling (Medication Guide).

  Instructions for Patients

  Advise patients to:

  • Strictly adhere to the prescribed dosage schedule [see
    Dosage and Administration (2.1)
    ].
  • If the prescribed dose of warfarin sodium is missed, take the dose as soon as possible on the same day but do not take a double dose of warfarin sodium the next day to make up for missed doses [see
    Dosage and Administration (2.6)
    ].
  • Obtain prothrombin time tests and make regular visits to their physician or clinic to monitor therapy [see
    Dosage and Administration (2.1)
    ].
  • Be aware that if therapy with warfarin sodium is discontinued, the anticoagulant effects of warfarin sodium may persist for about 2 to 5 days [see
    Clinical Pharmacology (12.2)
    ].
  • Avoid any activity or sport that may result in traumatic injury [see
    Use in Specific Populations (8.4)
    ]. And to tell their physician if they fall often as this may increase their risk for complications.
  • Eat a normal, balanced diet to maintain a consistent intake of vitamin K. Avoid drastic changes in dietary habits, such as eating large amounts of leafy, green vegetables [see
    Drug Interactions (7.5)
    ].
  • Contact their physician to report any serious illness, such as severe diarrhea, infection, or fever [see
    Warnings and Precautions (5)
    and
    Adverse Reactions (6)
    ].
  • Immediately contact their physician when experiencing pain and discoloration of the skin (a purple bruise like rash) mostly on areas of the body with a high fat content, such as breasts, thighs, buttocks, hips and abdomen [see
    Warnings and Precautions (5.2)
    ].
  • Immediately contact their physician when experiencing any unusual symptom or pain since warfarin sodium may cause small cholesterol or athero emboli. On feet it may appear as a sudden cool, painful, purple discoloration of toe(s) or forefoot [see
    Warnings and Precautions (5.5)
    ].
  • Immediately contact their physician when taking warfarin sodium after any heparin formulation therapy and experiencing bloody or black stools or appearence of bruises, or bleeding [see
    Warnings and Precautions (5.6)
    ].
  • To tell all of their healthcare professionals and dentists that they are taking warfarin sodium. This should be done before they have any surgery or dental procedure [see
    Dosage and Administration (2.7)
    ].
  • Carry identification stating that they are taking warfarin sodium.

  Bleeding Risks

  Advise patients to:

  • Notify their physician immediately if any unusual bleeding or symptoms occur. Signs and symptoms of bleeding include: pain, swelling or discomfort, prolonged bleeding from cuts, increased menstrual flow or vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or dark brown urine, red or tar black stools, headache, dizziness, or weakness [see
    Box Warning
    and
    Warnings and Precautions (5.1)
    ].

  Concomitant Medications and Botanicals (Herbals)

  Advise patients to:

  • Not take or discontinue any other drug, including salicylates (e.g., aspirin and topical analgesics), other over-the-counter drugs, and botanical (herbal) products except on advice of your physician [see
    Drug Interactions (7)
    ].

  Pregnancy and Nursing

  Advise patients to:

  • Notify their physician if they are pregnant or planning to become pregnant or considering breast feeding [see
    Use in Specific Populations (8.1, 8.2, 8.3)
    ].
  • Avoid warfarin sodium during pregnancy except in pregnant women with mechanical heart valves, who are at risk of thromboembolism [see
    Contraindications (4)
    ]. Use effective measures to avoid pregnancy while taking warfarin sodium. This is very important because their unborn baby could be seriously harmed if they take warfarin sodium while they are pregnant [see
    Use in Specific Populations (8.1, 8.3)
    ].
  ].
  

Warfarin sodium tablets, USP 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.

• Individualize dosing regimen for each patient, and adjust based on INR response. (
  
  
  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.
  )
  
• Knowledge of genotype can inform initial dose selection. (
  
  
  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) [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 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 [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 Daily Doses Based on CYP2C9 and VKORC1 GenotypesRanges are derived from multiple published clinical studies. VKORC1 −1639G>A (rs9923231) variant is used in this table. Other coinherited VKORC1 variants may also be important determinants of warfarin dose.

  VKORC1	CYP2C9
  	*1/*1	*1/*2	*1/*3	*2/*2	*2/*3	*3/*3
  GG	5-7 mg	5-7 mg	3-4 mg	3-4 mg	3-4 mg	0.5-2 mg
  AG	5-7 mg	3-4 mg	3-4 mg	3-4 mg	0.5-2 mg	0.5-2 mg
  AA	3-4 mg	3-4 mg	0.5-2 mg	0.5-2 mg	0.5-2 mg	0.5-2 mg
  )
  
• Monitoring: Obtain daily INR determinations upon initiation until stable in the therapeutic range. Obtain subsequent INR determinations every 1 to 4 weeks. (
  
  
  2.4 Monitoring to Achieve Optimal Anticoagulation

  Warfarin sodium has 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.
  )
  
• Review conversion instructions from other anticoagulants. (
  
  
  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.
  )
  

• Pregnant women with mechanical heart valves: Warfarin sodium may cause fetal harm; however, the benefits may outweigh the risks. (
  
  
  8.1 Pregnancy

  Risk Summary

  Warfarin sodium tablets, USP are 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 sodium may outweigh the risks [see

  Warnings and Precautions (5.7)

  ]. Warfarin sodium can cause fetal harm. Exposure to warfarin during the first trimester of pregnancy caused a pattern of congenital malformations in about 5% of exposed offspring. Because these data were not collected in adequate and well-controlled studies, this incidence of major birth defects is not an adequate basis for comparison to the estimated incidences in the control group or the U.S. general population and may not reflect the incidences observed in practice. Consider the benefits and risks of warfarin sodium and possible risks to the fetus when prescribing warfarin sodium to a pregnant woman.

  Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

  Clinical Considerations

  Fetal/Neonatal Adverse Reactions

  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 (4)

  ].
  )
  
• Lactation: Monitor breastfeeding infants for bruising or bleeding. (
  
  
  8.2 Lactation

  Risk Summary

  Warfarin was not present in human milk from mothers treated with warfarin from a limited published study. Because of the potential for serious adverse reactions, including bleeding in a breastfed infant, consider the developmental and health benefits of breastfeeding along with the mother's clinical need for warfarin sodium and any potential adverse effects on the breastfed infant from warfarin sodium or from the underlying maternal condition before prescribing warfarin sodium to a lactating woman.

  Clinical Considerations

  Monitor breastfeeding infants for bruising or bleeding.

  Data

  Human Data

  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. Effects in premature infants have not been evaluated.
  )
  
• Renal Impairment: Instruct patients with renal impairment to frequently monitor their INR. (
  
  
  8.6 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. Instruct patients with renal impairment taking warfarin to monitor their INR more frequently [see

  Warnings and Precautions (5.4)

  ].
  )