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warfarin (Rx)Brand and Other Names:Coumadin, Jantoven

 
 
 

Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

powder for injection

  • 5mg/vial (discontinued)

tablet

  • 1mg
  • 2mg
  • 2.5mg
  • 3mg
  • 4mg
  • 5mg
  • 6mg
  • 7.5mg
  • 10mg
more...

Venous Thrombosis

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

Initial dose: 2-5 mg PO/IV qDay for 2 days, OR 10 mg PO for 2 days in healthy individuals

Initiate warfarin on day 1 or 2 of LMWH or unfractionated heparin therapy and overlap until desired INR, THEN discontinue heparin

Check INR after 2 days and adjust dose according to results

Typical maintenance dose ranges between 2 and 10 mg/day

Consider dosage based on genotype (see Genomic Considerations)

DVT and PE treatment

  • Initiate warfarin on day 1 or 2 of parenteral anticoagulation therapy (eg, LMWH or unfractionated heparin)
  • Overlap warfarin and parenteral anticoagulant for at least 5 days until desired INR (>2.0) maintained for 24 hours, then discontinue parenteral therapy

INR range and treatment duration

  • Maintain an INR of 2.0-3.0
  • Surgery-provoked DVT or PE: Treatment duration of 3 months
  • Transient (reversible) risk factor-induced DVT or PE: Treatment duration of 3 months
  • First unprovoked proximal DVT or PE with low or moderate bleeding risk: Extended treatment consideration with periodic (ie, annual) risk-benefit analysis
  • First unprovoked proximal DVT or PE with high bleeding risk: Treatment duration of 3 months
  • First unprovoked distal DVT regardless of bleeding risk: Treatment duration of 3 months
  • Second unprovoked DVT or PE with low or moderate bleeding risk: Extended treatment
  • Second unprovoked DVT or PE with high bleeding risk: Treatment duration of 3 months
  • DVT/PE and active cancer: Extended treatment, with periodic risk-benefit analysis (ACCP recommends LMWH over vitamin K antagonist therapy)
  • Prevention of venous thromboembolism for total knee arthroplasty, total hip arthroplasty, and hip fracture surgery: Minimum treatment duration of 10-14 days, with a recommendation to extend outpatient therapy to 35 days (ACCP recommends LMWH over vitamin K antagonist therapy)

Stroke & Thromboembolism

Prophylaxis and treatment of systemic embolic complications (eg, stroke) associated with atrial fibrillation (AF)

Initial dose: 2-5 mg PO/IV qDay × 2 days, OR 10 mg PO × 2 days in healthy individuals

Check INR after 2 days and adjust dose according to results

Typical maintenance dose ranges between 2-10 mg/day

Consider dosage based on genotype (see Genomic Considerations)

ACCP guidelines recommend dabigatran 150 mg PO BID over adjusted-dose warfarin therapy for AF unless both AF and mitral stenosis are present

INR range and treatment duration

  • Nonvalvular AF: Maintain an INR of 2.0-3.0
  • AF and stable CAD: Adjusted-dose warfarin therapy (INR 2.0-3.0) without aspirin
  • AF with high stroke risk and placement of stent: Triple therapy of dose-adjusted warfarin (INR 2.0-3.0), clopidogrel, and aspirin; for 1 month if bare metal stent; for 3-6 months for drug-eluting stent
  • AF with intermediate to high stroke risk without stent placement: 12 months of warfarin therapy (INR 2.0-3.0) with single antiplatelet regimen
  • AF for more than 48 hours to undergo cardioversion: Warfarin therapy (INR 2.0-3.0) for 3 weeks prior to and 4 weeks after cardioversion

Indications for indefinite treatment duration

  • Persistent or paroxysmal nonvalvular AF in patients with a high risk of stroke: Ie, patients who have risk factors for stroke, such as prior ischemic stroke, transient ischemic attack, or systemic embolism or who have 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
  • Persistent or paroxysmal nonvalvular AF in patients with an intermediate risk of ischemic stroke: Ie, patients who have 1 of the following risk factors--age >75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus
  • AF and mitral stenosis
  • ≥2 episodes of documented DVT or PE

Cardiac Valve Replacement

Prophylaxis and treatment of thromboembolic complications associated with cardiac valve replacement

Initial dose: 2-5 mg PO/IV qDay × 2 days, OR 10 mg PO × 2 days in healthy individuals

Check INR after 2 days and adjust dose according to results

Typical maintenance dose ranges between 2 and 10 mg/day

Consider dosage based on genotype (see Genomic Considerations)

INR and treatment duration

  • Mitral bioprosthetic valve: INR 2.0-3.0 for a 3-month treatment duration; if other risk factors for thromboembolism are present (ie, AF, previous thromboembolism, left ventricular dysfunction), a longer duration may be necessary
  • Aortic mechanical valve: INR 2.0-3.0 for indefinite treatment duration
  • Mitral mechanical valve, caged ball or caged disk valve, or both aortic and mitral mechanical valves: INR 2.5-3.5 for indefinite treatment duration
  • Mechanical valves include bileaflet mechanical valves and Medtronic Hall tilting disk valves

Post-Myocardial Infarction

Reduction in the risk of death, recurrent MI, and thromboembolic events (eg, stroke, systemic embolization) after MI

Initial dose: 2-5 mg PO/IV qDay × 2 days, OR 10 mg PO × 2 days in healthy individuals

Check INR after 2 days and adjust dose according to results

Typical maintenance dose ranges between 2 and 10 mg/day

Consider dosage based on genotype (see Genomic Considerations)

INR and treatment duration

  • Maintain INR between 2.0 and 3.0
  • In patients who have not had stenting and who have anterior MI and left ventricular (LV) thrombus or high risk of LV thrombus (ie, ejection fraction <40%, anteroapical wall-motion abnormality), treatment involves dual therapy of warfarin (INR 2.0-3.0) and low-dose aspirin 75-100 mg, daily; treatment duration is 3 months, after which warfarin is discontinued
  • In patients who have had bare-metal stent placement and who have anterior MI and LV thrombus or high risk of LV thrombus (ejection fraction <40%, anteroapical wall-motion abnormality), treatment involves triple therapy of warfarin (INR 2.0-3.0), low-dose aspirin, and clopidogrel 75 mg, daily for 1 month, followed by warfarin (INR 2.0-3.0) and single antiplatelet therapy for second and third month, after which warfarin is discontinued
  • In patients who have had drug-eluting stent placement and who have anterior MI and LV thrombus or high risk of LV thrombus (ejection fraction <40%, anteroapical wall-motion abnormality), treatment involves triple therapy of warfarin (INR 2.0-3.0), low-dose aspirin, and clopidogrel 75 mg, daily for 3-6 months, after which warfarin is discontinued

Rheumatic Valve Disease (Off-label)

Rheumatic valve disease with any of the following: Atrial diameter >55 mm, left atrial thrombus, atrial fibrillation, and previous systemic embolism

Maintain INR 2.0-3.0 indefinitely

Cryptogenic Stroke and Patent Foramen Ovale With DVT (Off-label)

Maintain INR between 2.0 and 3.0 for 3 months

Cardioembolic Stroke or TIA (Off-label)

Maintain INR between 2.0 and 3.0 indefinitely

ACCP guidelines recommend dabigatran 150 mg PO twice daily over dose-adjusted warfarin therapy

Systolic LV Dysfunction (Off-label)

Systolic LV dysfunction without established CAD but with identified acute LV thrombus (eg, Takotsubo cardiomyopathy)

Maintain INR between 2.0 and 3.0 for at least 3 months

Antiphospholipid Antibody Syndrome (Off-label)

Antiphospholipid antibody syndrome with previous arterial or venous thromboembolism

Maintain INR between 2.0 and 3.0 indefinitely

Genomic Considerations

ACCP 2012 guidelines recommend against using pharmacogenetic testing for guiding doses

CYP2C9 and vitamin K epoxide reductase complex, subunit 1 (VKORC1) genotype information can assist in selecting starting dose

If genotype information unavailable, usual starting dose is 2-5 mg/day (modify based on other patient factors)

Range of expected therapeutic doses based on CYP2C9 and VKORC1 genotypes are listed below

VKORC1-GG

  • CYP2C9 *1/*1: 5-7 mg
  • CYP2C9 *1/*2: 5-7 mg
  • CYP2C9 *1/*3: 3-4 mg
  • CYP2C9 *2/*2: 3-4 mg
  • CYP2C9 *2/*3: 3-4 mg
  • CYP2C9 *3/*3: 0.5-2 mg

VKORC1-AG

  • CYP2C9 *1/*1: 5-7 mg
  • CYP2C9 *1/*2: 3-4 mg
  • CYP2C9 *1/*3: 3-4 mg
  • CYP2C9 *2/*2: 3-4 mg
  • CYP2C9 *2/*3: 0.5-2 mg
  • CYP2C9 *3/*3: 0.5-2 mg

VKORC1-AA

  • CYP2C9 *1/*1: 3-4 mg
  • CYP2C9 *1/*2: 3-4 mg
  • CYP2C9 *1/*3: 0.5-2 mg
  • CYP2C9 *2/*2: 0.5-2 mg
  • CYP2C9 *2/*3: 0.5-2 mg
  • CYP2C9 *3/*3: 0.5-2 mg

Dosing Considerations

Indication determines intensity and duration of therapy

Individualized doses and monitoring of PT/INR are necessary

Monitoring frequency should be daily or once every few days until stabilized; once stable, q4-6 weeks or longer may be appropriate (eg, 12 weeks)

Not all factors causing warfarin dose variability are known, but they include age, race, sex, body weight, concomitant medications, and comorbidities, in addition to genetic factors

Lower starting doses (ie, 2-5 mg/day × 2 days) recommended with the elderly, hepatic impairment, poor nutrition, CHF, high bleeding risk, debilitated patients, heart valve replacement, concomitant medications known to increase warfarin effect, or individuals suspected of having genomic variants

Perioperative management recommendations: Hold warfarin therapy approximately 5 days before surgery; resume warfarin 12-24 hr after surgery; bridge anticoagulation during interruption in patients at high thromboembolism risk

Minor procedures and dental procedures: See ACCP guidelines for specific recommendations

Warfarin has no direct effect on an established thrombus, nor does it reverse ischemic tissue damage

Systemic atheroemboli and cholesterol microemboli; some cases have progressed to necrosis or death; discontinue therapy if such emboli occur

Pregnant women with mechanical heart valves: Therapy may cause fetal harm; however, benefits may outweigh the risks

Dosing Modifications

Hepatic impairment: May potentiate warfarin response because of decreased metabolism and impaired synthesis of clotting factors

Administration

IV: Inject 2 mg/mL solution slow IV (over 1-2 min) into a peripheral vein

Not recommended for IM

Maintain consistent intake of vitamin K-containing foods; high vitamin K consumption may decrease warfarin effect

Dosage Forms & Strengths

powder for injection

  • 5mg/vial (discontinued)

tablets

  • 1mg
  • 2mg
  • 2.5mg
  • 3mg
  • 4mg
  • 5mg
  • 6mg
  • 7.5mg
  • 10mg
more...

Thrombosis

Prevention/treatment: If baseline INR is 1.0-1.3, administer loading dose of 0.1-0.2 mg/kg PO qDay × 1 day; check INR on days 2-4 and adjust daily dose to maintain INR between 2.0 and 3.0 (unless valve replacement indicates a higher range)  

Use 0.1 mg/kg to initiate therapy with liver impairment or in patients who have had a Fontan procedure

Typical maintenance dose: 0.09-0.33 mg/kg/day, with infants <12 months old often requiring doses at high end of range

Dosing considerations

  • Consistent anticoagulation in children is difficult and requires close supervision and frequent dose adjustments
  • Refer to ACCP recommendations or institutional protocol for treatment duration dependent on indication
  • Infants and children receiving vitamin K-supplemented nutrition (including infant formulas): May be resistant to warfarin therapy
  • Infants with human-milk diet: May be sensitive to warfarin therapy

Dosing Considerations

Hepatic impairment

  • Hepatic impairment may potentiate warfarin response because of decreased metabolism and impaired synthesis of clotting factors
  • Load: 0.1 mg/kg PO qDay × 2 days
  • Typical maintenance dose: 0.1 mg/kg PO qDay; adjust dose to achieve desired INR
  • Common maintenance dose range: 0.05-0.34 mg/kg PO qDay

Anticoagulation

Lower doses required to produce therapeutic level of anticoagulation

Initial: ≤5 mg PO qDay

Maintenance: 2-5 mg PO qDay

Dosing Considerations

Elderly show greater than expected PT/INR response to anticoagulant effects of warfarin, possibly because of decreased hepatic function resulting in decreased warfarin metabolism and impaired synthesis of clotting factors

Caution should be used in elderly individuals who have increased risk of hemorrhage

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Interactions

Interaction Checker

warfarin and

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    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

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            Adverse Effects

            Frequency Not Defined

            Cholesterol embolus syndrome

            Intraocular hemorrhage

            Abdominal pain

            Flatulence

            Alopecia

            Rash

            Pruritus

            Taste disturbance

            Tissue necrosis

            Headache

            Lethargy

            Dizziness

            Hematuria

            Anemia

            Hepatitis

            Respiratory tract bleeding

            Hypersensitivity reaction

            Hemorrhage

            Blood dyscrasias

            Fever

            "Purple toe" syndrome

            Increased fracture risk with long-term usage

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            Warnings

            Black Box Warnings

            Warfarin sodium can cause major or fatal bleeding; bleeding is more likely to occur during the starting period and with a higher dose (resulting in a higher INR)

            Risk factors for bleeding include high intensity of anticoagulation (INR greater than 4), age 65 years or older, highly variable INRs, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, serious heart disease, anemia, malignancy, trauma, renal insufficiency, concomitant drugs, and long duration of warfarin therapy

            Regular monitoring of INR should be performed on all treated patients; those at high risk of bleeding may benefit from more frequent INR monitoring, careful dose adjustment to desired INR, and a shorter duration of therapy

            Patients should be instructed about prevention measures to minimize the risk of bleeding and to immediately report any signs or symptoms of bleeding to their physician

            Contraindications

            Pregnancy, except in women with mechanical heart valves

            Hemorrhagic tendencies or blood dyscrasias

            Recent or contemplated CNS or eye surgery or traumatic surgery resulting in large open surfaces

            Bleeding tendencies associated with CNS hemorrhage, cerebral aneurysms, dissecting aorta, pericarditis and pericardial effusions, bacterial endocarditis, and active ulceration or overt bleeding of the GI, GU, or respiratory tract

            Threatened abortion, eclampsia, and preeclampsia

            Unsupervised patients with conditions associated with potential high level of noncompliance (eg, dementia, alcoholism, psychosis)

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

            Major regional or lumbar block anesthesia

            Known hypersensitivity

            Malignant hypertension

            Cautions

            Lower doses may be warranted in the elderly, debilitated patients, malnutrition, CHF, or liver disease

            Elicits no direct effect on an established thrombus, nor does it reverse ischemic tissue damage

            INR >4.0 appears to provide no additional therapeutic benefit in most patients and is associated with a higher risk of bleeding

            Skin necrosis reported with use; caution in patients at risk for hemorrhage, necrosis, or gangrene

            Heparin-induced thrombocytopenia, DVT (may defer warfarin until thrombin generation is controlled and thrombocytopenia has resolved)

            Genetic tests may be warranted to determine best dose for individual patients; variations in CYP2C9 and VKORC1 genes may modify response

            Advise patients receiving warfarin to carry a notice stating that they are undergoing anticoagulant therapy, to alert medical/emergency personnel

            Use caution in patients with acute infection or active TB or conditions that may alter normal GI flora; antibiotics and fever may change response to warfarin

            May release atheromatous plaque emboli; may experience symptoms depending on site of embolization common organs like pancreas, liver, kidneys, and spleen, which may lead to necrosis or death

            Use caution in patients with prolonged vitamin K insufficiencies

            Thyroid disease may increase warfarin responsiveness

            May impair synthesis of coagulation factors in patients with reduced liver function, regardless of etiology, which in turn may lead to increased warfarin sensitivity

            Lactation

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            Pregnancy & Lactation

            Pregnancy category: D for women with mechanical heart valves who are at high risk for thromboembolism; category X (ie, contraindicated) for other pregnant populations

            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

            Verify pregnancy status of females of reproductive potential prior to initiating therapy

            Advise females of reproductive potential to use effective contraception during treatment, and for at least 1 month after final dose of warfarin

            Lactation: Not excreted in breast milk as reported in limited published study (AAP Committee states compatible with nursing); because of potential for serious adverse reactions, including bleeding in breastfed infant, consider developmental and health benefits of breastfeeding along with mother’s clinical need for therapy; monitor breastfeeding infants for bruising or bleeding

            Pregnancy Categories

            A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA:Information not available.

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            Pharmacology

            Mechanism of Action

            Interferes with hepatic synthesis of vitamin K-dependent clotting factors II, VII, IX, and X, as well as proteins C and S; S-warfarin is 4 times more potent than R-warfarin

            Warfarin depletes functional vitamin K reserves, which in turn reduces synthesis of active clotting factors, by competitively inhibiting subunit 1 of the multi-unit vitamin K epoxide reductase complex 1 (VKOR1)

            Absorption

            Onset: 36-48 hr

            Duration: 2-5 days

            Peak plasma time: 1.5-3 days

            Distribution

            Protein bound: 99% (albumin)

            Vd: 0.14 L/kg

            Metabolism

            R-warfarin: Hepatic P450 enzymes CYP1A2, CYP2C19, CYP3A4

            S-warfarin: CYP2C9

            Elimination

            Half-life: 20-60 hr (patient specific)

            Pharmacogenomics

            Metabolized primarily via oxidation in the liver by CYP2C9; exerts its anticoagulant effect by inhibiting the protein VKORC1

            Dose influenced by genetic factors (CYP2C9, VKORC1 genotypes)

            Carriers of CYP2C9*2 and CYP2C9*3 require ~19-33% dose reduction, respectively, per allele compared with persons who carry the *1 allele

            Carriers of the VKORC1 A allele require ~28% dose reduction per allele in their genotype compared with persons who carry none

            Genetic testing laboratories

            • The following companies provide genetic testing for CYP2C9 and VKORC1 variants
            • AutoGenomics (http://www.autogenomics.com)
            • EntroGen (http://www.entrogen.com)
            • Kimball Genetics (http://www.kimballgenetics.com)
            • Nanosphere (http://www.nanosphere.us)
            • Osmetech (http://www.osmetech.com)
            • Specialty Laboratories (http://www.specialtylabs.com)
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            Administration

            IV Incompatibilities

            Solution: D10W, NS (?), LR (?)

            Syringe: Heparin

            Y-site: Aminophylline, NH4Cl (?), bretylium, ceftazidime, dobutamine, ciprofloxacin, cimetidine, esmolol, labetalol, metronidazole, Ringer's, vancomycin (may be compatible at low conc of warfarin), and promazine

            IV Preparation

            Reconstitute in 2.7 mL SWI to obtain 2 mg/mL injectable solution

            Use reconstituted solution within 4 hr; discard unused portion

            IV Administration

            Inject 2 mg/mL solution slowly (over 1-2 min) into a peripheral vein

            IV Storage

            Store at room temp and protect from light

            Do not refrigerate

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            Images

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
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