Warfarin

Warfarin is used to treat blood clots (such as in deep vein thrombosis-DVT or pulmonary embolus-PE) and/or to prevent new clots from forming in your body. Preventing harmful blood clots helps to reduce the risk of a stroke or heart attack. Conditions that increase your risk of developing blood clots include a certain type of irregular heart rhythm (atrial fibrillation), heart valve replacement, recent heart attack, and certain surgeries (such as hip/knee replacement).

Warfarin is commonly called a "blood thinner," but the more correct term is "anticoagulant." It helps to keep blood flowing smoothly in your body by decreasing the amount of certain substances (clotting proteins) in your blood.

Warfarin is available under the following different brand names: Coumadin, and Jantoven.

Adult Dosage Forms and Strengths

Tablet

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

Dosage Considerations – Should be Given as Follows:

Venous Thrombosis

Adult

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

Initial dose: 2-5 mg oral/intravenous (IV) once/day for 2 days, OR 10 mg orally for 2 days in healthy individuals

Initiate warfarin on day 1 or 2 of LMWH or unfractionated heparin therapy and overlap until desired international normalized ratio (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

DVT and PE treatment

• Initiate warfarin on day 1 or 2 of parenteral anticoagulation therapy (e.g., LMWH or unfractionated heparin)
• Overlap warfarin and parenteral anticoagulant for at least 5 days until desired INR (greater than 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 (i.e., 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 (American College of Clinical Pharmacy/ACCP recommends LMWH over vitamin K antagonist therapy)

Pediatric

Prevention/treatment: If baseline INR is 1.0-1.3, administer loading dose of 0.1-0.2 mg/kg orally once/day for 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 less than 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

Stroke and Thromboembolism

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

Initial dose: 2-5 mg oral/intravenous (IV) once/day for 2 days, OR 10 mg orally for 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 orally BID over adjusted-dose warfarin therapy for atrial fibrillation (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: i.e., 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: i.e., patients who have 1 of the following risk factors--age over 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 or more 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 oral/intravenous (IV) once/day for 2 days, OR 10 mg orally for 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

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 (i.e., 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 myocardial infarction (MI), and thromboembolic events (e.g., stroke, systemic embolization) after MI

Initial dose: 2-5 mg oral/intravenous (IV) once/day for 2 days, OR 10 mg orally for 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

INR and treatment duration

• Maintain INR between 2.0 and 3.0
• In patients who have not had stenting and who have anterior myocardial infarction (MI) and left ventricular (LV) thrombus or high risk of LV thrombus (i.e., ejection fraction less than 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 less than 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 less than 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

Anticoagulation, Geriatric

Lower doses required to produce therapeutic level of anticoagulation

Initial: Up to 5 mg orally once/day

Maintenance: 2-5 mg orally once/day

Rheumatic valve disease with any of the following: Atrial diameter greater than 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 orally twice daily over dose-adjusted warfarin therapy

Systolic LV Dysfunction (Off-label)

Systolic LV dysfunction without established CAD but with identified acute LV thrombus (e.g., 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

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, every 4-6 weeks or longer may be appropriate (e.g., 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 (i.e., 2-5 mg/day for 2 days) recommended with the elderly, hepatic impairment, poor nutrition, congestive heart failure (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 hours after surgery; bridge anticoagulation during interruption in patients at high thromboembolism risk

Minor procedures and dental procedures: See American College of Clinical Pharmacy/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

Pediatric

Hepatic impairment

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

Geriatric

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

Dosage Modifications

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

Side effects associated with use of Warfarin, include the following:

• Cholesterol embolus syndrome
• Intraocular hemorrhage
• Abdominal pain
• Gas (flatulence)
• Hair loss
• Rash
• Itching
• Taste disturbance
• Tissue necrosis
• Headache
• Lethargy
• Dizziness
• Blood in urine
• Anemia
• Hepatitis
• Respiratory tract bleeding
• Hypersensitivity reaction
• Bleeding
• Blood dyscrasias
• Fever
• "Purple toe" syndrome
• Increased fracture risk with long-term usage
• Calciphylaxis

This document does not contain all possible side effects and others may occur. Check with your physician for additional information about side effects.

If your medical doctor is using this medicine to treat your pain, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider or pharmacist first.

Severe Interactions of Warfarin Include:

• apixaban
• defibrotide
• mifepristone

Warfarin has serious interactions with at least 123 different drugs.

Warfarin has moderate interactions with at least 290 different drugs.

Warfarin has mild interactions with at least 52 different drugs.

This information does not contain all possible interactions or adverse effects. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share this information with your doctor and pharmacist. Check with your health care professional or doctor for additional medical advice, or if you have health questions, concerns or for more information about this medicine.

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
• This medication contains warfarin. Do not take Coumadin or Jantoven if you are allergic to warfarin or any ingredients contained in this drug
• Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center immediately

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

Effects of Drug Abuse

No information provided

Short-Term Effects

• See "What Are Side Effects Associated with Using Warfarin?"

Long-Term Effects

• Skin necrosis reported with use; caution in patients at risk for hemorrhage, necrosis, or gangrene.
• See "What Are Side Effects Associated with Using Warfarin?”

Cautions

• Lower doses may be warranted in the elderly, debilitated patients, malnutrition, congestive heart failure (CHF), or liver disease
• Elicits no direct effect on an established thrombus, nor does it reverse ischemic tissue damage
• INR greater than 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 gastrointestinal (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
• Calciphylaxis or calcium uremic arteriolopathy has been reported in patients with and without end-stage renal disease; discontinue warfarin and treat calciphylaxis as appropriate; consider alternative anticoagulant therapy
• Maintain consistent intake of vitamin K-containing foods; high vitamin K consumption may decrease warfarin effect

Pregnancy and Lactation

• Use warfarin during pregnancy only in LIFE-THREATENING emergencies when no safer drug is available
• There is positive evidence of human fetal risk
• For women with mechanical heart valves who are at high risk for thromboembolism; do not use warfarin in pregnancy
• Risks involved outweigh potential benefits
• Safer alternatives exist
• 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
• Warfarin is not excreted in breast milk as reported in a limited published study (American Academy of Pediatrics/AAP Committee states compatible with nursing); because of the potential for serious adverse reactions, including bleeding in a breastfed infant, consider developmental and health benefits of breastfeeding along with the mother's clinical need for therapy; monitor breastfeeding infants for bruising or bleeding