Warfarin

Warfarinis used to treatblood clots(such asindeep vein thrombosis-DVTorpulmonary embolus-PE) and/or to prevent new clots from forming in your body. Preventing harmfulbloodclots helps to reduce the risk of astrokeorheart attack. Conditions that increase your risk of developing blood clots include a certain type of irregularheart节奏(atrial fibrillation), heart valve replacement, recent heart attack, and certain surgeries (such as hip/kneereplacement).

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 (clottingproteins) in your blood.

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

Adult Dosage Forms and Strengths

Tablet

• 1mg
• 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:

VenousThrombosis

Adult

Prophylaxisand treatment of venous thrombosis and itsextension,pulmonary embolism(PE)

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

Initiate warfarin on day 1 or 2 of LMWH or unfractionatedheparintherapyand overlap until desiredinternational 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 ongenotype

DVT and PE treatment

• Initiate warfarin on day 1 or 2 ofparenteralanticoagulation 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

INRrangeand treatment duration

• 米aintain 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 unprovokedproximalDVT or PE with low or moderate bleeding risk: Extended treatment consideration with periodic (i.e., annual) risk-benefitanalysis
• First unprovoked proximal DVT or PE with high bleeding risk: Treatment duration of 3 months
• First unprovokeddistalDVT 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 activecancer: Extended treatment, with periodic risk-benefit analysis (ACCP recommends LMWH overvitamin Kantagonisttherapy)
• Prevention of venousthromboembolismfor total knee arthroplasty, total hip arthroplasty, andhip fracturesurgery: Minimum treatment duration of 10-14 days, with a recommendation to extendoutpatienttherapy to 35 days (American College ofClinicalPharmacy/ACCP recommends LMWH over vitamin K antagonist therapy)

Pediatric

Prevention/treatment: IfbaselineINR 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 withliverimpairment 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 onindication
• Infants and children receiving vitamin K-supplementednutrition(includinginfantformulas): May be resistant to warfarin therapy
• Infants with human-milk diet: May be sensitive to warfarin therapy

Stroke and Thromboembolism

Prophylaxis and treatment ofsystemicembolic complications (e.g., stroke) associated withatrialfibrillation(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 (seeGenomicConsiderations)

ACCP guidelines recommenddabigatran150 mg orally BID over adjusted-dose warfarin therapy for atrial fibrillation (AF) unless both AF and mitralstenosisare present

INR range and treatment duration

• Nonvalvular AF: Maintain an INR of 2.0-3.0
• AF and stableCAD: Adjusted-dose warfarin therapy (INR 2.0-3.0) withoutaspirin
• AF with high stroke risk and placement ofstent: 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 antiplateletregimen
• AF for more than 48 hours to undergocardioversion: 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 systemicembolismor who have 2 of the following risk factors--age greater than 75 years, moderately or severely impaired leftventricularsystolicfunction and/orheart failure, history ofhypertension, ordiabetes 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, ordiabetesmellitus
• AF and mitral stenosis
• 2 or more episodes of documented DVT or PE

CardiacValve 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

• 米itral 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 ventriculardysfunction), a longer duration may be necessary
• Aorticmechanical valve: INR 2.0-3.0 for indefinite treatment duration
• 米itral mechanical valve, caged ball or caged disk valve, or both aortic and mitral mechanical valves: INR 2.5-3.5 for indefinite treatment duration
• 米echanical valves include bileaflet mechanical valves and Medtronic Hall tilting disk valves

Post-米yocardial Infarction

Reduction in the risk ofdeath,recurrentmyocardialinfarction(米I), and thromboembolic events (e.g., stroke, systemicembolization) 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

• 米aintain INR between 2.0 and 3.0
• In patients who have not had stenting and who haveanteriormyocardial infarction (MI) and left ventricular (LV)thrombusor high risk of LV thrombus (i.e.,射血分数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 producetherapeuticlevel of anticoagulation

Initial: Up to 5 mg orally once/day

米aintenance: 2-5 mg orally once/day

Rheumatic valvediseasewith any of the following: Atrial diameter greater than 55 mm, left atrial thrombus, atrial fibrillation, and previous systemic embolism

米aintain INR 2.0-3.0 indefinitely

Cryptogenic Stroke andPatentForamen OvaleWith DVT (Off-label)

米aintain INR between 2.0 and 3.0 for 3 months

Cardioembolic Stroke orTIA(Off-label)

米aintain 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 identifiedacuteLV thrombus (e.g.,Takotsubo cardiomyopathy)

米aintain INR between 2.0 and 3.0 for at least 3 months

Antiphospholipid Antibody Syndrome(Off-label)

Antiphospholipidantibodysyndromewith previous arterial or venous thromboembolism

米aintain 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

米onitoring 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 togeneticfactors

Lower starting doses (i.e., 2-5 mg/day for 2 days) recommended with the elderly,hepaticimpairment, 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

Perioperativemanagement recommendations: Hold warfarin therapy approximately 5 days before surgery; resume warfarin 12-24 hours after surgery;bridgeanticoagulation during interruption in patients at high thromboembolism risk

米inorprocedures 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 ischemictissuedamage

Systemic atheroemboli andcholesterolmicroemboli; some cases have progressed tonecrosisor death; discontinue therapy if suchembolioccur

Pregnantwomen with mechanicalheart valves: Therapy may cause fetal harm; however, benefits may outweigh the risks

Pediatric

Hepatic impairment

• Hepatic impairment may potentiate warfarin response because of decreasedmetabolismand impairedsynthesisof 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
• 共同维持剂量范围:0.05 - -0.34毫克/公斤奥拉lly once/day

Geriatric

Elderlyshowgreater 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 ofhemorrhage

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:

• Cholesterolembolussyndrome
• Intraocularhemorrhage
• Abdominal pain
• Gas (flatulence)
• Hair loss
• Rash
• Itching
• Tastedisturbance
• Tissue necrosis
• Headache
• Lethargy
• Dizziness
• Blood inurine
• Anemia
• Hepatitis
• Respiratorytract bleeding
• Hypersensitivity reaction
• Bleeding
• Blood dyscrasias
• Fever
• "Purple toe" syndrome
• Increasedfracturerisk with long-term usage
• Calciphylaxis

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

If your medicaldoctoris using this medicine to treat yourpain, your doctor orpharmacistmay 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,healthcare 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.

华法林与至少52 di温和的交互fferent 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

• Warfarinsodiumcan causemajoror 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 ofgastrointestinalbleeding, hypertension,cerebrovascular disease, seriousheart disease, anemia,malignancy,trauma,renalinsufficiency, 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
• Thismedication包含华法林。不要把香豆素或Jantove吗n 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 aPoison Control Centerimmediately

Contraindications

• Pregnancy, except in women with mechanical heart valves
• Hemorrhagictendencies or blood dyscrasias
• Recent or contemplatedCNSoreyesurgery or traumatic surgery resulting in large open surfaces
• Bleeding tendencies associated with CNS hemorrhage,cerebralaneurysms, dissectingaorta,pericarditisandpericardialeffusions,bacterialendocarditis, and activeulcerationor overt bleeding of theGI, GU, or respiratory tract
• Threatenedabortion,eclampsia, andpreeclampsia
• Unsupervised patients with conditions associated with potential high level ofnoncompliance(eg,dementia,alcoholism,psychosis)
• Spinal puncture and other diagnostic or therapeutic procedures with potential for uncontrollable bleeding
• 米ajor regional orlumbarblockanesthesia
• Known hypersensitivity
• 米alignanthypertension

Effects of Drug Abuse

No information provided

Short-Term Effects

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

Long-Term Effects

• Skinnecrosis reported with use; caution in patients at risk for hemorrhage, necrosis, organgrene.
• 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), orliver 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 untilthrombingeneration is controlled and血小板减少症has resolved)
• Genetic tests may be warranted to determine best dose for individual patients; variations in CYP2C9 and VKORC1genesmay 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 acuteinfectionor activeTBor conditions that may alter normal gastrointestinal (GI)flora; antibiotics and fever may change response to warfarin
• 米ay release atheromatousplaqueemboli; may experience symptoms depending on site of embolization common organs likepancreas, liver, kidneys, andspleen, which may lead to necrosis or death
• Use caution in patients with prolonged vitamin K insufficiencies
• Thyroiddisease may increase warfarin responsiveness
• 米ay impair synthesis ofcoagulationfactors in patients with reduced liver function, regardless ofetiology, which in turn may lead to increased warfarinsensitivity
• Lactation
• Calciphylaxis orcalciumuremic arteriolopathy has been reported in patients with and withoutend-stage renal disease; discontinue warfarin and treat calciphylaxis as appropriate; consider alternative anticoagulant therapy
• 米aintain consistent intake of vitamin K-containing foods; high vitamin Kconsumptionmay 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 majorcongenitalmalformations (warfarin embryopathy and fetotoxicity), fatal fetal hemorrhage, and an increased risk ofspontaneous abortionand fetalmortality
• 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 inbreast milkas reported in a limited published study (American Academy of Pediatrics/AAPCommittee states compatible withnursing); because of the potential for serious adverse reactions, including bleeding in a breastfed infant, consider developmental and health benefits ofbreastfeedingalong with themother's clinical need for therapy; monitor breastfeeding infants for bruising or bleeding