Dosing and uses of Coumadin, Jantoven (warfarin)
Adult dosage forms and strengths
powder for injection
- 5mg/vial (discontinued)
tablet
- 1mg
- 2mg
- 2.5mg
- 3mg
- 4mg
- 5mg
- 6mg
- 7.5mg
- 10mg
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
Dosage modifications
Hepatic impairment: May potentiate warfarin response because of decreased metabolism and impaired synthesis of clotting factors
Pediatric dosage forms and strengths
powder for injection
- 5mg/vial (discontinued)
tablets
- 1mg
- 2mg
- 2.5mg
- 3mg
- 4mg
- 5mg
- 6mg
- 7.5mg
- 10mg
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
Geriatric dosage forms and strengths
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
Coumadin, Jantoven (warfarin) adverse (side) 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
Calciphylaxis
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
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
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.
Pharmacology of Coumadin, Jantoven (warfarin)
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 (https://www.autogenomics.com)
- EntroGen (https://www.entrogen.com)
- Kimball Genetics (https://www.kimballgenetics.com)
- Nanosphere (https://www.nanosphere.us)
- Osmetech (https://www.osmetech.com)
- Specialty Laboratories (https://www.specialtylabs.com)
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
