Warfarin (Lexi-Drugs)

ALERT: US Boxed Warning
  Bleeding risk:
Pronunciation

(WAR far in)

Brand Names: US

Coumadin; Jantoven

Brand Names: Canada

APO-Warfarin; Coumadin; MYLAN-Warfarin [DSC]; NOVO-Warfarin [DSC]; TARO-Warfarin

Dosing: Adult

Note: Labeling identifies genetic factors which may increase patient sensitivity to warfarin. Specifically, genetic variations in the proteins CYP2C9 and VKORC1, responsible for warfarin’s primary metabolism and pharmacodynamic activity, respectively, have been identified as predisposing factors associated with decreased dose requirement and increased bleeding risk. Genotyping tests are available, and may provide guidance on initiation of anticoagulant therapy. The American College of Chest Physicians recommends against the use of routine pharmacogenomic testing to guide dosing (ACCP [Holbrook 2012]).

Thromboembolic complications (prophylaxis/treatment) or myocardial infarction (risk reduction):

Oral: Initial dosing must be individualized. Consider the patient (hepatic function, cardiac function, age, nutritional status, concomitant medications, risk of bleeding) in addition to prior dose response (if available) and the clinical situation. Start 2 to 5 mg once daily or for healthy individuals, 10 mg once daily for 2 days, then reduce dose; lower initial doses (eg, 5 mg once daily) recommended for patients with confirmed HIT once platelet recovery has occurred (ACCP [Linkins 2012]). In patients with acute venous thromboembolism, initiation may begin on the first or second day of parenteral anticoagulation (ACCP [Kearon 2012]). Adjust dose according to INR results; usual maintenance dose ranges from 2 to 10 mg daily (individual patients may require loading and maintenance doses outside these general guidelines). When making dose adjustments during the maintenance phase (eg, after first week of daily dosing), the dose administered 2 to 3 days prior will have the most prominent effect on the current day INR (Gulseth 2007).

Note: Lower starting doses may be required for patients with hepatic impairment, poor nutrition, heart failure, elderly, high risk of bleeding, or patients who are debilitated, or those with reduced function genomic variants of the catabolic enzymes CYP2C9 (*2 or *3 alleles) or VKORC1 (-1639 polymorphism); see table. Higher initial doses may be reasonable in selected patients (ie, receiving enzyme-inducing agents and with low risk of bleeding). Overlapping a parenteral anticoagulant and warfarin therapy by at least 5 days is necessary in treatment of DVT/PE even if the INR is therapeutic earlier. Although an elevation in INR (due to factor VII depletion) may be seen early (within the first 24 to 48 hours) in warfarin therapy, it does not represent adequate anticoagulation. Factors II and X must also be depleted which takes considerably longer (ACCP [Ageno 2012]).

Range1 of Expected Therapeutic Maintenance Dose Based on CYP2C92 and VKORC13 Genotypes
VKORC1 CYP2C9
Note: Must also take into account other patient related factors when determining initial dose (eg, age, body weight, concomitant medications, comorbidities). The American College of Chest Physicians recommends against the use of routine pharmacogenomic testing to guide dosing (ACCP [Holbrook 2012]).
1Ranges derived from multiple published clinical studies.
2Patients with CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3 alleles may take up to 4 weeks to achieve maximum INR with a given dose regimen.
3VKORC1 -1639G>A (rs 9923231) variant is used in this table; other VKORC1 variants may also be important determinants of dose.
*1/*1 *1/*2 *1/*3 *2/*2 *2/*3 *3/*3
GG 5 to 7 mg 5 to 7 mg 3 to 4 mg 3 to 4 mg 3 to 4 mg 0.5 to 2 mg
AG 5 to 7 mg 3 to 4 mg 3 to 4 mg 3 to 4 mg 0.5 to 2 mg 0.5 to 2 mg
AA 3 to 4 mg 3 to 4 mg 0.5 to 2 mg 0.5 to 2 mg 0.5 to 2 mg 0.5 to 2 mg

Duration of therapy:

Warfarin Duration of Therapy by Indication
Indication Duration of therapy
1Indefinite therapy is defined as after first 3 months of treatment and with no scheduled stop date. All patients receiving extended or indefinite therapy should be reassessed at periodic intervals for continuing use of therapy.

2In patients with AF or atrial flutter of ≥48 hours duration or when the duration is unknown, anticoagulation is recommended for at least 3 weeks prior to and 4 weeks after cardioversion regardless of the CHA2DS2-VASc score and method used to restore sinus rhythm (AHA/ACC/HRS [January 2014]).

LV = left ventricular; DVT = deep vein thrombosis, AF = atrial fibrillation, VTE = venous thromboembolism, PE = pulmonary embolism, LMWH = low molecular weight heparin, MI = myocardial infarction
AF (nonvalvular or AF due to mitral stenosis) or atrial flutter (AHA/ACC/HRS [January 2014]) Indefinite1,2
Bioprosthetic valves in the mitral position (Whitlock 2012) 3 months after valve insertion
Mechanical prosthetic cardiac valves (Whitlock 2012) Indefinite1
Anterior MI with LV thrombus or at high risk for LV thrombus (Vandvik 2012) 3 months after MI
VTE (ACCP [Kearon 2012]; ACCP [Kearon 2016])
Provoked DVT or PE (without cancer) 3 months minimum or indefinite therapy1 may be considered in patients who do not have a high risk of bleeding
Unprovoked DVT or PE Indefinite therapyis recommended in patients who do not have a high risk of bleeding
In patients with DVT of the leg or PE and with cancer

Note: LMWH is preferred over oral anticoagulation for treatment of patients withcancer

Indefinite therapy1 is recommended, although high bleeding risk confers a lower grade of recommendation.
Dosing: Geriatric

Thromboembolic complications (prophylaxis/treatment) or myocardial infarction (risk reduction): Oral: Initial dose ≤5 mg. Usual maintenance dose: 2 to 5 mg/day. Patients >60 years of age tend to require lower dosages to produce a therapeutic level of anticoagulation (due to changes in the pattern of warfarin metabolism).

Dosing: Renal Impairment: Adult

No dosage adjustment necessary. However, patients with renal impairment have an increased risk for bleeding diathesis; monitor INR closely.

Hemodialysis: Not dialyzable (NCS/SCCM [Frontera 2016])

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer’s labeling. However, the response to oral anticoagulants may be markedly enhanced in obstructive jaundice, hepatitis, and cirrhosis. INR should be closely monitored.

Dosing: Pediatric

Note: Labeling identifies genetic factors which may increase patient sensitivity to warfarin based on experience in adult patients. Specifically, genetic variations in the proteins CYP2C9 and VKORC1, responsible for warfarin’s primary metabolism and pharmacodynamic activity, respectively, have been identified as predisposing factors associated with decreased dose requirement and increased bleeding risk. Genotyping tests are available, and may provide guidance on initiation of anticoagulant therapy. The American College of Chest Physicians recommends against the use of routine pharmacogenomic testing to guide dosing (Guyatt 2012). For management of elevated INRs as a result of warfarin therapy, see phytonadione monograph or ACCP Guidelines for additional information (ACCP [Monagle 2012]).

Thromboembolic complications; prophylaxis and treatment: Limited data available (ACCP [Monagle 2012]): Individualize dose to achieve target INR based on indication; INRs are primarily extrapolated from adult experience; although there may be some exceptions, for most indications the therapeutic target INR is 2.5 (range: 2 to 3), and for low-dose prophylaxis, a target INR is 1.7 (range: 1.5 to 1.9); see Reference Range for more information and consult expert guidelines. Infants, Children, and Adolescents: Oral:

Target International Normalized Ratio (INR) between 2 to 3 (eg, treatment):

Day 1: Initial loading dose (if baseline INR is 1 to 1.3): 0.2 mg/kg/day once daily; maximum dose: 10 mg/dose; use a reduced initial loading dose of 0.1 mg/kg if patient has undergone a Fontan procedure (AHA [Giglia 2013]) or has liver dysfunction (Streif 1999)

Days 2 to 4: Additional loading doses are dependent upon patient’s INR:

INR 1.1 to 1.3: Repeat the initial loading dose

INR 1.4 to 1.9: Dose is 50% of the initial loading dose

INR 2 to 3: Dose is 50% of the initial loading dose

INR 3.1 to 3.5: Dose is 25% of the initial loading dose

INR >3.5: Hold the drug until INR <3.5, then restart at 50% of previous dose

Days ≥5: Maintenance doses are dependent upon patient’s INR

INR 1.1 to 1.4: Increase dose by 20% of previous dose

INR 1.5 to 1.9: Increase dose by 10% of previous dose

INR 2 to 3: No change

INR 3.1 to 3.5: Decrease dose by 10% of previous dose

INR >3.5: Hold the drug until INR <3.5, then restart at 20% less than the previous dose

Usual maintenance dose: ~0.1 mg/kg/day once daily; range: 0.05 to 0.34 mg/kg/day; the dose in mg/kg/day is inversely related to age. In the largest pediatric study (n=319) (Streif 1999), infants <12 months required a mean dose of 0.33 mg/kg/day, but children 13 to 18 years required a mean dose of 0.09 mg/kg/day; a target INR of 2 to 3 was used for a majority of these patients (75% of warfarin courses). Overall, children required a mean dose of 0.16 mg/kg/day to achieve a target INR of 2 to 3. In another study (Andrew 1994), to attain an INR of 1.3 to 1.8, infants <12 months (n=2) required 0.24 and 0.27 mg/kg/day, but children >1 year required a mean of 0.08 mg/kg/day (range: 0.03 to 0.17 mg/kg/day). Consistent anticoagulation may be difficult to maintain in children <5 years. Children receiving phenobarbital, carbamazepine, or enteral nutrition may require higher maintenance doses (Streif 1999).

Dosing: Renal Impairment: Pediatric

No adjustment required; however, patients with renal failure have an increased risk of bleeding complications. Monitor closely.

Dosing: Hepatic Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer’s labeling. However, the response to oral anticoagulants may be markedly enhanced in obstructive jaundice (due to reduced vitamin K absorption) and also in hepatitis and cirrhosis (due to decreased production of vitamin K-dependent clotting factors); INR should be closely monitored.

Use: Labeled Indications

Thromboembolic complications: Prophylaxis and treatment of thromboembolic disorders (eg, venous, pulmonary) and embolic complications arising from atrial fibrillation or cardiac valve replacement

Myocardial infarction: Adjunct to reduce risk of systemic embolism (eg, recurrent MI, stroke) after myocardial infarction

Limitations of use: Warfarin has no direct effect on an established thrombus and does not reverse ischemic tissue damage. The goal of anticoagulant therapy is to prevent further extension of an already formed thrombus and to prevent secondary thromboembolic complications that may result in serious and potentially fatal sequelae.

Use: Off-Label: Adult

  Recurrent stroke/Transient ischemic attacks (secondary prevention)Level of Evidence [G]

Based on the American Heart Association/American Stroke Association (AHA/ASA) guidelines for the prevention of stroke in patients with stroke and transient ischemic attack (TIA), warfarin given for the prevention of recurrent stroke or transient ischemic attacks in patients with paroxysmal or permanent atrial fibrillation (AF), cardiomyopathy with left atrial or left ventricular thrombus, rheumatic mitral valve disease (with AF), or mechanical aortic or mitral heart valves is effective and recommended in these settings. Warfarin may also be considered in patients with prior ischemic stroke or TIA and cardiomyopathy in the setting of a mechanical left ventricular assist device (LVAD) or in the setting of an acute anterior STEMI (without demonstrable left ventricular mural thrombus formation but with anterior apical akinesis or dyskinesis), or in patients with rheumatic mitral valve disease (without AF), or in patients to prevent recurrent ischemic events.

Level of Evidence Definitions
  Level of Evidence Scale
Clinical Practice Guidelines

Atrial Fibrillation:

AAN, “Prevention of Stroke in Nonvalvular Atrial Fibrillation,” February 2014.

AHA/ACC/HRS, “2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation,” March 2014.

“ACC/AHA/ESC Guidelines for the Management of Patients With Supraventricular Arrhythmias,” October 2003

“Antithrombotic Therapy for Atrial Fibrillation: CHEST Guideline and Expert Panel Report,” July 2018

Canadian Cardiovascular Society, “2016 Focused Update of the Canadian Cardiovascular Society Guidelines for the Management of Atrial Fibrillation,” 2016

Heart Failure:

“HFSA 2010 Comprehensive Heart Failure Practice Guideline,” July 2010

Prevention:

“AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients with Coronary and Other Atherosclerotic Vascular Disease: 2011 Update,” November 2011

Pulmonary Embolism:

“British Thoracic Society Guideline for the Initial Management of Pulmonary Embolism” June 2018

“Management of Massive and Submassive Pulmonary Embolism, Iliofemoral Deep Vein Thrombosis, and Chronic Thromboembolic Pulmonary Hypertension: A Scientific Statement from the American Heart Association,” March, 2011

ST-Elevation Myocardial Infarction:

ACCF/AHA, “2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction,” December 2012.

Stroke:

AHA/ASA, “Diagnosis and Management of Cerebral Venous Thrombosis,” February 2011

AHA/ASA, “Guidelines for Prevention of Stroke in Patients with Stroke and Transient Ischemic Attack,” May 2014.

AHA/ASA, “Guidelines for the Prevention of Stroke in Women,” 2014

AHA/ASA, “Guidelines for the Primary Prevention of Stroke,” December 2014

Valvular Heart Disease:

AHA/ACC, “2014 AHA/ACC Guideline for the Management of Patients with Valvular Heart Disease,” March 2014

AHA/ACC, “2017 AHA/ACC Guideline for the Management of Patients with Valvular Heart Disease,” 2017

VTE:

“American Society of Clinical Oncology Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer, Clinical Practice Guideline Update,” 2013

“American Society of Clinical Oncology Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer, Clinical Practice Guideline Update,” 2014

“American Society of Hematology 2018 Guidelines for Management of Venous Thromboembolism,” December 2018

“Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report,” February 2016

Other:

“ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use,” October 2008

“ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension,” April 2009

AHA, “Prevention and Treatment of Thrombosis in Pediatric and Congenital Heart Disease,” December 2013

AHA, “The Postthrombotic Syndrome: Evidence-Based Prevention, Diagnosis, and Treatment Strategies,” October 2014

“American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (9th Edition),” February 2012

“The Use of Antiplatelet Therapy in the Outpatient Setting: Canadian Cardiovascular Society Guidelines,” 2011

Administration: Oral

Administer with or without food.

Administration: Pediatric

Oral: Administer with or without food. Take at the same time each day.

Parenteral: For IV use only. Administer by slow IV injection over 1 to 2 minutes into peripheral vein; do not administer IM and avoid all other IM injections.

Dietary Considerations

Foods high in vitamin K (eg, leafy green vegetables) inhibit anticoagulant effect. The list of usual foods with high vitamin K content is well known, however, some unique ones include green tea (Camellia sinensis), chewing tobacco, a variety of oils (canola, corn, olive, peanut, safflower, sesame seed, soybean, and sunflower) (Booth 1999; Kuykendall 2004; Nutescu 2011). Snack foods containing Olestra have 80 mcg of vitamin K added to each ounce (Harrell 1999). Some natural products may contain hidden sources of vitamin K (Nutescu 2006). Avoid drastic changes in diet (eg, intake of large amounts of alfalfa, asparagus, broccoli, Brussels sprouts, cabbage, cauliflower, green teas, kale, lettuce, spinach, turnip greens, watercress) which decrease efficacy of warfarin. A balanced diet with a consistent intake of vitamin K is essential. The recommended dietary allowance for vitamin K in adults is 75 to 120 mcg/day (USDA Dietary Reference Intake).

Hazardous Drugs Handling Considerations

Hazardous agent (NIOSH 2016 [group 3]).

Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage. NIOSH recommends single gloving for administration of intact tablets or capsules (NIOSH 2016). Assess risk to determine appropriate containment strategy (USP-NF 2017).

Storage/Stability

Store at 15°C to 30°C (59°F to 86°F). Protect from light.

Preparation for Administration: Pediatric

Parenteral: Reconstitute with 2.7 mL of SWFI (yields 2 mg/mL solution).

Medication Patient Education with HCAHPS Considerations

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Have patient report immediately to prescriber signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), angina, severe dizziness, passing out, edema, severe headache, skin discoloration to black or purple, body temperature change, pain, or severe loss of strength and energy (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Medication Safety Issues
  Sound-alike/look-alike issues:
  High alert medication:
  National Patient Safety Goals:
Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/009218s017lbl.pdf#page=31 (Coumadin), must be dispensed with this medication.

Contraindications

Hypersensitivity to warfarin or any component of the formulation; hemorrhagic tendencies (eg, active GI ulceration, patients bleeding from the GI, respiratory, or GU tract; cerebral aneurysm; CNS hemorrhage; dissecting aortic aneurysm; spinal puncture and other diagnostic or therapeutic procedures with potential for significant bleeding); recent or potential surgery of the eye or CNS; major regional lumbar block anesthesia or traumatic surgery resulting in large, open surfaces; blood dyscrasias; malignant hypertension; pericarditis or pericardial effusion; bacterial endocarditis; unsupervised patients with conditions associated with a high potential for noncompliance; eclampsia/preeclampsia, threatened abortion, pregnancy (except in women with mechanical heart valves at high risk for thromboembolism)

Warnings/Precautions

Concerns related to adverse effects:

• Acute kidney injury: Acute kidney injury, possibly as a result of episodes of excessive anticoagulation and hematuria, may occur in patients with a history of kidney disease or in patients with altered glomerular integrity.

• Anaphylaxis/hypersensitivity: May cause hypersensitivity reactions, including anaphylaxis; use with caution in patients with anaphylactic disorders.

• Bleeding: [US Boxed Warning]: May cause major or fatal bleeding. Perform regular INR monitoring in all treated patients. INR levels achieved with warfarin therapy may be affected by concomitant medication, dietary modifications and/or other factors (eg, smoking). Risk factors for bleeding include high intensity anticoagulation (INR >4), age (≥65 years), variable INRs, history of GI bleeding, hypertension, cerebrovascular disease, serious heart disease, anemia, severe diabetes, malignancy, trauma, renal insufficiency, polycythemia vera, vasculitis, open wound, history of PUD, indwelling catheters, menstruating and postpartum women, drug-drug interactions, long duration of therapy, or known genetic deficiency in CYP2C9 activity. Patient must be instructed to report bleeding, accidents, or falls as well as any new or discontinued medications, herbal or alternative products used, or significant changes in smoking or dietary habits. Unrecognized bleeding sites (eg, colon cancer) may be uncovered by anticoagulation.

• Calciphylaxis: Fatal and serious calciphylaxis (calcium uremic arteriolopathy) has been reported in patients with and without end-stage renal disease. If calciphylaxis is diagnosed, discontinue therapy and treat calciphylaxis as appropriate. Consider alternative anticoagulation therapy.

• Skin necrosis/gangrene: Necrosis or gangrene of the skin and other tissue can occur (rarely, <0.1%) due to paradoxical local thrombosis; onset is usually within the first few days of therapy and is frequently localized to the limbs, breast, or penis. The risk of this effect is increased in patients with protein C or S deficiency. Consider alternative therapies if anticoagulation is necessary.

• Atheroemboli/cholesterol microemboli: Warfarin therapy may release atheromatous plaque emboli; symptoms depend on site of embolization, most commonly kidneys, pancreas, liver, and spleen. In some cases may lead to necrosis or death. “Purple toe” syndrome, due to cholesterol microembolization, has been rarely described with coumarin-type anticoagulants. Typically, this occurs after several weeks of therapy, and may present as a dark, purplish, mottled discoloration of the plantar and lateral surfaces. Other manifestations of cholesterol microembolization may include rash; livedo reticularis; gangrene; abrupt and intense pain in lower extremities; abdominal, flank, or back pain; hematuria, renal insufficiency; hypertension; cerebral ischemia; spinal cord infarction; or other symptoms of vascular compromise.

Disease-related concerns:

• Dietary insufficiency: Use with caution in patients with prolonged dietary insufficiencies (vitamin K deficiency).

• Heparin-induced thrombocytopenia: Use with caution in patients with heparin-induced thrombocytopenia and DVT; limb ischemia, necrosis, and gangrene have occurred when warfarin was started or continued after heparin was stopped. Warfarin monotherapy is contraindicated in the initial treatment of active HIT; warfarin initially inhibits the synthesis of protein C, potentially accelerating the underlying active thrombotic process.

• Hepatic impairment: Reduced liver function, regardless of etiology, may impair synthesis of coagulation factors leading to increased warfarin sensitivity.

• Infection: Use with caution in patients with acute infection or active TB or any disruption of normal GI flora; antibiotics and fever may alter response to warfarin.

• Renal impairment: Use with caution in patients with renal impairment. Patients with renal impairment are at increased risk for bleeding diathesis; frequent INR monitoring is recommended.

• Thyroid disease: Use with caution in patients with thyroid disease; warfarin responsiveness may increase (Ageno 2012).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: The elderly may be more sensitive to anticoagulant therapy.

• Patients with genomic variants in CYP2C9 and/or VKORC1: Presence of the CYP2C9*2 or *3 allele and/or polymorphism of the vitamin K oxidoreductase (VKORC1) gene may increase the risk of bleeding. The *2 allele is reported to occur with a frequency of 4% to 11% in African-Americans and Caucasians, respectively, while the *3 allele frequencies are 2% to 7% respectively. Other variant 2C9 alleles (eg, *5, *6, *9, and *11) are also associated with reduced metabolic activity and thus may increase risk of bleeding, but are much less common. Lower doses may be required in these patients; genetic testing may help determine appropriate dosing.

Other warnings/precautions:

• Appropriate use: Surgical patients: When temporary interruption is necessary before surgery, discontinue for approximately 5 days before surgery; when there is adequate hemostasis, may reinstitute warfarin therapy ~12 to 24 hours after surgery (evening of or next morning). Decision to safely continue warfarin therapy through the procedure and whether or not bridging of anticoagulation is necessary is dependent upon risk of perioperative bleeding and risk of thromboembolism, respectively. If risk of thromboembolism is elevated, consider bridging warfarin therapy with an alternative anticoagulant (eg, unfractionated heparin, LMWH) (ACCP [Ageno 2012]).

• Patient selection: Use care in the selection of patients appropriate for this treatment; ensure patient cooperation especially from the alcoholic, illicit drug user, demented, or psychotic patient; ability to comply with routine laboratory monitoring is essential.

Geriatric Considerations

Before committing an elderly patient to long-term anticoagulation therapy, the risk for bleeding complications secondary to falls, drug interactions, living situation, and cognitive status should be considered. A risk of bleeding complications has been associated with increased age.

Warnings: Additional Pediatric Considerations

Vitamin K-antagonist (VKA) (eg, warfarin) therapy is usually avoided in neonates and infants <4 months due to pharmacodynamic and administration issues which result in a greater risk of bleeding and necessitate more frequent monitoring and dose adjustment in these patients. Pharmacodynamic issues which create problematic dosing and monitoring include: Physiologically decreased neonatal plasma levels of vitamin K-dependent clotting factors (comparable to an adult with an INR 2 to 3 on VKA therapy), and a lower concentration of vitamin K in breast milk relative to infant formula (which is supplemented) making breast-fed infants very sensitive to VKA therapy (eg, much lower doses required to achieve target INR). Administration is problematic since no oral liquid formulation of warfarin is available; although some centers dissolve the appropriate tablet/dose in water, data which verifies stability and full assessment of practice is lacking (ACCP [Monagle 2012]).

Rare hair loss has been reported with warfarin use (ACCP [Monagle 2012]); pediatric cases include two case reports occurring with accidental ingestions in a 2 year old and 6 year old (Watras 2016). Tracheal calcification has been reported in young children and initially was considered a rare observation (ACCP [Monagle 2012]). However, newer data suggests it occurs more frequently; an incidence of 35% (6 out of 17 subjects) was reported in a retrospective analysis evaluating patients ≤10 years of age who underwent cardiac valve replacement and were receiving long-term anticoagulation with warfarin (Golding 2013).

Decreased bone mineral density has been reported in children and adolescents receiving long-term warfarin therapy; a case control study reported a significant reduction in lumbar spinal bone mineral apparent density (BMAD) scores in pediatric patients on warfarin therapy (n=17) compared to age-matched controls (n=321); the mean age of the 17 case subjects was 14.7 years (range: 8 to 18 years) and the mean duration of warfarin treatment was 8.2 years (range: 1 to 14 years) (Barnes 2005). Another cohort study evaluated bone-mineral density in 26 subjects with single ventricle physiology (age range: 5 to 12 years; treatment group [warfarin], n=16) and reported significant reductions of spinal BMD z-score than controls; they also reported lower total body less head BMD z-score (Bendaly 2015). Some centers include bone density monitoring (eg, DXA) as part of routine management for long-term warfarin therapy (Barnes 2005).

Pregnancy Considerations

Warfarin crosses the placenta; concentrations in the fetal plasma are similar to maternal values. Teratogenic effects have been reported following first trimester exposure and may include coumarin embryopathy (nasal hypoplasia and/or stippled epiphyses; limb hypoplasia may also be present). Adverse CNS events to the fetus have also been observed following exposure during any trimester and may include CNS abnormalities (including ventral midline dysplasia, dorsal midline dysplasia). Spontaneous abortion, fetal hemorrhage, and fetal death may also occur. Use is contraindicated during pregnancy (or in women of reproductive potential) except in women with mechanical heart valves who are at high risk for thromboembolism; use is also contraindicated in women with threatened abortion, eclampsia, or preeclampsia. Frequent pregnancy tests are recommended for women who are planning to become pregnant and adjusted-dose heparin or low molecular weight heparin (LMWH) should be substituted as soon as pregnancy is confirmed or adjusted-dose heparin or LMWH should be used instead of warfarin prior to conception.

In pregnant women with high-risk mechanical heart valves, the benefits of warfarin therapy should be discussed with the risks of available treatments (ACCP [Bates 2012]; AHA/ACC [Nishimura 2014]); when possible avoid warfarin use during the first trimester (ACCP [Bates 2012]) and close to delivery (ACCP [Bates 2012]; AHA/ACC [Nishimura 2014]). Use of warfarin during the first trimester may be considered if the therapeutic INR can be achieved with a dose ≤5 mg/day (AHA/ACC [Nishimura 2014]). Adjusted-dose LMWH or adjusted-dose heparin may be used throughout pregnancy or until week 13 of gestation when therapy can be changed to warfarin. LMWH or heparin should be resumed close to delivery. In women who are at a very high risk for thromboembolism (older generation mechanical prosthesis in mitral position or history of thromboembolism), warfarin can be used throughout pregnancy and replaced with LMWH or heparin near term; the use of low-dose aspirin is also recommended (ACCP [Bates 2012] AHA/ACC [Nishimura 2014]). Women who require long-term anticoagulation with warfarin and who are considering pregnancy, LMWH substitution should be done prior to conception when possible. If anti-Xa monitoring cannot be done, do not use LMWH therapy in pregnant patients with a mechanical prosthetic valve (AHA/ACC [Nishimura 2014]). When choosing therapy, fetal outcomes (ie, pregnancy loss, malformations), maternal outcomes (ie, VTE, hemorrhage), burden of therapy, and maternal preference should be considered (ACCP [Bates 2012]).

Breast-Feeding Considerations

Based on available data, warfarin is not present in breast milk.

Breastfeeding women may be treated with warfarin. According to the American College of Chest Physicians (ACCP), warfarin may be used in lactating women who wish to breastfeed their infants (ACCP [Bates 2012]). The manufacturer recommends monitoring of breastfeeding infants for bruising or bleeding.

Briggs’ Drugs in Pregnancy & Lactation
Adverse Reactions

Bleeding is the major adverse effect of warfarin. Hemorrhage may occur at virtually any site. Risk is dependent on multiple variables, including the intensity of anticoagulation and patient susceptibility.

1% to 10%:

Hematologic & oncologic: Major hemorrhage (≤5%; INR 2.5 to 4.0 generally associated with more bleeding)

Frequency not defined:

Cardiovascular: Purple-toe syndrome, systemic cholesterol micro-embolism, vasculitis

Central nervous system: Chills

Dermatologic: Alopecia, bullous rash, dermatitis, pruritus, skin necrosis, urticaria

Gastrointestinal: Abdominal pain, bloating, diarrhea, dysgeusia, flatulence, nausea, vomiting

Hematologic & oncologic: Minor hemorrhage

Hepatic: Hepatitis

Hypersensitivity: Anaphylaxis, hypersensitivity reaction

Renal: Acute renal failure (in patients with altered glomerular integrity or with a history of kidney disease)

Respiratory: Tracheobronchial calcification

<1%, postmarketing, and/or case reports: Gangrene of skin or other tissue, skin necrosis, vascular calcification (calcium uremic arteriolopathy and calciphylaxis)

Allergy and Idiosyncratic Reactions
Toxicology
Metabolism/Transport Effects

Substrate of CYP1A2 (minor), CYP2C19 (minor), CYP2C9 (major), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions 

Acetaminophen: May enhance the anticoagulant effect of Vitamin K Antagonists. This appears most likely with daily acetaminophen doses exceeding 1.3 or 2 g/day for multiple consecutive days. Risk C: Monitor therapy

Adalimumab: May decrease the serum concentration of Warfarin. Risk C: Monitor therapy

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Alcohol (Ethyl): May decrease the serum concentration of Vitamin K Antagonists. More specifically, this effect has been described in heavy drinking alcoholic patients (over 250 g alcohol daily for over 3 months). The role of alcohol itself is unclear. Risk C: Monitor therapy

Allopurinol: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk D: Consider therapy modification

Amiodarone: May enhance the anticoagulant effect of Vitamin K Antagonists. Amiodarone may increase the serum concentration of Vitamin K Antagonists. Management: Monitor patients extra closely for evidence of increased anticoagulant effects if amiodarone is started. Consider empiric reduction of 30% to 50% in warfarin dose, though no specific guidelines on dose adjustment have been published. Risk D: Consider therapy modification

Androgens: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk D: Consider therapy modification

Anticoagulants: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Antihepaciviral NS5B RNA Polymerase Inhibitors: May diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Antithyroid Agents: May diminish the anticoagulant effect of Vitamin K Antagonists. Risk D: Consider therapy modification

Apalutamide: May decrease the serum concentration of Warfarin. Risk C: Monitor therapy

Aprepitant: May decrease the serum concentration of Warfarin. Risk C: Monitor therapy

Atazanavir: May increase the serum concentration of Warfarin. Risk C: Monitor therapy

AzaTHIOprine: May diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Barbiturates: May increase the metabolism of Vitamin K Antagonists. Management: Monitor INR more closely. An anticoagulant dose increase may be needed after a barbiturate is initiated or given at an increased dose. Anticoagulant dose decreases may be needed following barbiturate discontinuation or dose reduction. Risk D: Consider therapy modification

Benzbromarone: May increase the serum concentration of Warfarin. Risk C: Monitor therapy

Bicalutamide: May increase the serum concentration of Vitamin K Antagonists. Specifically, free concentrations of the vitamin K antagonists may be increased. Risk C: Monitor therapy

Bifonazole: May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Bile Acid Sequestrants: May decrease the absorption of Vitamin K Antagonists. Risk C: Monitor therapy

Bosentan: May increase the metabolism of Vitamin K Antagonists. Risk C: Monitor therapy

Bromperidol: May enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapy

Capecitabine: May increase the serum concentration of Vitamin K Antagonists. Risk D: Consider therapy modification

Caplacizumab: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

CarBAMazepine: May decrease the serum concentration of Vitamin K Antagonists. Management: Monitor for decreased INR and effects of vitamin K antagonists if carbamazepine is initiated/dose increased, or increased INR and effects if carbamazepine is discontinued/dose decreased. Warfarin dose adjustments will likely be required. Risk D: Consider therapy modification

Cephalosporins: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Ceritinib: May increase the serum concentration of Warfarin. Risk C: Monitor therapy

Chenodiol: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Chloral Betaine: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Chloral Hydrate: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Chloramphenicol (Systemic): May enhance the anticoagulant effect of Vitamin K Antagonists. Chloramphenicol (Systemic) may increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Chondroitin Sulfate: May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Cimetidine: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk D: Consider therapy modification

Clopidogrel: May enhance the anticoagulant effect of Warfarin. Risk D: Consider therapy modification

Cloxacillin: May diminish the anticoagulant effect of Vitamin K Antagonists. Cloxacillin may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Cobicistat: May increase the serum concentration of Warfarin. Risk C: Monitor therapy

Coenzyme Q-10: May diminish the anticoagulant effect of Vitamin K Antagonists. Coenzyme Q-10 may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Collagenase (Systemic): Anticoagulants may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Risk C: Monitor therapy

Corticosteroids (Systemic): May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Cranberry: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

CYP2C9 Inducers (Moderate): May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Risk C: Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP2C9 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Risk D: Consider therapy modification

Daclatasvir: May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Darunavir: May decrease the serum concentration of Warfarin. Darunavir may increase the serum concentration of Warfarin. Risk C: Monitor therapy

Dasatinib: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Deferasirox: Anticoagulants may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Risk C: Monitor therapy

Deoxycholic Acid: Anticoagulants may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Risk C: Monitor therapy

Desirudin: Anticoagulants may enhance the anticoagulant effect of Desirudin. Risk D: Consider therapy modification

Desvenlafaxine: May enhance the adverse/toxic effect of Vitamin K Antagonists. Specifically, the risk for bleeding may be increased. Risk C: Monitor therapy

Dexmethylphenidate: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Dicloxacillin: May diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Disulfiram: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Dronabinol: May increase the serum concentration of Warfarin. Specifically, dronabinol may displace warfarin from its protein-binding sites, leading to an increased concentration of active, unbound drug. Risk C: Monitor therapy

Dronedarone: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Econazole: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Efavirenz: May decrease the serum concentration of Vitamin K Antagonists. Efavirenz may increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Enzalutamide: May decrease the serum concentration of Warfarin. More specifically, enzalutamide may decrease concentrations of the S-warfarin enantiomer. Management: Avoid concurrent use of warfarin and enzalutamide whenever possible. If the combination must be used, conduct additional INR monitoring as serum concentrations may be decreased.Risk D: Consider therapy modification

Erlotinib: May increase the serum concentration of Warfarin. Risk C: Monitor therapy

Erythromycin (Ophthalmic): May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Eslicarbazepine: May decrease the serum concentration of Warfarin. Specifically, S-warfarin serum concentrations may be decreased. Risk C: Monitor therapy

Esomeprazole: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Estrogen Derivatives: May diminish the anticoagulant effect of Anticoagulants. More specifically, the potential prothrombotic effects of some estrogens and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of estrogens against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Exceptions: Tibolone. Risk D: Consider therapy modification

Estrogen Derivatives (Contraceptive): May diminish the anticoagulant effect of Vitamin K Antagonists. In contrast, enhanced anticoagulant effects have also been noted with some products. Risk D: Consider therapy modification

Ethacrynic Acid: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Ethotoin: May enhance the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may increase the serum concentration of Ethotoin. Management: Anticoagulant dose adjustment will likely be necessary when ethotoin is initiated or discontinued. Monitor patients extra closely (INR and signs/symptoms of bleeding) when using this combination.Risk D: Consider therapy modification

Etoposide: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Etoposide Phosphate: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Exenatide: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Fat Emulsion (Fish Oil and Plant Based): May diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Fat Emulsion (Fish Oil Based): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Fenofibrate and Derivatives: May enhance the anticoagulant effect of Warfarin. Fenofibrate and Derivatives may increase the serum concentration of Warfarin. Risk D: Consider therapy modification

Fenugreek: May enhance the anticoagulant effect of Vitamin K Antagonists. Management: Seek alternatives to fenugreek in patients receiving vitamin K antagonists. Monitor patients receiving these combinations closely for increases in INR and systemic effects of the vitamin K antagonist (particularly easy bruising and bleeding). Risk D: Consider therapy modification

Fibric Acid Derivatives: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk D: Consider therapy modification

Floxuridine: May increase the serum concentration of Vitamin K Antagonists. Management: Monitor INR and signs/symptoms of bleeding closely when starting or stopping floxuridine in a patient receiving a vitamin K antagonist. Anticoagulant dose adjustment will likely be necessary. Risk D: Consider therapy modification

Flucloxacillin: May diminish the anticoagulant effect of Vitamin K Antagonists. Flucloxacillin may decrease the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Fluconazole: May increase the serum concentration of Vitamin K Antagonists. Risk D: Consider therapy modification

Fluorouracil (Systemic): May increase the serum concentration of Vitamin K Antagonists. Risk D: Consider therapy modification

Fluorouracil (Topical): May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Fosamprenavir: May increase the serum concentration of Warfarin. Risk C: Monitor therapy

Fosaprepitant: May decrease the serum concentration of Warfarin. The active metabolite aprepitant is likely responsible for this effect. Risk C: Monitor therapy

Fosphenytoin: May enhance the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may increase the serum concentration of Fosphenytoin. Management: Anticoagulant dose adjustment will likely be necessary when phenytoin is initiated or discontinued. Monitor patients extra closely (INR and signs/symptoms of bleeding) when using this combination. Risk D: Consider therapy modification

Frankincense, Indian: May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of Vitamin K Antagonists. Management: Vitamin K antagonist dose adjustments may be required when used with systemic fusidic acid. Patients using this combination should be monitored extra closely for evidence of bleeding and to determine appropriate dose. Risk D: Consider therapy modification

Gefitinib: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Gemcitabine: May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Ginkgo Biloba: May enhance the adverse/toxic effect of Vitamin K Antagonists. Management: Consider avoiding the use of this combination of agents. Monitor for signs and symptoms of bleeding if vitamin K antagonists and Ginkgo biloba are used concomitantly. Risk D: Consider therapy modification

Ginseng (American): May decrease the serum concentration of Warfarin. Risk C: Monitor therapy

Glucagon: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Glucosamine: May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Glutethimide: May increase the metabolism of Vitamin K Antagonists. Risk D: Consider therapy modification

Grazoprevir: May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Green Tea: May enhance the adverse/toxic effect of Warfarin. Particularly, the risk of bleeding may be increased due to possible antiplatelet effects of green tea. Green Tea may diminish the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Griseofulvin: May decrease the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Hemin: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Anticoagulants. Bleeding may occur. Risk D: Consider therapy modification

HMG-CoA Reductase Inhibitors (Statins): May enhance the anticoagulant effect of Vitamin K Antagonists. Exceptions: AtorvaSTATin. Risk C: Monitor therapy

Ibritumomab Tiuxetan: Anticoagulants may enhance the adverse/toxic effect of Ibritumomab Tiuxetan. Both agents may contribute to an increased risk of bleeding. Risk C: Monitor therapy

Ibrutinib: May enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapy

Ifosfamide: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Imatinib: May enhance the anticoagulant effect of Warfarin. Imatinib may decrease the metabolism of Warfarin. Risk D: Consider therapy modification

Inotersen: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Itraconazole: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Ivermectin (Systemic): May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Ketoconazole (Systemic): May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Lansoprazole: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Leflunomide: May enhance the anticoagulant effect of Vitamin K Antagonists. Leflunomide may diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Letermovir: May decrease the serum concentration of Warfarin. Risk C: Monitor therapy

LevOCARNitine: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Levomilnacipran: May enhance the adverse/toxic effect of Vitamin K Antagonists. Specifically, the risk for bleeding may be increased. Risk C: Monitor therapy

Limaprost: May enhance the adverse/toxic effect of Anticoagulants. The risk for bleeding may be increased. Risk C: Monitor therapy

Lomitapide: May increase the serum concentration of Warfarin. Risk C: Monitor therapy

Lopinavir: May decrease the serum concentration of Warfarin. Risk C: Monitor therapy

Lumacaftor: May decrease the serum concentration of CYP2C9 Substrates (High Risk with Inhibitors or Inducers). Lumacaftor may increase the serum concentration of CYP2C9 Substrates (High Risk with Inhibitors or Inducers). Risk C: Monitor therapy

Macrolide Antibiotics: May increase the serum concentration of Vitamin K Antagonists. Exceptions: Fidaxomicin; Roxithromycin; Spiramycin. Risk C: Monitor therapy

Maitake: May increase the serum concentration of Warfarin. Risk C: Monitor therapy

Menadiol Diphosphate: May diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Menatetrenone: May diminish the anticoagulant effect of Vitamin K Antagonists. Risk D: Consider therapy modification

Mercaptopurine: May diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Methylphenidate: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Metreleptin: May decrease the serum concentration of Warfarin. Metreleptin may increase the serum concentration of Warfarin. Risk C: Monitor therapy

MetroNIDAZOLE (Systemic): May increase the serum concentration of Vitamin K Antagonists. Management: Consider alternatives to concomitant therapy with these agents. If concomitant therapy cannot be avoided, consider reducing the dose of the vitamin K antagonist and monitor for increased INR/bleeding. Risk D: Consider therapy modification

Miconazole (Oral): May increase the serum concentration of Warfarin. Risk C: Monitor therapy

Miconazole (Topical): May increase the serum concentration of Vitamin K Antagonists. Risk D: Consider therapy modification

MiFEPRIStone: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the risk of bleeding may be increased. Risk X: Avoid combination

Milnacipran: May enhance the adverse/toxic effect of Vitamin K Antagonists. Specifically, the risk for bleeding may be increased. Risk C: Monitor therapy

Mirtazapine: May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Multivitamins/Fluoride (with ADE): May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the anticoagulant effect of Vitamin K Antagonists. Multivitamins/Minerals (with ADEK, Folate, Iron) may diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Multivitamins/Minerals (with AE, No Iron): May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Nafcillin: May diminish the anticoagulant effect of Vitamin K Antagonists. Management: Consider choosing an alternative antibiotic. Monitor for decreased therapeutic effects and need for dose adjustments of oral anticoagulants if nafcillin is initiated/dose increased, or increased effects if nafcillin is discontinued/dose decreased. Risk D: Consider therapy modification

Nelfinavir: May decrease the serum concentration of Warfarin. Nelfinavir may increase the serum concentration of Warfarin. Risk C: Monitor therapy

Neomycin: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Nevirapine: May diminish the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Nintedanib: Anticoagulants may enhance the adverse/toxic effect of Nintedanib. Specifically, the risk for bleeding may be increased. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): May enhance the anticoagulant effect of Vitamin K Antagonists. Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective) may increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents (Nonselective): May enhance the anticoagulant effect of Vitamin K Antagonists. Risk D: Consider therapy modification

Obeticholic Acid: May diminish the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Obinutuzumab: Anticoagulants may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Risk C: Monitor therapy

Omacetaxine: Anticoagulants may enhance the adverse/toxic effect of Omacetaxine. Specifically, the risk for bleeding-related events may be increased. Management: Avoid concurrent use of anticoagulants with omacetaxine in patients with a platelet count of less than 50,000/uL. Risk X: Avoid combination

Ombitasvir, Paritaprevir, and Ritonavir: May diminish the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Omega-3 Fatty Acids: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Omeprazole: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Oritavancin: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Oritavancin: May diminish the therapeutic effect of Anticoagulants. Specifically, oritavancin may artificially increase the results of laboratory tests commonly used to monitor anticoagulant effectiveness, which could lead to incorrect decisions to decrease anticoagulant doses. Risk C: Monitor therapy

Orlistat: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Oxatomide: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk X: Avoid combination

Penicillins: May enhance the anticoagulant effect of Vitamin K Antagonists. Exceptions: Dicloxacillin; Nafcillin. Risk C: Monitor therapy

Pentosan Polysulfate Sodium: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Pentoxifylline: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Phenytoin: May enhance the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may increase the serum concentration of Phenytoin. Management: Anticoagulant dose adjustment will likely be necessary when phenytoin is initiated or discontinued. Monitor patients extra closely (INR and signs/symptoms of bleeding) when using this combination. Risk D: Consider therapy modification

Phytonadione: May diminish the anticoagulant effect of Vitamin K Antagonists. Risk D: Consider therapy modification

Posaconazole: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Progestins: May diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of progestins against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Risk D: Consider therapy modification

Progestins (Contraceptive): May diminish the anticoagulant effect of Vitamin K Antagonists. In contrast, enhanced anticoagulant effects have also been noted with some products. Management: When possible, concomitant hormonal contraceptives and coumarin derivatives should be avoided in order to eliminate the risk of thromboembolic disorders. Consider using an alternative, nonhormonal contraceptive. Risk D: Consider therapy modification

Proguanil: May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Propacetamol: May enhance the anticoagulant effect of Vitamin K Antagonists. This appears most likely with higher doses (equivalent to acetaminophen doses exceeding 1.3 to 2 g/day) for multiple consecutive days. Risk C: Monitor therapy

Propafenone: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Prostacyclin Analogues: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the antiplatelet effects of these agents may lead to an increased risk of bleeding with the combination. Risk C: Monitor therapy

QuiNIDine: May enhance the anticoagulant effect of Vitamin K Antagonists. Note that the INR/PT might be unchanged in the face of increased bleeding. Risk C: Monitor therapy

QuiNINE: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Quinolones: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

RaNITIdine: May increase the serum concentration of Warfarin. Risk C: Monitor therapy

Regorafenib: Warfarin may enhance the adverse/toxic effect of Regorafenib. Specifically, the risk for bleeding may be increased. Risk C: Monitor therapy

Revaprazan: May diminish the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Ribavirin (Systemic): May diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Rifamycin Derivatives: May increase the metabolism of Vitamin K Antagonists. Risk C: Monitor therapy

Rifapentine: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Risk C: Monitor therapy

Ritonavir: May decrease the serum concentration of Warfarin. Risk C: Monitor therapy

RomiDEPsin: May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Roxithromycin: May enhance the anticholinergic effect of Warfarin. Risk C: Monitor therapy

Rucaparib: May increase the serum concentration of Warfarin. Risk C: Monitor therapy

Salicylates: May enhance the anticoagulant effect of Vitamin K Antagonists. Exceptions: Salsalate. Risk D: Consider therapy modification

Salicylates: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Salicylates (Topical): May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Saquinavir: May increase the serum concentration of Warfarin. Risk C: Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Simeprevir: May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Sodium Zirconium Cyclosilicate: May increase the serum concentration of Warfarin. Management: Separate the administration of sodium zirconium cyclosilicate and warfarin by at least 2 hours. If simultaneous administration is required, monitor for signs and symptoms of warfarin toxicity (eg, elevated INR, bleeding). Risk D: Consider therapy modification

SORAfenib: May enhance the anticoagulant effect of Warfarin. SORAfenib may increase the serum concentration of Warfarin. Management: Warfarin dose adjustment will likely be necessary. Increase frequency of INR monitoring during sorafenib therapy (particularly when starting or stopping therapy), and increase monitoring for signs and symptoms of bleeding. Risk D: Consider therapy modification

St John’s Wort: May increase the metabolism of Vitamin K Antagonists. Risk D: Consider therapy modification

Streptokinase: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk X: Avoid combination

Sucralfate: May diminish the anticoagulant effect of Vitamin K Antagonists. Sucralfate may decrease the serum concentration of Vitamin K Antagonists. Specifically, sucralfate may decrease the absorption of Vitamin K Antagonists. Management: Administer vitamin K antagonists at least 2 hours before or at least 6 hours after sucralfate. Risk D: Consider therapy modification

Sugammadex: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Sulfinpyrazone: May decrease the metabolism of Vitamin K Antagonists. Sulfinpyrazone may decrease the protein binding of Vitamin K Antagonists. Risk D: Consider therapy modification

Sulfonamide Antibiotics: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk D: Consider therapy modification

Sulfonylureas: May enhance the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may enhance the hypoglycemic effect of Sulfonylureas. Risk C: Monitor therapy

Sulodexide: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Tamoxifen: May increase the serum concentration of Vitamin K Antagonists. Risk X: Avoid combination

Tegafur: May increase the serum concentration of Vitamin K Antagonists. Management: Monitor INR and signs/symptoms of bleeding closely when starting or stopping this combination. Anticoagulant dose adjustment will likely be necessary. Risk D: Consider therapy modification

Telavancin: May diminish the therapeutic effect of Anticoagulants. Specifically, telavancin may artificially increase the results of laboratory tests commonly used to monitor anticoagulant effectiveness, which could lead to incorrect decisions to decrease anticoagulant doses. Risk C: Monitor therapy

Teriflunomide: May decrease the serum concentration of Warfarin. Risk C: Monitor therapy

Tetracyclines: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Thrombolytic Agents: May enhance the anticoagulant effect of Anticoagulants. Management: See full drug monograph for guidelines for the use of alteplase for acute ischemic stroke during treatment with oral anticoagulants. Risk C: Monitor therapy

Thyroid Products: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Tibolone: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Tigecycline: May increase the serum concentration of Warfarin. Risk C: Monitor therapy

Tipranavir: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Tobacco (Smoked): May decrease the serum concentration of Warfarin. Risk C: Monitor therapy

Tolterodine: May enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Toremifene: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Torsemide: May increase the serum concentration of Warfarin. Risk C: Monitor therapy

TraMADol: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Tranilast (Systemic): May enhance the adverse/toxic effect of Warfarin. Tranilast (Systemic) may diminish the therapeutic effect of Warfarin. Risk C: Monitor therapy

TraZODone: May diminish the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Tricyclic Antidepressants: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Urokinase: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination

Vemurafenib: May increase the serum concentration of Warfarin. Risk C: Monitor therapy

Venetoclax: May increase the serum concentration of Warfarin. Risk C: Monitor therapy

Venlafaxine: May enhance the adverse/toxic effect of Vitamin K Antagonists. Specifically, the risk for bleeding may be increased. Risk C: Monitor therapy

Vitamin E (Systemic): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Vorapaxar: May enhance the adverse/toxic effect of Anticoagulants. More specifically, this combination is expected to increase the risk of bleeding. Risk X: Avoid combination

Voriconazole: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Vorinostat: May enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Zafirlukast: May increase the serum concentration of Vitamin K Antagonists. Risk C: Monitor therapy

Zileuton: May increase the serum concentration of Warfarin. Risk C: Monitor therapy

Food Interactions

Ethanol: Acute ethanol ingestion (binge drinking) decreases the metabolism of oral anticoagulants and increases PT/INR. Chronic daily ethanol use increases the metabolism of oral anticoagulants and decreases PT/INR. Management: Avoid ethanol.

Food: The anticoagulant effects of warfarin may be decreased if taken with foods rich in vitamin K. Vitamin E may increase warfarin effect. Cranberry juice may increase warfarin effect. Management: Maintain a consistent diet; consult prescriber before making changes in diet. Take warfarin at the same time each day.

Monitoring Parameters

Prothrombin time, hematocrit; INR (frequency varies depending on INR stability); may consider genotyping of CYP2C9 and VKORC1 prior to initiation of therapy, if available

Reference Range

INR = patient prothrombin time/mean normal prothrombin time

ISI = international sensitivity index

INR should be increased by 2 to 3.5 times depending upon indication. An INR >4 does not generally add additional therapeutic benefit and is associated with increased risk of bleeding. Note: To prevent gastrointestinal bleeding events in patients receiving the combination of warfarin, aspirin, and clopidogrel, an INR of 2 to 2.5 is recommended unless condition requires a higher INR target (eg, certain mechanical heart valves) (Bhatt 2008).

Adult Target INR Ranges Based Upon Indication
Indication Targeted INR Targeted INR Range
1If coronary stent placed, triple therapy (warfarin, low-dose aspirin, and clopidogrel) is recommended for 1 month (bare-metal stent) or 3 to 6 months (drug-eluting stent) followed by discontinuation of warfarin and use of dual antiplatelet therapy (eg, aspirin and clopidogrel) for up to 12 months.
2If coronary stent not placed, maintain anticoagulation (in combination with low-dose aspirin) for 3 months followed by discontinuation of warfarin and use of dual antiplatelet therapy (eg, aspirin and clopidogrel) for up to 12 months.
3The ACC/AHA guidelines for the management of STEMI, suggest that a lower INR range of 2 to 2.5 might be considered in patients with STEMI receiving dual antiplatelet therapy (ACC/AHA [O’Gara 2013]).
4Recommended for those patients with nonvalvular AF or atrial flutter with prior stroke, TIA, or a CHA2DS2-VASc score ≥2 (AHA/ACC/HRS [January 2014]).
5Recommendation from Stein 2001.
6Aspirin 75 to 100 mg once daily is also recommended for mechanical valves and is reasonable for bioprosthetic valves (AHA/ACC [Nishimura 2017]).
7The AHA/ASA recommends use in patients with bileaflet mechanical or current-generation, single-tilting-disk prostheses (AHA/ASA [Meschia 2014]).
8The On-X prosthetic aortic valve requires an initial INR of 2 to 3 for 3 months after valve insertion. A lower INR target of 1.5 to 2 thereafter may be reasonable if no thromboembolic risk factors. Unless contraindicated, continuous use of concurrent aspirin 75 to 100 mg once daily is also recommended (AHA/ACC [Nishimura 2017]; Puskas 2014).
9Risk factors include atrial fibrillation, previous thromboembolism, left ventricular dysfunction, and hypercoagulable conditions (AHA/ACC [Nishimura 2017]; AHA/ASA [Meschia 2014]).
10Maintain anticoagulation for at least 3 months and up to 6 months (if low risk of bleeding) after valve insertion then continue aspirin 75 to 100 mg once daily alone if no other indications for warfarin exist. Clinically reassess need for warfarin in patients with prior history of systemic embolism (AHA/ACC [Nishimura 2017]).
11Recommendation from AHA/ACC [Nishimura 2014].
12Recommendation from ACCP [Kearon 2012] and ACCP [Kearon 2016].
13Recommendation from the ACC/AHA 2009 Expert Consensus Document on Pulmonary Hypertension (ACC/AHA [McLaughlin 2009]).
14Recommendation from ACCP [Ageno 2012].
15Continue for at least 10 to 14 days; up to 35 days after surgery is suggested (ACCP [Falck-Ytter 2012]).
Cardiac
Anterior myocardial infarction with LV thrombus or high risk for LV thrombus (EF<40%, anteroapical wall motion abnormality)1,2,3,14 2.5 2 to 3
Atrial fibrillation (nonvalvular) or atrial flutter4 2.5 2 to 3
LV systolic dysfunction (without established CAD) (eg, Takotsubo cardiomyopathy) with an LV thrombus14 2.5 2 to 3
Valvular
Caged ball or caged disk mechanical valve5,6 3 2.5 to 3.5
Mechanical bileaflet or current generation single tilting disc aortic valve with no risk factors for thromboembolism6,7,8,9 2.5 2 to 3
Mechanical aortic valve (with risk factors6,9), mechanical mitral valve6or mechanical valves in both the aortic and mitral positions6 3 2.5 to 3.5
Bioprosthetic mitral valve6,10 2.5 2 to 3
Rheumatic mitral valve disease (particularly mitral stenosis) and normal sinus rhythm (LA diameter >5.5 cm), AF, previous systemic embolism, or LA thrombus11 2.5 2-3
Thromboembolism Treatment
Venous thromboembolism12 2.5 2 to 3
Thromboprophylaxis
Idiopathic pulmonary artery hypertension (IPAH)13 2 1.5 to 2.5
Antiphospholipid syndrome and recurrent thromboembolism14 2.5 2 to 3
Total hip or knee replacement or hip fracture surgery15 2.5 2 to 3
Other Indications
Cryptogenic stroke (recurrent) and either patent foramen ovale (PFO) or atrial septal aneurysm14 2.5 2 to 3

Warfarin levels are not used for monitoring degree of anticoagulation. They may be useful if a patient with unexplained coagulopathy is using the drug surreptitiously or if it is unclear whether clinical resistance is due to true drug resistance or lack of drug intake.

Normal prothrombin time (PT): 10.9 to 12.9 seconds. Healthy premature newborns have prolonged coagulation test screening results (eg, PT, aPTT, TT) which return to normal adult values at approximately 6 months of age. Healthy prematures, however, do not develop spontaneous hemorrhage or thrombotic complications because of a balance between procoagulants and inhibitors.

Advanced Practitioners Physical Assessment/Monitoring

Obtain prothrombin time, hematocrit, and INR. Consider genotyping of CYP2C9 and VKORC1 prior to initiation of therapy, if available. Assess other medicines patient may be taking, alternate therapy or dosage adjustments may be needed. Assess for signs and symptoms of bleeding.

Nursing Physical Assessment/Monitoring

Check ordered labs and report any abnormalities. Monitor for and educate patient to report signs and symptoms of bleeding. Educate patient on importance of a consistent diet and following up with lab work. Educate patient to report warfarin use to all providers due to drug interactions and increased risk of bleeding.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral, as sodium:

Coumadin: 1 mg [scored]

Coumadin: 2 mg [scored; contains fd&c blue #2 aluminum lake, fd&c red #40 aluminum lake]

Coumadin: 2.5 mg [scored; contains fd&c blue #1 aluminum lake, fd&c yellow #10 aluminum lake]

Coumadin: 3 mg [scored; contains fd&c blue #2 aluminum lake, fd&c red #40 aluminum lake, fd&c yellow #6 aluminum lake]

Coumadin: 4 mg [scored; contains fd&c blue #1 aluminum lake]

Coumadin: 5 mg [scored; contains fd&c yellow #6 aluminum lake]

Coumadin: 6 mg [scored; contains fd&c blue #1 aluminum lake, fd&c yellow #6 aluminum lake]

Coumadin: 7.5 mg [scored; contains fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake]

Coumadin: 10 mg [scored; dye free]

Jantoven: 1 mg [scored; contains fd&c red #40 aluminum lake]

Jantoven: 2 mg [scored; contains fd&c blue #2 aluminum lake, fd&c red #40 aluminum lake]

Jantoven: 2.5 mg [scored; contains fd&c blue #1 aluminum lake, fd&c yellow #10 aluminum lake]

Jantoven: 3 mg [scored]

Jantoven: 4 mg [scored; contains fd&c blue #1 aluminum lake]

Jantoven: 5 mg [scored; contains fd&c yellow #6 aluminum lake]

Jantoven: 6 mg [scored; contains fd&c blue #1 aluminum lake]

Jantoven: 7.5 mg [scored; contains fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake]

Jantoven: 10 mg [scored]

Generic: 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7.5 mg, 10 mg

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral, as sodium:

Coumadin: 1 mg

Coumadin: 2 mg [contains FD&C BLUE #2 ALUMINUM LAKE, FD&C RED #40 ALUMINUM LAKE]

Coumadin: 2.5 mg [contains FD&C BLUE #1 ALUMINUM LAKE, FD&C YELLOW #10 ALUMINUM LAKE]

Coumadin: 3 mg [contains FD&C BLUE #2 ALUMINUM LAKE, FD&C RED #40 ALUMINUM LAKE, FD&C YELLOW #6 ALUMINUM LAKE]

Coumadin: 4 mg [contains FD&C BLUE #1 ALUMINUM LAKE]

Coumadin: 5 mg [contains FD&C YELLOW #6 ALUMINUM LAKE]

Coumadin: 6 mg, 10 mg

Generic: 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7.5 mg, 10 mg

Anatomic Therapeutic Chemical (ATC) Classification
  • B01AA03
Generic Available (US)

Yes

Pricing: US

Tablets (Coumadin Oral)

1 mg (per each): $2.47

2 mg (per each): $2.58

2.5 mg (per each): $2.66

3 mg (per each): $2.67

4 mg (per each): $2.68

5 mg (per each): $2.78

6 mg (per each): $3.58

7.5 mg (per each): $3.70

10 mg (per each): $3.84

Tablets (Jantoven Oral)

1 mg (per each): $0.61

2 mg (per each): $0.64

2.5 mg (per each): $0.66

3 mg (per each): $0.66

4 mg (per each): $0.66

5 mg (per each): $0.69

6 mg (per each): $0.89

7.5 mg (per each): $0.92

10 mg (per each): $0.95

Tablets (Warfarin Sodium Oral)

1 mg (per each): $0.58 – $0.61

2 mg (per each): $0.61 – $0.64

2.5 mg (per each): $0.63 – $0.66

3 mg (per each): $0.63 – $0.66

4 mg (per each): $0.63 – $0.66

5 mg (per each): $0.64 – $0.67

6 mg (per each): $0.90 – $0.95

7.5 mg (per each): $0.93 – $0.98

10 mg (per each): $0.97 – $1.02

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer’s AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Mechanism of Action

Hepatic synthesis of coagulation factors II (half-life 42 to 72 hours), VII (half-life 4 to 6 hours), IX, and X (half-life 27 to 48 hours), as well as proteins C and S, requires the presence of vitamin K. These clotting factors are biologically activated by the addition of carboxyl groups to key glutamic acid residues within the proteins’ structure. In the process, “active” vitamin K is oxidatively converted to an “inactive” form, which is then subsequently reactivated by vitamin K epoxide reductase complex 1 (VKORC1). Warfarin competitively inhibits the subunit 1 of the multi-unit VKOR complex, thus depleting functional vitamin K reserves and hence reduces synthesis of active clotting factors.

Pharmacodynamics/Kinetics

Onset of action: Initial anticoagulant effect on INR may be seen as soon as 24 to 72 hours (Harrison 1997; O’Reilly 1968).

Note: Full therapeutic effect generally seen between 5 and 7 days after initiation; dependent on reduction in vitamin K-dependent coagulation factors, especially prothrombin (factor II), which has a half-life of 60 to 72 hours (ACCP [Ageno 2012]; Crowther 1999; Kovacs 2003; manufacturer’s labeling).

Duration: 2 to 5 days

Absorption: Rapid, complete

Distribution: 0.14 L/kg

Protein binding: 99%

Metabolism: Hepatic, primarily via CYP2C9; minor pathways include CYP2C8, 2C18, 2C19, 1A2, and 3A4

Genomic variants: Approximately 37% reduced clearance of S-warfarin in patients heterozygous for 2C9 (*1/*2 or *1/*3), and ~70% reduced in patients homozygous for reduced function alleles (*2/*2, *2/*3, or *3/*3)

Half-life elimination: 20 to 60 hours; Mean: 40 hours; highly variable among individuals

Time to peak, plasma: ~4 hours

Excretion: Urine (92%, primarily as metabolites; minimal as unchanged drug)

Pharmacodynamics/Kinetics: Additional Considerations

Renal function impairment: Renal Cl is a minor determinant of anticoagulant response to warfarin.

Hepatic function impairment: Hepatic impairment can potentiate the response to warfarin through impaired synthesis of clotting factors and decreased metabolism of warfarin.

Geriatric: Patients 60 years and older appear to exhibit greater than expected INR response to warfarin.

Race: Asian patients may require lower initiation and maintenance doses.

Pharmacogenetics: Vitamin K epoxide reductase (VKORC1) and CYP2C9 gene variants generally explain the largest proportion of known variability in warfarin dose requirements.

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Dental Health Professional Considerations

It is important to discuss patient with physician or to ask for recent INR result to ensure that patient is within a reasonable range prior to an invasive dental procedure. One clue to determine how stable a patient is on warfarin therapy is to assess how often the patient gets INRs drawn. Recent frequent blood draws may suggest poor control on the patient’s warfarin regimen. Surgery is generally acceptable for patients on warfarin with an INR between 2 to 3. Assess potential interactions when prescribing an antibiotic in patients on warfarin. Educate patients, who may require significant acetaminophen doses for multiple consecutive days to control dental pain, on the effects on warfarin (increased INR). NSAIDs do not have effects on INR but may increase the risk of bleeding while on warfarin.

Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Increased risk of bleeding, mouth ulcers, and taste disturbance.

Signs of warfarin overdose may first appear as bleeding from gingival tissue (see Effects on Bleeding and Dental Health Professional Considerations)

For stroke patients undergoing dental procedures (see Effects on Bleeding and Dental Health Professional Considerations)

Effects on Bleeding

As with all anticoagulants, bleeding is a potential adverse effect of warfarin during dental surgery; risk is dependent on multiple variables, including the intensity of anticoagulation and patient susceptibility. Consultation with prescribing physician is advisable prior to surgery to determine if temporary dose reduction or withdrawal of medication is indicated. Stroke patients maintained on warfarin should continue therapy during dental procedures as warfarin is unlikely to increase bleeding risk (Armstrong 2013)

Tooth extraction: A recent study assessed the amount of bleeding during a single tooth extraction in patients who remained on warfarin during the procedure versus those who discontinued warfarin (Karsli 2011). All patients had coronary artery disease. There was no significant difference in bleeding with or without warfarin. The mean blood loss was 2486 ± 1408 g in the warfarin group, compared to 1736 ± 876 g in the patients who stopped warfarin. The mean INR value in the warfarin group was 2.6 ± 0.7. Hemostasis was successfully established locally by packing the extraction sockets with oxidized cellulose (Surgicel) and suturing with 3-0 silk sutures.

Concurrent antibiotic use: A retrospective study evaluating over 38,000 patients ≥65 years of age showed exposure to any antibiotic agent was associated with at least a 2-fold increased risk of bleeding that required hospitalization among continuous warfarin users (Baillargeon 2012). All five antibiotic drug classes examined (macrolides, quinolones, cotrimoxazole, penicillins, and cephalosporins) were associated with an increased risk of bleeding. Exposure to an azole antifungal (fluconazole, ketoconazole, or miconazole) while on warfarin was associated with a 4-fold increased risk of bleeding.

Index Terms

Warfarin Sodium

FDA Approval Date
June 08, 1954
References

<800> Hazardous Drugs—Handling in Healthcare Settings. United States Pharmacopeia and National Formulary (USP 40-NF 35). Rockville, MD: United States Pharmacopeia Convention; 2017:83-102.

Ageno W, Gallus AS, Wittkowsky A, et al, “Oral Anticoagulant Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines,” Chest, 2012, 141(2 Suppl):e44-88.[PubMed 22315269]

Anand SS, Yusuf S, Pogue J, et al, “Long-Term Oral Anticoagulant Therapy in Patients With Unstable Angina or Suspected Non-Q-Wave Myocardial Infarction: Organization to Assess Strategies for Ischemic Syndromes (OASIS) Pilot Study Results,” Circulation, 1998, 98(11):1064-70.[PubMed 9736592]

Arepally GM and Ortel TL, “Heparin-Induced Thrombocytopenia,” N Engl J Med, 2006, 355 (8):809-17.[PubMed 16928996]

Armstrong MJ, Gronseth G, Anderson DC, et al. Summary of evidence-based guideline: Periprocedural management of antithrombotic medications in patients with ischemic cerebrovascular disease: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2013;80(22):2065-9.[PubMed 23713086]

Baillargeon J, Holmes HM, Lin YL, et al, “Concurrent Use of Warfarin and Antibiotics and the Risk of Bleeding in Older Adults,” Am J Med, 2012, 125(2):183-9.[PubMed 22269622]

Bates SM, Greer IA, Middeldorp S, et al. “VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines,” Chest, 2012, 141(2 Suppl):e691-736.[PubMed 22315276]

Bell AD, Roussin A, Cartier R, et al, “The Use of Antiplatelet Therapy in the Outpatient Setting: Canadian Cardiovascular Society Guidelines,” Can J Cardiol, 2011, 27(Suppl A):1-59.[PubMed 21640290]

Bhatt DL, Scheiman J, Abraham NS, et al, “ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risk of Antiplatelet Therapy and NSAID Use. A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents,” J Am Coll Cardiol, 2008, 52(18):1502-17.[PubMed 19017521]

Booth SL, Centurelli MA. Vitamin K: a practical guide to the dietary management of patients on warfarin. Nutr Rev.1999;57(9):288-296.[PubMed 10568341]

Carabello PJ, Heit JA, Atkinson EJ, et al, “Long-Term Use of Oral Anticoagulants and the Risk of Fracture,” Arch Intern Med, 1999, 159(15):1750-6.[PubMed 10448778]

Chimowitz MI, Lynn MJ, Howlett-Smith H, et al, “Comparison of Warfarin and Aspirin for Symptomatic Intracranial Arterial Stenosis,” N Engl J Med, 2005, 352(13):1305-16.[PubMed 15800226]

Coumadin (warfarin) [prescribing information]. Princeton, NJ: Bristol-Meyers Squibb; August 2017.

Crowther MA, Ginsberg JB, Kearon C, et al. A randomized trial comparing 5-mg and 10-mg warfarin loading doses. Arch Intern Med. 1999;159(1):46-48.[PubMed 9892329]

Culebras A, Messe SR, Chaturvedi S, et al. Summary of evidence-based guideline update: Prevention of stroke in nonvalvular atrial fibrillation. Neurology. 2014;82:716-724.[PubMed 24566225]

Dager WE and White RH, “Pharmacotherapy of Heparin-Induced Thrombocytopenia,” Expert Opin Pharmacother, 2003, 4(6):919-40.[PubMed 12783589]

Dager WE, King JF, Regalia RC, et al, “Reversal of Elevated International Normalized Ratios and Bleeding With Low-Dose Recombinant Activated Factor VII in Patients Receiving Warfarin,” Pharmacotherapy, 2006, 26(8):1091-8.[PubMed 16863486]

“Effect of Long-Term Oral Anticoagulant Treatment on Mortality and Cardiovascular Morbidity After Myocardial Infarction. Anticoagulants in the Secondary Prevention of Events in Coronary Thrombosis (ASPECT) Research Group,” Lancet, 1994, 343(8896):499-503.[PubMed 7906757]

Frontera JA, Lewin JJ 3rd, Rabinstein AA, et al; Guideline for reversal of antithrombotics in intracranial hemorrhage: a statement for healthcare professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care. 2016;24(1):6-46.[PubMed 26714677]

Gage BF, Birman-Deych E, Radford MJ, et al, “Risk of Osteoporotic Fracture in Elderly Patients Taking Warfarin. Results From the National Registry of Atrial Fibrillation 2,” Arch Intern Med, 2006, 166(2):241-6.[PubMed 16432096]

Grand’Maison A, Charest AF, and Geerts WH, “Anticoagulant Use in Patients With Chronic Renal Impairment,” Am J Cardiovasc Drugs, 2005, 5(5):291-305.[PubMed 16156685]

Gulseth MP. Managing Anticoagulation Patients in the Hospital: The Inpatient Anticoagulation Service. Bethesda, MD: American Society of Health-System Pharmacists Inc; 2007.

Guyatt GH, Akl EA, Crowther M, et al, “Executive Summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines,” Chest, 2012, 141(2 Suppl):7-47.[PubMed 22315257]

Harrell CC, Kline SS. Vitamin K-supplemented snacks containing olestra: implication for patients taking warfarin. JAMA. 1999; 282(12):1133-1134.[PubMed 10501114]

Harrison L, Johnston M, Massicotte MP, Crowther M, Moffat K, Hirsh J. Comparison of 5-mg and 10-mg loading doses in initiation of warfarin therapy. Ann Intern Med. 1997;126(2):133-136.[PubMed 9005747]

Healthcare Environmental Resource Center (HERC), “Pharmaceutical Wastes in Healthcare Facilities.” Available at http://www.hercenter.org/hazmat/pharma.cfm#listed. Last accessed April 8, 2013.

Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 suppl):e152S-e184S. doi: 10.1378/chest.11-2295.[PubMed 22315259]

Jaff MR, McMurtry MS, Archer SL, et al, “Management of Massive and Submassive Pulmonary Embolism, Iliofemoral Deep Vein Thrombosis, and Chronic Thromboembolic Pulmonary Hypertension: A Scientific Statement from the American Heart Association,” Circulation, 2011, 123(16):1788-830.[PubMed 21422387]

Jamal SA, Browner WS, Bauer DC, et al, “Warfarin Use and Risk for Osteoporosis in Elderly Women. Study of Osteoporotic Fractures Research Group,” Ann Intern Med, 1998, 128(10):829-32.[PubMed 9599195]

January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society [published online March 28, 2014]. Circulation. doi:10.1161/CIR.0000000000000041.[PubMed 24682347]

Jeske AH, Suchko GD, ADA Council on Scientific Affairs and Division of Science, et al, “Lack of a Scientific Basis for Routine Discontinuation of Oral Anticoagulation Therapy Before Dental Treatment,” J Am Dent Assoc, 2003, 134(11):1492-7.[PubMed 14664269 ]

Karsli ED, Erdogan Ö, Esen E, et al, “Comparison of the Effects of Warfarin and Heparin on Bleeding Caused by Dental Extraction: A Clinical Study,” J Oral Maxillofac Surg, 2011, 69(10):2500-7.[PubMed 21764203]

Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines [published correction appears in Chest. 2012;142(6):1698-1704]. Chest. 2012;141(2)(suppl):e419S-e496S. doi: 10.1378/chest.11-2301.[PubMed 22315268]

Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149(2):315-352. doi: 10.1016/j.chest.2015.11.026.[PubMed 26867832]

Kernan WN, Ovbiagele B, Black HR, et al; American Heart Association Stroke Council; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Peripheral Vascular Disease. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association [published correction appears in Stroke. 2015;46(2):e54]. Stroke. 2014;45(7):2160-2236. doi: 10.1161/STR.0000000000000024.[PubMed 24788967]

Kovacs MJ, Rodger M, Anderson DR, et al, “Comparison of 10-mg and 5-mg Warfarin Initiation Nomograms Together With Low-Molecular-Weight Heparin for Outpatient Treatment of Acute Venous Thromboembolism. A Randomized, Double-Blind, Controlled Trial,” Ann Intern Med, 2003, 138(9):714-9.[PubMed 12729425]

Kuykendall JR , Houle MD, Rhodes RS. Possible warfarin failure due to interaction with smokeless tobacco. Ann Pharmacother. 2004;38(4):595-597.[PubMed 14766993]

Lindenfeld J, Albert NM, Boehmer JP, et al, “HFSA 2010 Comprehensive Heart Failure Practice Guideline,” J Card Fail, 2010, 16(6):e1-194.[PubMed 20610207]

Linkins LA, Dans AL, Moores LK, et al. Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines [published correction appears in Chest. 2015;148(6):1529]. Chest. 2012;141(2 suppl):e495S-e530S. doi: 10.1378/chest.11-2303.[PubMed 22315270]

Little JW, Miller CS, Henry RG, et al, “Antithrombotic Agents: Implications in Dentistry,” Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 2002, 93(5):544-51.[PubMed 12075203 ]

McLaughlin VV, Archer SL, Badesch DB, et al, “ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension. A Report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association,” Circulation, 2009, 119(16):2250-94.[PubMed 19332472]

McMahan DA, Smith DM, Carey MA, et al, “Risk of Major Hemorrhage for Outpatients Treated With Warfarin,” J Gen Intern Med, 1998, 13(5):311-6.[PubMed 9613886]

Meschia JF, Bushnell C, Boden-Albala B, et al; American Heart Association Stroke Council; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Functional Genomics and Translational Biology; Council on Hypertension. Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45(12):3754-3832.[PubMed 25355838]

Monagle P, Chan A, Goldenberg NA, et al, “Antithrombotic Therapy in Neonates and Children: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (9th Edition),” Chest, 2012, 141(2 Suppl):e737-801.[PubMed 22315277]

Nigwekar SU, Kroshinsky D, Nazarian RM, et al. Calciphylaxis: risk factors, diagnosis, and treatment. Am J Kidney Dis. 2015;66(1):133-146.[PubMed 25960299]

Nishimura RA, Otto CM, Bonow RO, et al, 2014 AHA/ACC Guideline for the Management of Patients with Valvular Heart Disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(23):2440-92. doi: 10.1161/CIR.0000000000000029.[PubMed 24589852]

Nishimura RA, Otto CM, Bonow RO, et al. 2017 AHA/ACC Focused Update of the 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2017;70(2):252-289.[PubMed 28315732]

Nutescu E, Chuatrisorn I, Hellenbart E. Drug and dietary interactions of warfarin and novel oral anticoagulants: an update. J Thromb Thrombolysis. 2011;31:326-343.[PubMed 21359645]

Nutescu E, Shapiro NL, Ibrahim S, West P. Warfarin and its interactions with foods, herbs and other dietary supplements. Expert Opin Drug Saf. 2006;5(3):433-451.[PubMed 16610971]

O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines [published correction appears in Circulation. 2013;128(25):e481.] Circulation. 2013;127(4):e362-e425.[PubMed 23247304]

O’Reilly RA, Aggeler PM. Studies on coumarin anticoagulant drugs. Initiation of warfarin therapy without a loading dose. Circulation. 1968;38(1):169-177.[PubMed 11712286]

Patriquin C and Crowther M, “Treatment of Warfarin-associated Coagulopathy With Vitamin K,” Expert Rev Hematol, 2011, 4(6):657-67.[PubMed 22077529]

Puskas J, Gerdisch M, Nichols D, et al; PROACT Investigators. Reduced anticoagulation after mechanical aortic valve replacement: Interim results from the Prospective Randomized On-X Valve Anticoagulation Clinical Trial randomized Food and Drug Administration investigational device exemption trial. J Thorac Cardiovasc Surg. 2014;147(4):1202-1211.[PubMed 24512654 ]

“Randomised Double-Blind Trial of Fixed Low-Dose Warfarin With Aspirin After Myocardial Infarction. Coumadin Aspirin Reinfarction Study (CARS) Investigators,” Lancet, 1997, 350(9075):389-96.[PubMed 9259652]

Sacco RL, Adams R, Albers G, et al, “Guidelines for Prevention of Stroke in Patients With Ischemic Stroke or Transient Ischemic Attack: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association Council on Stroke: Co-Sponsored by the Council on Cardiovascular Radiology and Intervention: The American Academy of Neurology Affirms the Value of this Guideline,” Stroke, 2006, 37(2):577-617.[PubMed 16432246]

Scully C and Wolff A, “Oral Surgery in Patients on Anticoagulant Therapy,” Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 2002, 94(1):57-64.[PubMed 12193895 ]

Singer DE, Albers GW, Dalen JE, et al, “Antithrombotic Therapy in Atrial Fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition),” Chest, 2008, 133(6 Suppl):546-92.[PubMed 18574273]

Skanes AC, Healey JS, Cairns JA, et al, “Focused 2012 Update of the Canadian Cardiovascular Society Atrial Fibrillation Guidelines: Recommendations for Stroke Prevention and Rate/Rhythm Control,” Can J Cardiol, 2012, 28(2):125-36.[PubMed 22433576]

Smith P, Arnesen H, and Holme I, “The Effect of Warfarin on Mortality and Reinfarction After Myocardial Infarction,” N Engl J Med, 1990, 323(3):147-52.[PubMed 2194126]

Smith SC Jr, Benjamin EJ, Bonow RO, et al, “AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients With Coronary and Other Atherosclerotic Vascular Disease: 2011 Update: A Guideline From the American Heart Association and American College of Cardiology Foundation,” Circulation, 2011, 124(22):2458-73.[PubMed 22052934]

Smythe MA, Warkentin TE, Stephens JL, et al, “Venous Limb Gangrene During Overlapping Therapy With Warfarin and a Direct Thrombin Inhibitor for Immune Heparin-Induced Thrombocytopenia,” Am J Hematol, 2002, 71(1):50-2.[PubMed 12221676]

Stein PD, Alpert JS, Bussey HI, et al, “Antithrombotic Therapy in Patients With Mechanical and Biological Prosthetic Heart Valves,” Chest, 2001, 119(1 Suppl):220-7.[PubMed 11157651]

Suvarna R, Pirmohamed M, and Henderson L, “Possible Interaction Between Warfarin and Cranberry Juice,” BMJ, 2003, 327(7429):1454.[PubMed 14684645]

US Department of Health and Human Services; Centers for Disease Control and Prevention; National Institute for Occupational Safety and Health. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings 2016. http://www.cdc.gov/niosh/topics/antineoplastic/pdf/hazardous-drugs-list_2016-161.pdf. Updated September 2016. Accessed October 5, 2016.

United States Department of Agriculture (USDA), National Agricultural Library (NAL) Dietary Reference Intake. Available at http://fnic.nal.usda.gov/dietary-guidance/dietary-reference-intakes/dri-tables. Accessed January 8, 2015.

Whitlock RC, Sun JC, Fremes, SE, et al. Antithrombotic and thrombolytic therapy for valvular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e576S-e600S. doi: 10.1378/chest.11-2305.[PubMed 22315272]

Vandvik PO, Lincoff AM, Gore JM, et al.. Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e637S-e668S. doi: 10.1378/chest.11-2306.[PubMed 22315274]

Yung D, Kapral MK, Asllani E, et al, Reinitiation of anticoagulation after warfarin-associated intracranial hemorrhage and mortality risk: the best practice for reinitiating anticoagulation therapy after intracranial bleeding (BRAIN) study. Can J Cardiol. 2012;28:33-39.[PubMed 22153256]

Brand Names: International

Aldocumar (ES); Azwar (LK); Befarin (TH); Circuvit (AR); Cofarin (TW); Coumadan (AR); Coumadin (AE, AU, BB, BF, BH, BJ, CI, CL, CY, DE, EC, ET, GH, GM, GN, IL, IQ, IR, IT, JO, KE, KR, KW, LB, LR, LY, MA, ML, MR, MU, MW, MX, NE, NG, NZ, OM, PH, PK, SA, SC, SD, SL, SN, SY, TN, TR, TZ, UG, VE, YE, ZM, ZW); Coumadine (FR, VN); Dagonal (UY); Farin (BD); Haemofarin (EG); Lawarin (CZ); Lennon-Warfarin (ZA); Mafarin (TW); Maforan (TH); Marevan (AE, AU, BE, BR, CN, DK, EE, EG, FI, GB, IE, LU, MT, NO, NZ, SG); Marfarin (HN); Marivarin (HR); Martefarin (HR); Morfarin (TH); Oldin (PY); Orfarin (JO, LV, MY, TH, TW); Panwarfin (GR); Rilaquin (PY); Simarc-2 (ID); UniWarfin (IN); Varfarin (HR); Varfine (PT); Waran (SE); Warf (LK); Warfant (IE, TR); Warfar (CO, KR); Warfarina (PE); Warfil 5 (DO); Warfin (PL); Warik (PH); Warin (BD); Win (BD); Xclot (PH); Zofarin (LK); Zydarin (TH)

Warfarin (Patient Education – Adult Medication)
You must carefully read the “Consumer Information Use and Disclaimer” below in order to understand and correctly use this information
Pronunciation

(WAR far in)

Brand Names: US

Coumadin; Jantoven

Brand Names: Canada

Apo-Warfarin; Coumadin; Taro-Warfarin

Warning
  • This drug may cause very bad and sometimes deadly bleeding. Talk with the doctor.
  • Call your doctor right away if you have any signs of bleeding problems, like bruising; black, tarry, or bloody stools; bleeding gums; blood in the urine; coughing up blood; cuts that take a long time to stop bleeding; feel dizzy; feeling very tired or weak; nosebleeds; pain or swelling; throwing up blood or throw up that looks like coffee grounds; or very bad headache.
  • Call your doctor right away if you have vaginal bleeding that is not normal or very heavy periods (menstrual bleeding).
  • You will need to have your blood work (PT/INR) checked while you take this drug. This is important to make sure the drug works right and to check your risk of bleeding. Have your PT/INR checked as you have been told by your doctor or other health care provider. If you are not sure when you need to have your PT/INR checked, call your doctor or other health care provider.
  • Your diet and certain drugs may affect your PT/INR level. Talk with your doctor.
  • Avoid actions or sports that may raise the chance of injury or bleeding.
What is this drug used for?
  • It is used to treat blood clots.
  • It is used to thin the blood so that clots will not form.
  • It is used to lower the chance of heart attack, stroke, and death in some people.
What do I need to tell my doctor BEFORE I take this drug?
  • If you have an allergy to warfarin or any other part of this drug.
  • If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
  • If you have any of these health problems: Blood vessel problems like, aneurysm or dissecting aorta; bleeding problems; bleeding in the brain; active ulcer; bleeding of the stomach, bowel, urinary tract, genitals, or respiratory tract; blood problems; heart infection; low platelet count; pericarditis, recent surgery of the eye, brain, or spine; or very high blood pressure.
  • If you have any of these health problems: A certain health problem called pre-eclampsia, seizures during pregnancy (eclampsia), induction of labor, or threatened spontaneous abortion.
  • If you are having surgery, talk with your doctor.
  • If you will be getting spinal anesthesia or a spinal treatment.
  • If you have had spinal anesthesia, surgery, or any spinal care, talk with your doctor.
  • If you know that you will not take the drug or have your blood work (PT/INR) checked as you have been told.
  • If you have thrombocytopenia caused by heparin.
  • If you are pregnant.
  • This is not a list of all drugs or health problems that interact with this drug.
  • Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this drug with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.
What are some things I need to know or do while I take this drug?
  • Tell all of your health care providers that you take this drug. This includes your doctors, nurses, pharmacists, and dentists.
  • Use care to prevent injury and avoid falls or crashes.
  • If you fall or hurt yourself, or if you hit your head, call your doctor right away. Talk with your doctor even if you feel fine.
  • You may bleed more easily. Be careful and avoid injury. Use a soft toothbrush and an electric razor.
  • If you drink grapefruit juice or eat grapefruit often, talk with your doctor.
  • Talk with your doctor before using products that have aspirin, blood thinners, garlic, ginseng, ginkgo, ibuprofen or like products, pain drugs, or vitamin E.
  • Certain foods can affect your PT/INR levels. Follow the diet plan that your doctor or other health care provider told you about.
  • Talk with your doctor about the amount of vitamin K in your diet. Vitamin K may change how this drug works. You do not have to avoid all foods with vitamin K. However, you will need to keep the amount of foods with vitamin K in your diet about the same from day to day. Many foods have vitamin K in them. This includes some green, leafy vegetables; broccoli; liver; and certain vegetable oils. Get a list of foods that have vitamin K in them from your doctor. Do not make big changes in your normal diet without talking with your doctor.
  • Talk with your doctor before taking multivitamins, natural products, and diet aids. These may have vitamin K in them.
  • Have patient safety card with you at all times.
  • Call your doctor right away if you have diarrhea, a fever, or an infection.
  • If you start or stop smoking, talk with your doctor. How much drug you take may need to be changed.
  • A very bad and sometimes deadly health problem involving the skin (calciphylaxis) has happened with this drug. This has happened in people with and without very bad kidney problems. Talk with the doctor.
  • If you are of Asian descent, use this drug with care. You could have more side effects.
  • If you are 60 or older, use this drug with care. You could have more side effects.
  • This drug may cause harm to the unborn baby if you take it while you are pregnant.
  • If you are able to get pregnant, a pregnancy test will be done to show that you are NOT pregnant before starting this drug. Talk with your doctor.
  • Use birth control that you can trust to prevent pregnancy while taking this drug and for at least 1 month after stopping this drug.
  • If you get pregnant while taking this drug or within 1 month after your last dose, call your doctor right away.
  • Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.
What are some side effects that I need to call my doctor about right away?
  • WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:
  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight.
  • Chest pain.
  • Very bad dizziness or passing out.
  • Swelling, warmth, numbness, change of color, or pain in a leg or arm.
  • Very bad headache.
  • Feeling very tired or weak.
  • Swelling.
  • Change in skin color to black or purple.
  • Death of skin tissue may rarely happen. This can lead to loss of the body part (amputation) and can be deadly. Call your doctor right away if you have pain, color, or temperature change in any part of the body.
  • If you have kidney problems or have had kidney problems in the past, talk with your doctor. Kidney problems may happen. Call your doctor right away if you have signs of kidney problems like not able to pass urine, change in how much urine is passed, blood in the urine, or a big weight gain.
What are some other side effects of this drug?
  • All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if you have any side effects that bother you or do not go away.
  • These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.
  • You may report side effects to your national health agency.
How is this drug best taken?
  • Use this drug as ordered by your doctor. Read all information given to you. Follow all instructions closely.
  • Use this drug exactly as you have been told, even if you feel well. This is important for the drug to work right and to lower the risk of bleeding.
  • Take this drug at the same time of day.
  • To gain the most benefit, do not miss doses.
  • Pregnant women must not handle crushed or broken tablets. Talk with the doctor.
What do I do if I miss a dose?
  • Take a missed dose as soon as you think about it on the same day you missed the dose.
  • If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
  • Do not take 2 doses at the same time or extra doses.
  • Do not take more than 1 dose of this drug in the same day.
How do I store and/or throw out this drug?
  • Store at room temperature.
  • Store in a dry place. Do not store in a bathroom.
  • Protect from light.
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Throw away unused or expired drugs. Do not flush down a toilet or pour down a drain unless you are told to do so. Check with your pharmacist if you have questions about the best way to throw out drugs. There may be drug take-back programs in your area.
General drug facts
  • If your symptoms or health problems do not get better or if they become worse, call your doctor.
  • Do not share your drugs with others and do not take anyone else’s drugs.
  • Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
  • Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
  • Some drugs may have another patient information leaflet. If you have any questions about this drug, please talk with your doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.
Warfarin (Patient Education – Pediatric Medication)
You must carefully read the “Consumer Information Use and Disclaimer” below in order to understand and correctly use this information
Pronunciation

(WAR far in)

Brand Names: US

Coumadin; Jantoven

Brand Names: Canada

Apo-Warfarin; Coumadin; Taro-Warfarin

Warning
  • This drug may cause very bad and sometimes deadly bleeding. Talk with the doctor.
  • Call the doctor right away if your child has any signs of bleeding problems, like bruising; black, tarry, or bloody stools; bleeding gums; blood in the urine; coughing up blood; cuts that take a long time to stop bleeding; feeling dizzy; feeling very tired or weak; nosebleeds; pain or swelling; throwing up blood or throw up that looks like coffee grounds; or very bad headache.
  • Call the doctor right away if your child has vaginal bleeding that is not normal or very heavy periods (menstrual bleeding).
  • You will need to have your child’s blood work (PT/INR) checked while your child takes this drug. This is important to make sure the drug works right and to check your child’s risk of bleeding. Have your child’s PT/INR checked as you have been told by your child’s doctor or other health care provider. If you are not sure when you need to have your child’s PT/INR checked, call your child’s doctor or other health care provider.
  • Your child’s diet and certain drugs may affect your child’s PT/INR level. Talk with the doctor.
  • Have your child avoid actions or sports that may raise the chance of injury.
What is this drug used for?
  • It is used to treat blood clots.
  • It is used to thin the blood so that clots will not form.
  • It is used to lower the chance of heart attack, stroke, and death in some people.
What do I need to tell the doctor BEFORE my child takes this drug?
  • If your child has an allergy to this drug or any part of this drug.
  • If your child is allergic to any drugs like this one or any other drugs, foods, or other substances. Tell the doctor about the allergy and what signs your child had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
  • If your child has any of these health problems: Blood vessel problems like aneurysm or dissecting aorta; bleeding problems; bleeding in the brain; active ulcer; bleeding of the stomach, bowel, urinary tract, genitals, or respiratory tract; blood problems; heart infection; low platelet count; pericarditis; recent surgery of the eye, brain, or spine; or very high blood pressure.
  • If your child is pregnant or may be pregnant.
  • If your child is having surgery, talk with the doctor.
  • Tell your child’s doctor he/she uses this drug before he/she gets spinal anesthesia or a spinal treatment.
  • If your child has had spinal anesthesia, surgery, or any spinal care, talk with your child’s doctor.
  • If you know that your child will not take the drug or have blood work (PT/INR) checked as you have been told by the doctor.
  • If your child has thrombocytopenia caused by heparin.
  • If your child is pregnant:
  • If your child has any of these health problems: A certain health problem called pre-eclampsia, seizures during pregnancy (eclampsia), induction of labor, or threatened spontaneous abortion.
  • This is not a list of all drugs or health problems that interact with this drug.
  • Tell the doctor and pharmacist about all of your child’s drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for your child to take this drug with all of his/her drugs and health problems. Do not start, stop, or change the dose of any drug your child takes without checking with the doctor.
What are some things I need to know or do while my child takes this drug?
  • Tell all of your child’s health care providers that your child is taking this drug. This includes your child’s doctors, nurses, pharmacists, and dentists.
  • Use care to prevent your child from getting hurt and have your child avoid falls or crashes.
  • If your child falls, gets hurt, or hits his/her head, call the doctor right away. Talk with the doctor even if your child feels fine.
  • Your child may bleed more easily. Make sure your child is careful and avoids injury. Be sure your child has a soft toothbrush.
  • If your child drinks grapefruit juice or eats grapefruit often, talk with your child’s doctor.
  • Talk with the doctor before giving your child products that have aspirin, blood thinners, garlic, ginseng, ginkgo, ibuprofen or like products, pain drugs, or vitamin E.
  • Certain foods can affect your child’s PT/INR levels. Have your child follow the diet plan your child’s doctor or other health care provider told you about.
  • Talk with the doctor about the amount of vitamin K in your child’s diet. Vitamin K may change how this drug works. Your child does not have to avoid all foods with vitamin K. However, you will need to keep the amount of foods with vitamin K in your child’s diet about the same from day to day. Many foods have vitamin K in them. This includes some green, leafy vegetables; broccoli; liver; and certain vegetable oils. Get a list of foods that have vitamin K in them from your child’s doctor. Do not make big changes in your child’s normal diet without talking with the doctor.
  • Talk to your child’s doctor before giving your child multivitamins, natural products, and diet aids. These may have vitamin K in them.
  • Have your child’s patient safety card with you at all times.
  • Call the doctor right away if your child has diarrhea, a fever, or an infection.
  • If your child stops or starts smoking, talk with the doctor. How much drug your child takes may need to be changed.
  • If your child is of Asian descent, use this drug with care. Your child could have more side effects.
  • A very bad and sometimes deadly health problem involving the skin (calciphylaxis) has happened with this drug. This has happened in people with and without very bad kidney problems. Talk with the doctor.
  • If your child is or may be sexually active:
  • If your child is of childbearing age, a pregnancy test will need to be done before starting this drug to make sure she is not pregnant.
  • Have your child use birth control to prevent pregnancy while taking this drug and for 1 month after stopping this drug.
  • If your child is pregnant or breast-feeding a baby:
  • This drug may cause harm to the unborn baby if your child takes it during pregnancy.
  • If your child gets pregnant while taking this drug or within 1 month after the last dose, call the doctor right away.
  • Tell the doctor if your child is breast-feeding a baby. You will need to talk about any risks to the baby.
What are some side effects that I need to call my child’s doctor about right away?
  • WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your child’s doctor or get medical help right away if your child has any of the following signs or symptoms that may be related to a very bad side effect:
  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight.
  • Chest pain.
  • Very bad dizziness or passing out.
  • Swelling, warmth, numbness, change of color, or pain in a leg or arm.
  • Very bad headache.
  • Feeling very tired or weak.
  • Swelling.
  • Change in skin color to black or purple.
  • Death of skin tissue may rarely happen. This can lead to loss of the body part (amputation) and can be deadly. Call the doctor right away if your child has pain, color, or temperature change in any part of the body.
  • If your child has kidney problems or has had kidney problems in the past, talk with your child’s doctor. Kidney problems may happen. Call your child’s doctor right away if your child has signs of kidney problems like not able to pass urine, change in how much urine is passed, blood in the urine, or a big weight gain.
What are some other side effects of this drug?
  • All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your child’s doctor or get medical help if your child has any side effects that bother your child or do not go away.
  • These are not all of the side effects that may occur. If you have questions about side effects, call your child’s doctor. Call your child’s doctor for medical advice about side effects.
  • You may report side effects to your national health agency.
How is this drug best given?
  • Give this drug as ordered by your child’s doctor. Read all information given to you. Follow all instructions closely.
  • Give this drug exactly as you have been told, even if your child feels well. This is important for the drug to work right and to lower the risk of bleeding.
  • Give this drug at the same time of day.
  • To gain the most benefit, do not miss giving your child doses.
  • Pregnant women must not handle crushed or broken tablets. Talk with the doctor.
What do I do if my child misses a dose?
  • Give a missed dose as soon as you think about it on the same day your child missed the dose.
  • If it is close to the time for your child’s next dose, skip the missed dose and go back to your child’s normal time.
  • Do not give 2 doses at the same time or extra doses.
  • Do not give more than 1 dose of this drug in the same day.
How do I store and/or throw out this drug?
  • Store at room temperature.
  • Protect from light.
  • Store in a dry place. Do not store in a bathroom.
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Throw away unused or expired drugs. Do not flush down a toilet or pour down a drain unless you are told to do so. Check with your pharmacist if you have questions about the best way to throw out drugs. There may be drug take-back programs in your area.
General drug facts
  • If your child’s symptoms or health problems do not get better or if they become worse, call your child’s doctor.
  • Do not share your child’s drug with others and do not give anyone else’s drug to your child.
  • Keep a list of all your child’s drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your child’s doctor.
  • Talk with your child’s doctor before giving your child any new drug, including prescription or OTC, natural products, or vitamins.
  • Some drugs may have another patient information leaflet. If you have any questions about this drug, please talk with your child’s doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.