Coumadin

Vitamin K Antagonists

Hazardous Drugs Classification
NIOSH 2016 List: Group 3
NIOSH (Draft) 2020 List: Table 2
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Eye/face and respiratory protection may be needed during preparation and administration.

Oral Administration

Administer dose at the same time every day. May be taken with or without food; food decreases the rate but not the extent of absorption.

Severe

ocular hemorrhage / Delayed / 3.0-11.4
intracranial bleeding / Delayed / 0.3-0.3
tissue necrosis / Delayed / 0-0.1
skin necrosis / Delayed / 0-0.1
coma / Early / Incidence not known
exfoliative dermatitis / Delayed / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
retroperitoneal bleeding / Delayed / Incidence not known
GI bleeding / Delayed / Incidence not known
cholesterol microembolization / Early / Incidence not known
purple-toe syndrome / Delayed / Incidence not known
teratogenesis / Delayed / Incidence not known
spontaneous fetal abortion / Delayed / Incidence not known
bone fractures / Delayed / Incidence not known
calciphylaxis / Delayed / Incidence not known

Moderate

bleeding / Early / 6.0-39.0
hypotension / Rapid / Incidence not known
anemia / Delayed / Incidence not known
angina / Early / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
edema / Delayed / Incidence not known
chest pain (unspecified) / Early / Incidence not known
jaundice / Delayed / Incidence not known
hepatitis / Delayed / Incidence not known
hematuria / Delayed / Incidence not known
vaginal bleeding / Delayed / Incidence not known
priapism / Early / Incidence not known

Mild

vomiting / Early / Incidence not known
chills / Rapid / Incidence not known
dysgeusia / Early / Incidence not known
lethargy / Early / Incidence not known
nausea / Early / Incidence not known
diarrhea / Early / Incidence not known
paresthesias / Delayed / Incidence not known
alopecia / Delayed / Incidence not known
asthenia / Delayed / Incidence not known
fatigue / Early / Incidence not known
pallor / Early / Incidence not known
fever / Early / Incidence not known
syncope / Early / Incidence not known
dizziness / Early / Incidence not known
malaise / Early / Incidence not known
flatulence / Early / Incidence not known
epistaxis / Delayed / Incidence not known
petechiae / Delayed / Incidence not known
headache / Early / Incidence not known
ecchymosis / Delayed / Incidence not known
pruritus / Rapid / Incidence not known
maculopapular rash / Early / Incidence not known
urticaria / Rapid / Incidence not known

Anemia, aneurysm, aortic dissection, atrial fibrillation, bleeding, cardiac disease, cerebrovascular disease, eclampsia, endocarditis, epidural anesthesia, GI bleeding, head trauma, hematological disease, hemophilia, hypertension, intracranial bleeding, leukemia, lumbar puncture, neoplastic disease, peptic ulcer disease, pericardial effusion, pericarditis, polycythemia vera, preeclampsia, renal disease, renal failure, renal impairment, retinal bleeding, spinal anesthesia, stroke, surgery, vasculitis

Warfarin can cause major or fatal bleeding. Warfarin is contraindicated in patients with conditions in which therapy with warfarin may result in uncontrolled bleeding including hematological disease; GI bleeding, genitourinary bleeding, respiratory tract bleeding, retinal bleeding, or intracranial bleeding; head trauma; hemorrhagic stroke; aneurysm; aortic dissection; pericarditis or pericardial effusion; bacterial endocarditis; threatened abortion; eclampsia and preeclampsia; recent or planned surgery of the central nervous system, eye, or following trauma that results in large open surfaces; diagnostic or therapeutic procedures with potential for uncontrolled bleeding including epidural anesthesia, spinal anesthesia, spinal puncture and lumbar puncture; and malignant hypertension. Due to the risk of bleeding, warfarin should be used only with extreme caution in patients with hemophilia, leukemia, peptic ulcer disease, and polycythemia vera. Usually, warfarin therapy is stopped 4 to 5 days prior to surgery. In patients with an intermediate- or high-risk for thromboembolism, give either heparin or low molecular weight heparin (LMWH) as the INR falls. Administration of vitamin K 24 to 48 hours prior to surgery will shorten the duration of heparin or LMWH prior to surgery; however, it may make it more difficult to reinstitute warfarin anticoagulations. In situations with a low risk of bleeding, another option is to lower the dose of warfarin and operate at an INR of 1.3 to 1.5. This INR level has shown to be safe in randomized trials of gynecologic and orthopedic surgery patients. A severe elevation (more than 50 seconds) in activated partial thromboplastin time (aPTT) with a PT/INR in the desired range has been identified as a risk factor for postoperative hemorrhage. Warfarin should be used cautiously in the following conditions because bleeding, should it occur, would be extremely serious during warfarin therapy: vasculitis; polyarthritis; moderate to severe hypertension; or indwelling catheters. The risk of major bleeding with warfarin therapy is increased during the drug initiation phase, in patients 65 years of age and older, in patients with highly variable INRs, in patients requiring long-term treatment, in patients with certain genetic polymorphisms of CYP2C9 and/or VKORC1, and in patients with a history of cerebrovascular disease (e.g., stroke), GI bleeding, atrial fibrillation, or in the presence of serious comorbid conditions such as cardiac disease, malignancy (neoplastic disease), renal disease including renal impairment or renal failure, or anemia. An INR more than 4 appears to provide no additional therapeutic benefit in most patients and is associated with a higher risk of bleeding. High-intensity oral anticoagulations (INR 3 to 4.5) is associated with an unacceptable incidence of intracranial hemorrhage when used in patients with cerebral ischemia of presumed arterial origin (e.g., patients with recent TIA or minor ischemic stroke). Acute kidney injury may occur as a result of excessive anticoagulation or hematuria in patients with altered glomerular integrity or a history of renal disease; monitor INR more frequently in this population. Warfarin therapy must be individualized for the patient. Warfarin has a narrow therapeutic range and may be affected by factors such as other drugs, dietary vitamin K, and other disease states. Warfarin dosage should be controlled by periodic monitoring of the INR or other suitable coagulation tests; consideration should be given for more frequent monitoring in patients that have risk factors for major bleeding. Determination of whole blood clotting or bleeding times are not effective measures to monitor warfarin therapy. Monitor INR response and for signs of bleeding during warfarin therapy. ACCP guidelines for managing elevated INR and/or serious bleeding in adult patients are detailed in the dosage section.

Coumadin, Jantoven

Rx

Coumarin anticoagulant
Used to prevent and treat thromboembolic disease
Major hemorrhagic risks have decreased due to the adoption of INR method of monitoring and decreasing the intensity of anticoagulation for most indications; observe for drug interactions

For general dosing information in patients requiring warfarin anticoagulation.
NOTE: Clinical practice guidelines recommend against the routine use of pharmacogenetic testing for guiding dosing in patients initiating warfarin therapy.
Oral dosage Adults without known risks for enhanced INR response to warfarin

2 to 5 mg PO once daily. Typical maintenance doses are 2 to 10 mg PO once daily. Clinical practice guidelines recommend 10 mg PO once daily for the first 2 days for patients healthy enough to be treated as outpatients.

Geriatric, malnourished or debilitated patients, patients with cardiac failure, hepatic insufficiency, or a higher bleeding risk

Initially, 5 mg or less PO may be appropriate to reduce the risk of excessive INR elevation and potential bleeding events.

Adults who have undergone heart valve replacement

Initially, 2 to 3 mg PO may be appropriate to reduce the risk of excessive INR elevation and potential bleeding events. These patients have a higher sensitivity to warfarin probably due to effects of cardiopulmonary bypass and concomitant therapies.

Adults with VKORC1 variant GG and CYP2C9 variant *1/*1 or *1/*2

Initially, 5 to 7 mg PO once daily. Of note, this dose range is the stable maintenance dose observed in multiple patients having this combination of CYP2C9 and VKORC1 gene variants.

Adults with VKORC1 variant GG and CYP2C9 variant *1/*3, *2/*2, or *2/*3

Initially, 3 to 4 mg PO once daily. Of note, this dose range is the stable maintenance dose observed in multiple patients having this combination of CYP2C9 and VKORC1 gene variants. Patients with these CYP2C9 variants may require more prolonged time (more than 2 to 4 weeks) to achieve maximum INR effect for a given dosage regimen.

Adults with VKORC1 variant AG and CYP2C9 variant *1/*1

Initially, 5 to 7 mg PO once daily. Of note, this dose range is the stable maintenance dose observed in multiple patients having this combination of CYP2C9 and VKORC1 gene variants.

Adults with VKORC1 variant AG and CYP2C9 variant *1/*2, *1/*3, or *2/*2

Initially, 3 to 4 mg PO once daily. Of note, this dose range is the stable maintenance dose observed in multiple patients having this combination of CYP2C9 and VKORC1 gene variants. Patients with CYP2C9 *1/*3 or *2/*2 may require more prolonged time (more than 2 to 4 weeks) to achieve maximum INR effect for a given dosage regimen.

Adults with VKORC1 variant AG and CYP2C9 variant *2/*3

Initially, 0.5 to 2 mg PO once daily. Of note, this dose range is the stable maintenance dose observed in multiple patients having this combination of CYP2C9 and VKORC1 gene variants. Patients with this CYP2C9 variant may require more prolonged time (more than 2 to 4 weeks) to achieve maximum INR effect for a given dosage regimen.

Adults with VKORC1 variant AA and CYP2C9 variant *1/*1 or *1/*2

Initially, 3 to 4 mg PO once daily. Of note, this dose range is the stable maintenance dose observed in multiple patients having this combination of CYP2C9 and VKORC1 gene variants.

Adults with VKORC1 variant AA and CYP2C9 variant *1/*3, *2/*2 or *2/*3

Initially, 0.5 to 2 mg PO once daily. Of note, this dose range is the stable maintenance dose observed in multiple patients having this combination of CYP2C9 and VKORC1 gene variants. Patients with these CYP2C9 variants may require more prolonged time (more than 2 to 4 weeks) to achieve maximum INR effect for a given dosage regimen.

Adults with VKORC1 variant AA, AG, or GG and CYP2C9 variant *3/*3

Initially, 0.5 to 2 mg PO once daily. Of note, this dose range is the stable maintenance dose observed in multiple patients having this combination of CYP2C9 and VKORC1 gene variants. Patients with this CYP2C9 variant may require more prolonged time (more than 2 to 4 weeks) to achieve maximum INR effect for a given dosage regimen.

Infants, Children, and Adolescents

Individualize dose to achieve target INR based on indication. The following is recommended to maintain an INR 2 to 3 in pediatric patients: LOADING DOSE: DAY 1 (baseline INR 1 to 1.3): 0.2 mg/kg/dose PO once; reduce to 0.1 mg/kg/dose in patients with Fontan circulation or hepatic impairment. DAYS 2 thru 4: INR 1.1 to 1.3 = repeat initial load; INR 1.4 to 3 = 50% of initial load; INR 3.1 to 3.5 = 25% of initial load; INR more than 3.5 = hold until INR less than 3.5 then restart at 50% of previous dose. MAINTENANCE DOSE: INR 1.1 to 1.4 = increase dose 20%; INR 1.5 to 1.9 = increase dose 10%; INR 2 to 3 = maintain current dose; INR 3.1 to 3.5 = decrease dose 10%; INR more than 3.5 = hold until INR is less than 3.5 then restart at 20% decreased dose. Max dose is not defined; however, most adult patients are maintained on a dose of 2 to 10 mg/day. Weight-based dosage requirements for warfarin have been determined to be age-dependent. In a large cohort of pediatric patients (n = 263), infants required an average daily dose of 0.33 mg/kg while adolescents required an average daily dose of 0.09 mg/kg to maintain the INR between 2 and 3. Specific dosing recommendations for use in pediatric patients are not available in the FDA-approved product labeling; dosage initiation and adjustments must be made carefully to prevent subtherapeutic or excessive anticoagulation.

Neonates

Individualize dose to achieve target INR based on indication. The following is recommended to maintain an INR 2 to 3 in pediatric patients: LOADING DOSE: DAY 1 (baseline INR 1 to 1.3): 0.2 mg/kg/dose PO once; reduce to 0.1 mg/kg/dose in patients with Fontan circulation or hepatic impairment. DAYS 2 thru 4: INR 1.1 to 1.3 = repeat initial load; INR 1.4 to 3 = 50% of initial load; INR 3.1 to 3.5 = 25% of initial load; INR more than 3.5 = hold until INR less than 3.5 then restart at 50% of previous dose. MAINTENANCE DOSE: INR 1.1 to 1.4 = increase dose 20%; INR 1.5 to 1.9 = increase dose 10%; INR 2 to 3 = maintain current dose; INR 3.1 to 3.5 = decrease dose 10%; INR more than 3.5 = hold until INR is less than 3.5 then restart at 20% decreased dose. Max dose is not defined; however, most adult patients are maintained on a dose of 2 to 10 mg/day. Weight-based dosage requirements for warfarin have been determined to be age-dependent. In a large cohort of pediatric patients (n = 263), infants required an average daily dose of 0.33 mg/kg while adolescents required an average daily dose of 0.09 mg/kg to maintain the INR between 2 and 3. Specific dosing recommendations for use in pediatric patients are not available in the FDA-approved product labeling; dosage initiation and adjustments must be made carefully to prevent subtherapeutic or excessive anticoagulation.

For the treatment of deep venous thrombosis (DVT) or pulmonary embolism (PE). Oral dosage Adults 18 to 59 years

2 to 10 mg PO once daily, initially. 10 mg PO once daily for 2 days may initially be considered in persons eligible for outpatient initiation. Adjust dose to maintain INR 2 to 3. Continue therapy for at least 3 months.

Adults 60 years and older

2 to 5 mg PO once daily, initially. 10 mg PO once daily for 2 days may initially be considered in persons eligible for outpatient initiation. Adjust dose to maintain INR 2 to 3. Continue therapy for at least 3 months.

For thrombosis prophylaxis, including arterial thromboembolism prophylaxis, coronary artery thrombosis prophylaxis, deep venous thrombosis (DVT) prophylaxis, pulmonary embolism prophylaxis, or stroke prophylaxis. For coronary artery thrombosis prophylaxis in high or very high-risk persons with stable angina† or chronic coronary artery disease†. Oral dosage Adult males at high-risk for cardiovascular events

Low-intensity warfarin (target INR 1.5) has been recommended in men at high risk of cardiovascular events in the prevention of those events and for reduction of overall mortality.

Adult males at very high-risk for cardiovascular events

The combination of low-dose aspirin (75 to 80 mg/day) and low-intensity warfarin (target INR 1.5) may be considered over either agent alone for the prevention of cardiovascular events and reduction in mortality for men at very high-risk for such events.

For thrombosis prophylaxis in persons with prosthetic heart valves. Oral dosage Adults with bioprosthetic heart valves

Clinical practice guidelines recommend a target INR of 2.5 is recommended for the first 3 months after valve insertion. After 3 months, aspirin 75 to 100 mg PO daily is recommended. Therapy for as long as 6 months may be considered for up to 6 months in patients who have had aortic valve insertion. Patients with risk factors for thromboembolism (e.g., atrial fibrillation) should receive lifelong warfarin therapy.

Adults with mechanical prosthetic mitral valve replacement

Clinical practice guidelines recommend a target INR of 3 (range 2.5 to 3.5) with aspirin 75 to 100 mg PO daily.

Adults with mechanical prosthetic aortic valve replacement and no risk factors for thromboembolism

Clinical practice guidelines recommend a target INR of 2.5 (range 2 to 3) with aspirin 75 to 100 mg PO daily.

Adults with mechanical prosthetic aortic valve replacement and risk factors for thromboembolism

Clinical practice guidelines recommend a target INR of 3 (range 2.5 to 3.5) with aspirin 75 to 100 mg PO daily. Risk factors for thromboembolism include atrial fibrillation, previous thromboembolism, left ventricular dysfunction, hypercoagulable condition or an older generation mechanical aortic valve (e.g., ball-in cage).

Pregnant persons

If possible, avoid the use of warfarin during the first trimester of pregnancy and near term. As an alternative to adjusted-dose heparin or adjusted-dose LMWH throughout the pregnancy, warfarin may be initiated after the thirteenth week of pregnancy. Heparin or LMWH should be resumed close to delivery. In persons who are high risk for thromboembolism (e.g., older generation prosthesis in the mitral position or history of thromboembolism), warfarin may be used throughout the pregnancy and replaced with heparin or LMWH close to delivery; low-dose aspirin is also recommended. Long-term anticoagulation should be resumed postpartum when hemostasis is assured. Other practice guidelines suggest warfarin plus low-dose aspirin may be used during the first trimester in patients who can achieve therapeutic INR with doses of 5 mg/day or less with frequent monitoring and only after full discussion of the risks and benefits of warfarin therapy during the first trimester of pregnancy.

Adults with mechanical prosthetic heart valves and infective endocarditis

Discontinue warfarin therapy at the time of initial presentation until the need for invasive procedures are ruled out and the patient has been stabilized without signs of central nervous system involvement. Warfarin can be reinstituted when the patient is stable and has not contraindications for therapy or neurologic complications.

Children with mechanical prosthetic heart valves

Based on adult data, the recommended target INR is 3 (range 2.5 to 3.5). If systemic embolism occurs despite adequate anticoagulation, add aspirin (6 to 20 mg/day) or dipyridamole (2 to 5 mg/kg/day). When full-dose anticoagulation therapy is contraindicated, long-term therapy with warfarin to a target INR of 2.5 (range 2 to 3) in combination with aspirin (6 to 20 mg/day) and dipyridamole (2 to 5 mg/kg/day) may be used.

For thrombosis prophylaxis in persons with mechanical prosthetic heart valves and a history of bleeding while receiving warfarin therapy. Oral dosage Adults

Every effort should be made to maintain the INR at the lower limit of the therapeutic range (See standard dosage guidelines for prosthetic heart valve patients). For patients with a mechanical prosthetic heart valve and a persistent risk of increased bleeding, the anticoagulant intensity can be reduced to an INR of 2 to 2.5.

For stroke prophylaxis in persons with cerebral venous sinus thrombosis (CVST) after primary treatment with heparin or LMWH. Oral dosage Adults

Target INR of 2.5 (range 2 to 3) for 3 to 6 months has been recommended.

For thrombosis prophylaxis in persons with valvular heart disease. Oral dosage Adults with rheumatic mitral valve disease

Target INR of 2.5 (range 2 to 3) is recommended in patients with a history of systemic embolism or presence of paroxysmal or chronic atrial fibrillation. For patients in normal sinus rhythm and left atrial diameter more than 5.5 cm, consider long-term warfarin (target INR 2.5, range 2 to 3) based on risk factors for thromboembolism. For patients with recurrent systemic embolism despite adequate warfarin therapy, increase INR goal to 3 (range 2.5 to 3.5), or add aspirin (80 to 100 mg/day): for patients unable to take aspirin add dipyridamole (400 mg/day), ticlopidine (250 mg PO twice daily), or clopidogrel (75 mg/day PO).

Adults with mitral valve prolapse and documented systemic embolism, recurrent TIA, chronic or paroxysmal atrial fibrillation despite aspirin

Long-term warfarin therapy (INR target 2.5, range 2 to 3) is recommended.

Adults with mitral annular calcification and systemic embolism not calcified or atrial fibrillation

Long-term warfarin therapy (INR target 2.5, range 2 to 3) is recommended.

Adults with non-rheumatic mitral regurgitation and atrial fibrillation or history of systemic embolism

Long-term warfarin therapy (INR target 2.5, range 2 to 3) is recommended.

Adults with aortic valve and aortic arch disorders

Only in patients with mobile aortic atheroma and aortic plaque more than 4 mm (by TEE) is long-term warfarin therapy (INR target 2.5, range 2 to 3) recommended.

Adults with patent foramen ovale (PFO)or atrial septal aneurysm with unexplained systemic embolism or TIA or documented DVT or PE

Long term warfarin therapy (INR target 2.5, range 2 to 3) is recommended unless venous interruption or PFO closure is considered preferable therapy. In selecting therapy, consider the possibility of paradoxic embolism and systemic embolism from the arterial side of the aneurysm.

For stroke prophylaxis in persons with dilated cardiomyopathy (DCM), particularly in the subgroup of persons with concomitant atrial fibrillation or with a prior history of systemic embolization. Oral dosage Adults

The use of anticoagulation in patients with dilated cardiomyopathy (DCM) is controversial. In patients with concomitant atrial fibrillation or with a prior history of systemic embolization, a target INR of 2 to 3 has been recommended. Not recommended for patients with DCM and no coexisting risk factors.

For secondary myocardial infarction prophylaxis (i.e., prevention of a subsequent myocardial infarction or coronary artery thrombosis prophylaxis) or for stroke prophylaxis in high-risk postmyocardial infarction patients (e.g., persons with acute MI complicated by severe LV dysfunction, CHF, atrial fibrillation, previous emboli, or 2D echocardiograph evidence of mural thrombosis). Oral dosage Adults

The use of warfarin following myocardial infarction (MI) is controversial. After MI, warfarin may be used to reduce the risk of systemic or pulmonary embolism in high-risk patients such as those with anterior Q-wave infarction, AF, severe LV dysfunction, or cardiac failure. The optimal antithrombotic regimen for long-term management in patients post-MI has not been established. Three potential strategies for antithrombotic therapy following MI have been recommended: 1) aspirin alone, 2) aspirin plus moderate-intensity (INR 2 to 3) warfarin, or 3) high-intensity (INR 3 to 4) warfarin alone. The ASPECT-2 study reported reduced cardiovascular events and deaths with high-intensity (INR 3 to 4) warfarin or moderate-intensity (INR 2 to 2.5) warfarin plus aspirin 80 mg/day compared to aspirin alone (80 mg/day). A similar trial, WARIS II, compared warfarin (INR 2.8 to 4.2), aspirin 75 mg/day, or aspirin 75 mg/day plus warfarin (INR 2 to 2.5), initiated at discharge post-MI. Consistent with the ASPECT-2 trial, the WARIS II warfarin regimens are more effective in reducing composite events (death, MI, stroke) vs. aspirin alone, but have a higher rate of bleeding and require greater monitoring. Further study is needed to evaluate other strategies such as aspirin plus low-intensity warfarin (INR less than 2) or monotherapy with moderate intensity warfarin (INR 2 to 3). Previously, in the ASPECT-1 study comparing oral anticoagulation to placebo, patients given anticoagulants were less likely to suffer a recurrent MI; however, since the benefits were not better than studies of aspirin and since the risk of bleeding complications is greater with oral anticoagulants, many clinicians traditionally prescribed aspirin in this setting. Aspirin has been recommended over warfarin for long-term therapy in patients with a low risk of embolism. Warfarin therapy (target INR of 2.5 (range: 2 to 3) for 3 months or less) has been recommended in the clinical setting of increased embolic risk or if aspirin or other anti-platelet therapy is contraindicated. Warfarin should be continued indefinitely in patients with atrial fibrillation. Some patients with recurrent ischemic episodes following acute MI may benefit from a combination of warfarin and aspirin. Treatment with low-dose aspirin and low-intensity warfarin (target INR of 1.5) has been suggested.

For the coronary artery thrombosis prophylaxis in persons with unstable angina†. Oral dosage Adults

Patients who have contraindications to aspirin, ticlopidine, and clopidogrel should receive heparin, followed by warfarin (INR 2 to 3) for a period of several months. Aspirin in combination with therapeutic anticoagulation (heparin for the first 3 to 4 days after the onset of acute unstable angina followed by warfarin for up to 12 weeks) was found to be superior to aspirin alone in 214 patients with unstable angina. In this study, therapy was initiated within a mean of 9.5 hours of qualifying pain and warfarin was dosed to achieve an INR of 2 to 3. NOTE: ACCP guidelines recommend against routine use of warfarin after percutaneous coronary intervention (PCI) unless there is a specific indication for systemic anticoagulation.

For deep vein thrombosis (DVT) prophylaxis or pulmonary embolism prophylaxis in persons undergoing total hip or knee replacement surgery or hip fracture surgery. Oral dosage Adults 18 to 59 years

2 to 10 mg PO once daily, initially. 10 mg PO once daily for 2 days may initially be considered in persons eligible for outpatient initiation. Adjust dose to maintain INR 2 to 3. Continue prophylaxis for at least 10 to 14 days; up to 35 days is recommended. Guidelines recommend warfarin as an alternative to the preferred agent, low molecular weight heparin, as antithrombotic prophylaxis for patients undergoing total hip or total knee replacement surgery or hip fracture surgery.

Adults 60 years and older

2 to 5 mg PO once daily, initially. 10 mg PO once daily for 2 days may initially be considered in persons eligible for outpatient initiation. Adjust dose to maintain INR 2 to 3. Continue prophylaxis for at least 10 to 14 days; up to 35 days is recommended. Guidelines recommend warfarin as an alternative to the preferred agent, low molecular weight heparin, as antithrombotic prophylaxis for patients undergoing total hip or total knee replacement surgery or hip fracture surgery.

For deep vein thrombosis (DVT) prophylaxis or pulmonary embolism prophylaxis. Oral dosage Adults 18 to 59 years

2 to 10 mg PO once daily, initially. 10 mg PO once daily for 2 days may initially be considered in persons eligible for outpatient initiation. Adjust dose to maintain INR 2 to 3. For patients receiving long-term anticoagulant therapy, periodically reassess risks versus benefits of continued therapy.

Adults 60 years and older

2 to 5 mg PO once daily, initially. 10 mg PO once daily for 2 days may initially be considered in persons eligible for outpatient initiation. Adjust dose to maintain INR 2 to 3. For patients receiving long-term anticoagulant therapy, periodically reassess risks versus benefits of continued therapy.

For the treatment of arterial or venous thromboembolism associated with antiphospholipid antibody syndrome. Oral dosage Adults 18 to 59 years

10 mg PO once daily for 2 days, initially for young otherwise healthy adults. Adjust dose to maintain INR 2 to 3.

Adults 60 years and older

5 mg PO once daily for 2 days, initially for most patients. Adjust dose to maintain INR 2 to 3.

For thromboprophylaxis† in patients with heart failure† who are in sinus rhythm. Oral dosage Adults

Dosage not established. Oral dosing to maintain a target INR of 2 to 3.5 has been studied. Warfarin use in patients with heart failure in sinus rhythm is not associated with a reduction in thromboembolism and can result in major hemorrhage.

For stroke and systemic embolism prophylaxis in nonvalvular atrial fibrillation, valvular atrial fibrillation, and atrial fibrillation or atrial flutter† in persons undergoing cardioversion. For stroke and systemic embolism prophylaxis in nonvalvular atrial fibrillation. Oral dosage Adults 18 to 59 years

2 to 10 mg PO once daily, initially for young, otherwise healthy adults. 10 mg PO once daily for 2 days may initially be considered in persons eligible for outpatient initiation. Adjust dose to maintain INR 2 to 3. Time in therapeutic range goal of at least 70% is associated with improved outcomes. For eligible persons, direct oral anticoagulants are preferred over warfarin therapy.

Adults 60 years and older

2 to 5 mg PO once daily, initially. 10 mg PO once daily for 2 days may initially be considered in persons eligible for outpatient initiation. Adjust dose to maintain INR 2 to 3. Time in therapeutic range goal of at least 70% is associated with improved outcomes. For eligible persons, direct oral anticoagulants (i.e., apixaban, dabigatran, edoxaban, rivaroxaban) are preferred over warfarin therapy.

For stroke and systemic embolism prophylaxis in valvular atrial fibrillation (e.g., persons with valvular heart disease, mechanical valves, prosthetic valves). Oral dosage Adults 18 to 59 years

2 to 10 mg PO once daily, initially for young, otherwise healthy adults. 10 mg PO once daily for 2 days may initially be considered in persons eligible for outpatient initiation. Adjust dose to maintain INR 2 to 3 for persons with rheumatic mitral stenosis or moderate to severe mitral stenosis and 2.5 to 3.5 for persons with mechanical heart valves. Time in therapeutic range goal of at least 70% is associated with improved outcomes.

Adults 60 years and older

2 to 5 mg PO once daily, initially. 10 mg PO once daily for 2 days may initially be considered in persons eligible for outpatient initiation. Adjust dose to maintain INR 2 to 3 for persons with rheumatic mitral stenosis or moderate to severe mitral stenosis and 2.5 to 3.5 for persons with mechanical heart valves. Time in therapeutic range goal of at least 70% is associated with improved outcomes.

For stroke and systemic embolism prophylaxis in persons with atrial fibrillation or atrial flutter† who are undergoing cardioversion. Oral dosage Adults 18 to 59 years

2 to 10 mg PO once daily, initially for young, otherwise healthy adults. 10 mg PO once daily for 2 days may initially be considered in persons eligible for outpatient initiation. Adjust dose to maintain INR 2 to 3 for 3 weeks before and 4 weeks or more after cardioversion in persons with atrial fibrillation or atrial flutter of 48 hours duration or longer who do not require immediate cardioversion. Time in therapeutic range goal of at least 70% is associated with improved outcomes.

Adults 60 years and older

2 to 5 mg PO once daily, initially. 10 mg PO once daily for 2 days may initially be considered in persons eligible for outpatient initiation. Adjust dose to maintain INR 2 to 3 for 3 weeks before and 4 weeks or more after cardioversion in persons with atrial fibrillation or atrial flutter of 48 hours duration or longer who do not require immediate cardioversion. Time in therapeutic range goal of at least 70% is associated with improved outcomes.

†Indicates off-label use

Hepatic Impairment

Although specific guidelines for dosage adjustment are not available, patients with hepatic impairment may require a lower dosage of warfarin due to decreased warfarin metabolism and decreased production of coagulation factors.

Renal Impairment

No dosage adjustment is necessary in patients with renal failure. Monitor INR more frequently in those with renal impairment to maintain the therapeutic range.

Abciximab: (Moderate) The use of abciximab within 7 days of use an oral anticoagulant is contraindicated unless the patient's prothrombin time is less than or equal to 1.2 times the control value. Because abciximab inhibits platelet aggregation, additive effects may be seen when abciximab is given in combination with other agents that affect hemostasis such as other platelet inhibitors (e.g., aspirin, ASA, clopidogrel, dipyridamole, ticlopidine), thrombolytic agents (e.g., alteplase, reteplase, streptokinase), and anticoagulants (e.g., heparin, warfarin). However, in clinical trials with abciximab, aspirin and heparin were administered concomitantly. The bleeding risk is significantly increased with concurrent abciximab and thrombolytic therapy; the risks of combination therapy should be weighed against the potential benefits. The GUSTO V study evaluated reduced-dose reteplase in combination with full dose abciximab, in comparison to full dose reteplase alone in patients with acute myocardial infarction (MI); all patients received concurrent aspirin and heparin therapy. The combination regimen was associated with a two-fold increase in moderate to severe non-intracranial bleeding complications, including spontaneous GI bleeding. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Although NSAIDs lacks platelet inhibitory effects, an increased risk for GI bleeding is possible when NSAIDs are administered during abciximab therapy.
Acarbose: (Minor) One case report of an interaction between warfarin and acarbose has been published. The addition of acarbose at a dosage of 25 mg three times per day resulted in an increased INR of 4.85 within two weeks. INRs should be closely observed during the first month of acarbose or miglitol therapy.
Acetaminophen: (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
Acetaminophen; Aspirin, ASA; Caffeine: (Major) Co-administration of aspirin and warfarin is associated with an increased risk of bleeding. Consider alternate therapy for aspirin for analgesic or antipyretic uses. If aspirin and warfarin are coadministered, monitor the patient for signs or symptoms of bleeding. Gastrointestinal irritation and impaired hemostasis secondary to platelet inhibition have been observed with relatively small doses of aspirin. In addition, aspirin may displace warfarin from protein binding sites leading to increased anticoagulation effects. Large doses (more than 3 to 4 g/day) of aspirin can cause hypoprothrombinemia, an additional risk factor for bleeding; hypoprothrombinemia has also been reported with aspirin doses less than 2 g/day. Lower doses (less than 100 mg) of aspirin are recommended for use in combination with aspirin for the prevention of cardiovascular events in specific cases, including in patients with mechanical mitral or aortic valve or atrial fibrillation after percutaneous coronary intervention or revascularization. The addition of warfarin to aspirin and a P2Y12 inhibitor in patients after ST-elevation myocardial infarction should be limited to situations where the risk of systemic or venous thromboembolism or stent thrombosis is considered to exceed that of bleeding. Data regarding the benefit vs. risk of combination therapy for other cardiovascular conditions remains unclear. (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
Acetaminophen; Aspirin: (Major) Co-administration of aspirin and warfarin is associated with an increased risk of bleeding. Consider alternate therapy for aspirin for analgesic or antipyretic uses. If aspirin and warfarin are coadministered, monitor the patient for signs or symptoms of bleeding. Gastrointestinal irritation and impaired hemostasis secondary to platelet inhibition have been observed with relatively small doses of aspirin. In addition, aspirin may displace warfarin from protein binding sites leading to increased anticoagulation effects. Large doses (more than 3 to 4 g/day) of aspirin can cause hypoprothrombinemia, an additional risk factor for bleeding; hypoprothrombinemia has also been reported with aspirin doses less than 2 g/day. Lower doses (less than 100 mg) of aspirin are recommended for use in combination with aspirin for the prevention of cardiovascular events in specific cases, including in patients with mechanical mitral or aortic valve or atrial fibrillation after percutaneous coronary intervention or revascularization. The addition of warfarin to aspirin and a P2Y12 inhibitor in patients after ST-elevation myocardial infarction should be limited to situations where the risk of systemic or venous thromboembolism or stent thrombosis is considered to exceed that of bleeding. Data regarding the benefit vs. risk of combination therapy for other cardiovascular conditions remains unclear. (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
Acetaminophen; Aspirin; Diphenhydramine: (Major) Co-administration of aspirin and warfarin is associated with an increased risk of bleeding. Consider alternate therapy for aspirin for analgesic or antipyretic uses. If aspirin and warfarin are coadministered, monitor the patient for signs or symptoms of bleeding. Gastrointestinal irritation and impaired hemostasis secondary to platelet inhibition have been observed with relatively small doses of aspirin. In addition, aspirin may displace warfarin from protein binding sites leading to increased anticoagulation effects. Large doses (more than 3 to 4 g/day) of aspirin can cause hypoprothrombinemia, an additional risk factor for bleeding; hypoprothrombinemia has also been reported with aspirin doses less than 2 g/day. Lower doses (less than 100 mg) of aspirin are recommended for use in combination with aspirin for the prevention of cardiovascular events in specific cases, including in patients with mechanical mitral or aortic valve or atrial fibrillation after percutaneous coronary intervention or revascularization. The addition of warfarin to aspirin and a P2Y12 inhibitor in patients after ST-elevation myocardial infarction should be limited to situations where the risk of systemic or venous thromboembolism or stent thrombosis is considered to exceed that of bleeding. Data regarding the benefit vs. risk of combination therapy for other cardiovascular conditions remains unclear. (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
Acetaminophen; Caffeine: (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
Acetaminophen; Caffeine; Dihydrocodeine: (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
Acetaminophen; Caffeine; Pyrilamine: (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
Acetaminophen; Chlorpheniramine: (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
Acetaminophen; Codeine: (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
Acetaminophen; Dextromethorphan: (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
Acetaminophen; Dextromethorphan; Doxylamine: (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
Acetaminophen; Dextromethorphan; Phenylephrine: (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
Acetaminophen; Dextromethorphan; Pseudoephedrine: (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
Acetaminophen; Dichloralphenazone; Isometheptene: (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
Acetaminophen; Diphenhydramine: (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
Acetaminophen; Guaifenesin; Phenylephrine: (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
Acetaminophen; Hydrocodone: (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
Acetaminophen; Ibuprofen: (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs). To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients. (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
Acetaminophen; Oxycodone: (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
Acetaminophen; Pamabrom; Pyrilamine: (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
Acetaminophen; Phenylephrine: (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
Acetaminophen; Pseudoephedrine: (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
Acyclovir: (Moderate) Closely monitor the INR if coadministration of warfarin with acyclovir is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. The R-enantiomer of warfarin is a CYP1A2 substrate and acyclovir is a CYP1A2 inhibitor. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Adagrasib: (Moderate) Closely monitor the INR if coadministration of warfarin with adagrasib is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Warfarin is a CYP3A and CYP2C9 substrate and adagrasib is a strong CYP3A and moderate CYP2C9 inhibitor. Concomitant use of adagrasib 600 mg twice daily is predicted to increase warfarin overall exposure by 2.9-fold.
Ado-Trastuzumab emtansine: (Moderate) Use caution if coadministration of anticoagulants with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
Aliskiren: (Minor) Coadministration of warfarin with aliskrien decreases the absorption (Cmax) of warfarin by up to 12%. During clinical evaluation, coadministration did not reveal any significant effect on blood coagulation parameters in tested blood samples. Nevertheless, blood coagulation markers should be closely monitored in patients taking both of these medications.
Aliskiren; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of warfarin with aliskrien decreases the absorption (Cmax) of warfarin by up to 12%. During clinical evaluation, coadministration did not reveal any significant effect on blood coagulation parameters in tested blood samples. Nevertheless, blood coagulation markers should be closely monitored in patients taking both of these medications.
Allopurinol: (Moderate) Closely monitor the INR if coadministration of warfarin with allopurinol is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. The R-enantiomer of warfarin is a CYP1A2 substrate and allopurinol is a CYP1A2 inhibitor. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Alpelisib: (Moderate) Closely monitor the INR if coadministration of warfarin with alpelisib is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Alpelisib is a weak CYP2C9 inducer and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Alteplase: (Contraindicated) Based on the pharmacology of warfarin, other thrombolytic agents could cause additive risk of bleeding when given concurrently with warfarin. Pre-treatment with oral anticoagulants is reported to be an independent risk factor for intracranial hemorrhage in thrombolytic-treated patients. Prothrombin times stabilized during administration of both agents will change slightly when heparin is discontinued.
Altretamine: (Moderate) Due to the thrombocytopenic effects of altretamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
Amikacin: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including aminoglycosides, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Amiloride: (Minor) Per the prescribing information for warfarin sodium, concomitant use of diuretics (carbonic anhydrase inhibitors, loop diuretics, osmotic diuretics, potassium-sparing diuretics, and thiazide diuretics) and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed.
Amiloride; Hydrochlorothiazide, HCTZ: (Minor) Per the prescribing information for warfarin sodium, concomitant use of diuretics (carbonic anhydrase inhibitors, loop diuretics, osmotic diuretics, potassium-sparing diuretics, and thiazide diuretics) and warfarin may result in an increased or decreased PT/INR. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed.
Amiodarone: (Major) Closely monitor the INR if coadministration of warfarin with amiodarone is necessary as concurrent use results in at least a doubling of prothrombin time, significantly increasing the INR in virtually all patients and can cause serious or potentially fatal hemorrhagic complications. Consider an empiric 33% to 50% reduction in warfarin dosage when amiodarone therapy is initiated. Intensive clinical observation for bleeding and frequent determination of PT and INR values are warranted. Amiodarone is a moderate CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate. Amiodarone is also a CYP3A4/CYP1A2 inhibitor, and the R-enantiomer is a CYP3A4/CYP1A2 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. Interactions may be seen as early as 4 to 6 days or as delayed as weeks following the initial administration of the drugs in combination. Given the extremely long half-life of amiodarone, the interaction may persist for weeks or even months after discontinuation of amiodarone.
Amlodipine: (Moderate) Closely monitor the INR if coadministration of warfarin with amlodipine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Amlodipine is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Amlodipine; Atorvastatin: (Moderate) Closely monitor the INR if coadministration of warfarin with amlodipine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Amlodipine is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. (Moderate) Per the manufacturer of atorvastatin, a clinically significant effect on the prothrombin time when atorvastatin is administered to patients receiving chronic warfarin therapy has not been documented. In a study by the manufacturer, patients chronically maintained on warfarin were administered atorvastatin (80 mg/day) for 2 weeks. Mean prothrombin times decreased slightly, but only for the first few days of treatment. Per prescribing information for warfarin sodium (Coumadin), however, all HMG-CoA reductase inhibitors (statins), including atorvastatin, have been associated with potentiation of warfarin's clinical effect. In patients taking atorvastatin, it may be prudent to monitor the INR at baseline, at initiation of atorvastatin, and after subsequent dosage changes. Adjust warfarin dosage based on INR and clinical response. Once a stable INR is documented, the INR can be monitored at the intervals otherwise recommended based on the indication for anticoagulation and co-existing conditions.
Amlodipine; Benazepril: (Moderate) Closely monitor the INR if coadministration of warfarin with amlodipine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Amlodipine is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Amlodipine; Celecoxib: (Moderate) Closely monitor the INR if coadministration of warfarin with amlodipine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Amlodipine is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs). To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients.
Amlodipine; Olmesartan: (Moderate) Closely monitor the INR if coadministration of warfarin with amlodipine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Amlodipine is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Amlodipine; Valsartan: (Moderate) Closely monitor the INR if coadministration of warfarin with amlodipine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Amlodipine is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Closely monitor the INR if coadministration of warfarin with amlodipine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Amlodipine is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Amobarbital: (Moderate) Closely monitor the INR if coadministration of warfarin with barbiturates is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Barbiturates are CYP1A2 and moderate CYP2C9/CYP3A4 inducers and warfarin's enantiomers are substrates of CYP1A2/CYP2C9/CYP3A4. Discontinuation of a barbiturate during warfarin therapy has led to fatal bleeding episodes when the hepatic enzyme-inducing properties of the barbiturate subside. Clinicians should note that warfarin doses will require readjustment if a barbiturate is added or discontinued during warfarin therapy. Dosage adjustments of warfarin may be necessary within 2 weeks of beginning barbiturate treatment, but the effect of the barbiturate on warfarin metabolism may persist for more than a month after discontinuing the barbiturate.
Amoxicillin: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Closely monitor the INR if coadministration of warfarin with clarithromycin is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Clarithromycin is a strong CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. (Moderate) The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Amoxicillin; Clavulanic Acid: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Ampicillin: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Ampicillin; Sulbactam: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Anagrelide: (Moderate) Closely monitor the INR if coadministration of warfarin with anagrelide is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Anagrelide is a CYP1A2 inhibitor and the R-enantiomer of warfarin is a CYP1A2 substrate. Since anagrelide inhibits platelet aggregation at high doses, additive risk for bleeding is possible when anagrelide is given in combination with anticoagulants such as warfarin. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Antithrombin III: (Major) As a regulator of hemostasis, antithrombin III (AT III) may increase bleeding risk in patients receiving warfarin concomitantly. The half-life of AT III may be altered during concomitant administration with anticoagulants. Patients should be monitored for appropriate anticoagulation during coadministration of AT III and coumarin anticoagulants.
Apalutamide: (Moderate) Closely monitor the INR if coadministration of warfarin with apalutamide is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Apalutamide is a weak CYP2C9 and strong CYP3A4 inducer and the enantiomers of warfarin are CYP2C9/CYP3A4 substrates.
Apixaban: (Major) Avoid concomitant use of apixaban and with other anticoagulants due to the increased risk for bleeding. Short-term overlaps in anticoagulation therapy may be necessary for patients transitioning from one anticoagulant to another. Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if the use of multiple anticoagulants is necessary. Additionally, apixaban may increase INR.
Aprepitant, Fosaprepitant: (Moderate) INR should be closely monitored during the 2-week period (particularly at 7 to 10 days) after the initiation of an aprepitant or fosaprepitant dosage regimen cycle, regardless of the indication or dose. An increase or decrease in the exposure of warfarin is possible, leading to an increase in the risk of bleeding or reduction in efficacy. Aprepitant and fosaprepitant are weak inducers of CYP2C9 and warfarin is a CYP2C9 substrate. Coadministration may result in a decrease in warfarin exposure leading to reduced efficacy. Studies have noted a 34% decrease in S-warfarin trough concentrations, accompanied by a 14% decrease in the INR at 5 days after completion of a 3-day regimen of aprepitant (125 mg/80 mg/80 mg) given to healthy patients on stabilized chronic warfarin therapy, although there was no effect on the plasma AUC of R(+) or S(-) warfarin. Additionally, aprepitant and fosaprepitant are moderate CYP3A4 inhibitors and warfarin is a CYP3A4 substrate. This may increase warfarin exposure leading to increased risk of bleeding.
Argatroban: (Major) An additive risk of bleeding may be seen in patients receiving other anticoagulants (e.g., heparin, warfarin) in combination with argatroban.
Armodafinil: (Moderate) Closely monitor the INR if coadministration of warfarin with armodafinil is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Armodafinil is a weak CYP3A4 inducer and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Asciminib: (Moderate) Closely monitor the INR if coadministration of warfarin with asciminib is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. The active metabolite of warfarin, the S-enantiomer, is a CYP2C9 substrate and asciminib is a CYP2C9 inhibitor. Coadministration of warfarin with asciminib 40 mg twice daily, 80 mg once daily, and 200 mg twice daily increased the exposure of S-warfarin by 41%,52% and 314%, respectively. Additionally, the R-enantiomer of warfarin is a CYP3A substrate and asciminib is a weak CYP3A inhibitor. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Ascorbic Acid, Vitamin C: (Minor) Monitor INR as per current standards of care when patients take vitamin C with warfarin. Limited case reports have suggested that high doses of ascorbic acid with warfarin may decrease the anticoagulation effects of warfarin. However, controlled studies have not confirmed an interaction. No effect was observed in patients on warfarin therapy treated with ascorbic acid doses up to 1,000 mg/day for 2 weeks.
Aspirin, ASA: (Major) Co-administration of aspirin and warfarin is associated with an increased risk of bleeding. Consider alternate therapy for aspirin for analgesic or antipyretic uses. If aspirin and warfarin are coadministered, monitor the patient for signs or symptoms of bleeding. Gastrointestinal irritation and impaired hemostasis secondary to platelet inhibition have been observed with relatively small doses of aspirin. In addition, aspirin may displace warfarin from protein binding sites leading to increased anticoagulation effects. Large doses (more than 3 to 4 g/day) of aspirin can cause hypoprothrombinemia, an additional risk factor for bleeding; hypoprothrombinemia has also been reported with aspirin doses less than 2 g/day. Lower doses (less than 100 mg) of aspirin are recommended for use in combination with aspirin for the prevention of cardiovascular events in specific cases, including in patients with mechanical mitral or aortic valve or atrial fibrillation after percutaneous coronary intervention or revascularization. The addition of warfarin to aspirin and a P2Y12 inhibitor in patients after ST-elevation myocardial infarction should be limited to situations where the risk of systemic or venous thromboembolism or stent thrombosis is considered to exceed that of bleeding. Data regarding the benefit vs. risk of combination therapy for other cardiovascular conditions remains unclear.
Aspirin, ASA; Butalbital; Caffeine: (Major) Co-administration of aspirin and warfarin is associated with an increased risk of bleeding. Consider alternate therapy for aspirin for analgesic or antipyretic uses. If aspirin and warfarin are coadministered, monitor the patient for signs or symptoms of bleeding. Gastrointestinal irritation and impaired hemostasis secondary to platelet inhibition have been observed with relatively small doses of aspirin. In addition, aspirin may displace warfarin from protein binding sites leading to increased anticoagulation effects. Large doses (more than 3 to 4 g/day) of aspirin can cause hypoprothrombinemia, an additional risk factor for bleeding; hypoprothrombinemia has also been reported with aspirin doses less than 2 g/day. Lower doses (less than 100 mg) of aspirin are recommended for use in combination with aspirin for the prevention of cardiovascular events in specific cases, including in patients with mechanical mitral or aortic valve or atrial fibrillation after percutaneous coronary intervention or revascularization. The addition of warfarin to aspirin and a P2Y12 inhibitor in patients after ST-elevation myocardial infarction should be limited to situations where the risk of systemic or venous thromboembolism or stent thrombosis is considered to exceed that of bleeding. Data regarding the benefit vs. risk of combination therapy for other cardiovascular conditions remains unclear. (Moderate) Closely monitor the INR if coadministration of warfarin with barbiturates is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Barbiturates are CYP1A2 and moderate CYP2C9/CYP3A4 inducers and warfarin's enantiomers are substrates of CYP1A2/CYP2C9/CYP3A4. Discontinuation of a barbiturate during warfarin therapy has led to fatal bleeding episodes when the hepatic enzyme-inducing properties of the barbiturate subside. Clinicians should note that warfarin doses will require readjustment if a barbiturate is added or discontinued during warfarin therapy. Dosage adjustments of warfarin may be necessary within 2 weeks of beginning barbiturate treatment, but the effect of the barbiturate on warfarin metabolism may persist for more than a month after discontinuing the barbiturate.
Aspirin, ASA; Caffeine: (Major) Co-administration of aspirin and warfarin is associated with an increased risk of bleeding. Consider alternate therapy for aspirin for analgesic or antipyretic uses. If aspirin and warfarin are coadministered, monitor the patient for signs or symptoms of bleeding. Gastrointestinal irritation and impaired hemostasis secondary to platelet inhibition have been observed with relatively small doses of aspirin. In addition, aspirin may displace warfarin from protein binding sites leading to increased anticoagulation effects. Large doses (more than 3 to 4 g/day) of aspirin can cause hypoprothrombinemia, an additional risk factor for bleeding; hypoprothrombinemia has also been reported with aspirin doses less than 2 g/day. Lower doses (less than 100 mg) of aspirin are recommended for use in combination with aspirin for the prevention of cardiovascular events in specific cases, including in patients with mechanical mitral or aortic valve or atrial fibrillation after percutaneous coronary intervention or revascularization. The addition of warfarin to aspirin and a P2Y12 inhibitor in patients after ST-elevation myocardial infarction should be limited to situations where the risk of systemic or venous thromboembolism or stent thrombosis is considered to exceed that of bleeding. Data regarding the benefit vs. risk of combination therapy for other cardiovascular conditions remains unclear.
Aspirin, ASA; Caffeine; Orphenadrine: (Major) Co-administration of aspirin and warfarin is associated with an increased risk of bleeding. Consider alternate therapy for aspirin for analgesic or antipyretic uses. If aspirin and warfarin are coadministered, monitor the patient for signs or symptoms of bleeding. Gastrointestinal irritation and impaired hemostasis secondary to platelet inhibition have been observed with relatively small doses of aspirin. In addition, aspirin may displace warfarin from protein binding sites leading to increased anticoagulation effects. Large doses (more than 3 to 4 g/day) of aspirin can cause hypoprothrombinemia, an additional risk factor for bleeding; hypoprothrombinemia has also been reported with aspirin doses less than 2 g/day. Lower doses (less than 100 mg) of aspirin are recommended for use in combination with aspirin for the prevention of cardiovascular events in specific cases, including in patients with mechanical mitral or aortic valve or atrial fibrillation after percutaneous coronary intervention or revascularization. The addition of warfarin to aspirin and a P2Y12 inhibitor in patients after ST-elevation myocardial infarction should be limited to situations where the risk of systemic or venous thromboembolism or stent thrombosis is considered to exceed that of bleeding. Data regarding the benefit vs. risk of combination therapy for other cardiovascular conditions remains unclear.
Aspirin, ASA; Carisoprodol: (Major) Co-administration of aspirin and warfarin is associated with an increased risk of bleeding. Consider alternate therapy for aspirin for analgesic or antipyretic uses. If aspirin and warfarin are coadministered, monitor the patient for signs or symptoms of bleeding. Gastrointestinal irritation and impaired hemostasis secondary to platelet inhibition have been observed with relatively small doses of aspirin. In addition, aspirin may displace warfarin from protein binding sites leading to increased anticoagulation effects. Large doses (more than 3 to 4 g/day) of aspirin can cause hypoprothrombinemia, an additional risk factor for bleeding; hypoprothrombinemia has also been reported with aspirin doses less than 2 g/day. Lower doses (less than 100 mg) of aspirin are recommended for use in combination with aspirin for the prevention of cardiovascular events in specific cases, including in patients with mechanical mitral or aortic valve or atrial fibrillation after percutaneous coronary intervention or revascularization. The addition of warfarin to aspirin and a P2Y12 inhibitor in patients after ST-elevation myocardial infarction should be limited to situations where the risk of systemic or venous thromboembolism or stent thrombosis is considered to exceed that of bleeding. Data regarding the benefit vs. risk of combination therapy for other cardiovascular conditions remains unclear.
Aspirin, ASA; Carisoprodol; Codeine: (Major) Co-administration of aspirin and warfarin is associated with an increased risk of bleeding. Consider alternate therapy for aspirin for analgesic or antipyretic uses. If aspirin and warfarin are coadministered, monitor the patient for signs or symptoms of bleeding. Gastrointestinal irritation and impaired hemostasis secondary to platelet inhibition have been observed with relatively small doses of aspirin. In addition, aspirin may displace warfarin from protein binding sites leading to increased anticoagulation effects. Large doses (more than 3 to 4 g/day) of aspirin can cause hypoprothrombinemia, an additional risk factor for bleeding; hypoprothrombinemia has also been reported with aspirin doses less than 2 g/day. Lower doses (less than 100 mg) of aspirin are recommended for use in combination with aspirin for the prevention of cardiovascular events in specific cases, including in patients with mechanical mitral or aortic valve or atrial fibrillation after percutaneous coronary intervention or revascularization. The addition of warfarin to aspirin and a P2Y12 inhibitor in patients after ST-elevation myocardial infarction should be limited to situations where the risk of systemic or venous thromboembolism or stent thrombosis is considered to exceed that of bleeding. Data regarding the benefit vs. risk of combination therapy for other cardiovascular conditions remains unclear.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Major) Co-administration of aspirin and warfarin is associated with an increased risk of bleeding. Consider alternate therapy for aspirin for analgesic or antipyretic uses. If aspirin and warfarin are coadministered, monitor the patient for signs or symptoms of bleeding. Gastrointestinal irritation and impaired hemostasis secondary to platelet inhibition have been observed with relatively small doses of aspirin. In addition, aspirin may displace warfarin from protein binding sites leading to increased anticoagulation effects. Large doses (more than 3 to 4 g/day) of aspirin can cause hypoprothrombinemia, an additional risk factor for bleeding; hypoprothrombinemia has also been reported with aspirin doses less than 2 g/day. Lower doses (less than 100 mg) of aspirin are recommended for use in combination with aspirin for the prevention of cardiovascular events in specific cases, including in patients with mechanical mitral or aortic valve or atrial fibrillation after percutaneous coronary intervention or revascularization. The addition of warfarin to aspirin and a P2Y12 inhibitor in patients after ST-elevation myocardial infarction should be limited to situations where the risk of systemic or venous thromboembolism or stent thrombosis is considered to exceed that of bleeding. Data regarding the benefit vs. risk of combination therapy for other cardiovascular conditions remains unclear.
Aspirin, ASA; Dipyridamole: (Major) Co-administration of aspirin and warfarin is associated with an increased risk of bleeding. Consider alternate therapy for aspirin for analgesic or antipyretic uses. If aspirin and warfarin are coadministered, monitor the patient for signs or symptoms of bleeding. Gastrointestinal irritation and impaired hemostasis secondary to platelet inhibition have been observed with relatively small doses of aspirin. In addition, aspirin may displace warfarin from protein binding sites leading to increased anticoagulation effects. Large doses (more than 3 to 4 g/day) of aspirin can cause hypoprothrombinemia, an additional risk factor for bleeding; hypoprothrombinemia has also been reported with aspirin doses less than 2 g/day. Lower doses (less than 100 mg) of aspirin are recommended for use in combination with aspirin for the prevention of cardiovascular events in specific cases, including in patients with mechanical mitral or aortic valve or atrial fibrillation after percutaneous coronary intervention or revascularization. The addition of warfarin to aspirin and a P2Y12 inhibitor in patients after ST-elevation myocardial infarction should be limited to situations where the risk of systemic or venous thromboembolism or stent thrombosis is considered to exceed that of bleeding. Data regarding the benefit vs. risk of combination therapy for other cardiovascular conditions remains unclear. (Moderate) Because dipyridamole is a platelet inhibitor, there is a potential additive risk for bleeding if dipyridamole is given in combination with other agents that affect hemostasis. Per the manufacturer, dipyridamole does not influence prothrombin time or activity when administered with warfarin; bleeding frequency and severity are similar when dipyridamole is administered with or without warfarin. In rare cases, however, increased bleeding has been observed during or after surgery. Regardless, caution is advised as both anticoagulants including warfarin and platelet inhibitors such as dipyridamole affect hemostasis and combination therapy could increase the risk of bleeding.
Aspirin, ASA; Omeprazole: (Major) Co-administration of aspirin and warfarin is associated with an increased risk of bleeding. Consider alternate therapy for aspirin for analgesic or antipyretic uses. If aspirin and warfarin are coadministered, monitor the patient for signs or symptoms of bleeding. Gastrointestinal irritation and impaired hemostasis secondary to platelet inhibition have been observed with relatively small doses of aspirin. In addition, aspirin may displace warfarin from protein binding sites leading to increased anticoagulation effects. Large doses (more than 3 to 4 g/day) of aspirin can cause hypoprothrombinemia, an additional risk factor for bleeding; hypoprothrombinemia has also been reported with aspirin doses less than 2 g/day. Lower doses (less than 100 mg) of aspirin are recommended for use in combination with aspirin for the prevention of cardiovascular events in specific cases, including in patients with mechanical mitral or aortic valve or atrial fibrillation after percutaneous coronary intervention or revascularization. The addition of warfarin to aspirin and a P2Y12 inhibitor in patients after ST-elevation myocardial infarction should be limited to situations where the risk of systemic or venous thromboembolism or stent thrombosis is considered to exceed that of bleeding. Data regarding the benefit vs. risk of combination therapy for other cardiovascular conditions remains unclear.
Aspirin, ASA; Oxycodone: (Major) Co-administration of aspirin and warfarin is associated with an increased risk of bleeding. Consider alternate therapy for aspirin for analgesic or antipyretic uses. If aspirin and warfarin are coadministered, monitor the patient for signs or symptoms of bleeding. Gastrointestinal irritation and impaired hemostasis secondary to platelet inhibition have been observed with relatively small doses of aspirin. In addition, aspirin may displace warfarin from protein binding sites leading to increased anticoagulation effects. Large doses (more than 3 to 4 g/day) of aspirin can cause hypoprothrombinemia, an additional risk factor for bleeding; hypoprothrombinemia has also been reported with aspirin doses less than 2 g/day. Lower doses (less than 100 mg) of aspirin are recommended for use in combination with aspirin for the prevention of cardiovascular events in specific cases, including in patients with mechanical mitral or aortic valve or atrial fibrillation after percutaneous coronary intervention or revascularization. The addition of warfarin to aspirin and a P2Y12 inhibitor in patients after ST-elevation myocardial infarction should be limited to situations where the risk of systemic or venous thromboembolism or stent thrombosis is considered to exceed that of bleeding. Data regarding the benefit vs. risk of combination therapy for other cardiovascular conditions remains unclear.
Atazanavir: (Moderate) Monitor the INR and adjust the dose as necessary if warfarin is coadministered with atazanavir. Concurrent use may increase the INR and the risk of bleeding. Atazanavir is a CYP3A4 inhibitor and the R-enantiomer of warfarin is a 3A4 substrate. The S-enantiomer exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Atazanavir; Cobicistat: (Moderate) Closely monitor the INR if coadministration of warfarin with cobicistat is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Cobicistat is a strong CYP3A4 inhibitor and the R-e

nantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. (Moderate) Monitor the INR and adjust the dose as necessary if warfarin is coadministered with atazanavir. Concurrent use may increase the INR and the risk of bleeding. Atazanavir is a CYP3A4 inhibitor and the R-enantiomer of warfarin is a 3A4 substrate. The S-enantiomer exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Atenolol; Chlorthalidone: (Moderate) Chlorthalidone has been associated with a decreased anticoagulation response to warfarin. Monitor coagulation parameters and adjust warfarin dosage as needed.
Atorvastatin: (Moderate) Per the manufacturer of atorvastatin, a clinically significant effect on the prothrombin time when atorvastatin is administered to patients receiving chronic warfarin therapy has not been documented. In a study by the manufacturer, patients chronically maintained on warfarin were administered atorvastatin (80 mg/day) for 2 weeks. Mean prothrombin times decreased slightly, but only for the first few days of treatment. Per prescribing information for warfarin sodium (Coumadin), however, all HMG-CoA reductase inhibitors (statins), including atorvastatin, have been associated with potentiation of warfarin's clinical effect. In patients taking atorvastatin, it may be prudent to monitor the INR at baseline, at initiation of atorvastatin, and after subsequent dosage changes. Adjust warfarin dosage based on INR and clinical response. Once a stable INR is documented, the INR can be monitored at the intervals otherwise recommended based on the indication for anticoagulation and co-existing conditions.
Atorvastatin; Ezetimibe: (Moderate) Coadministration with ezetimibe has not demonstrated significant effects on the bioavailability or the anticoagulant effects of warfarin when studied in 12 healthy adult males. However, according to the manufacturer, increases in PT/INR have been reported and accordingly recommends that if ezetimibe is added to warfarin, the INR should be monitored. (Moderate) Per the manufacturer of atorvastatin, a clinically significant effect on the prothrombin time when atorvastatin is administered to patients receiving chronic warfarin therapy has not been documented. In a study by the manufacturer, patients chronically maintained on warfarin were administered atorvastatin (80 mg/day) for 2 weeks. Mean prothrombin times decreased slightly, but only for the first few days of treatment. Per prescribing information for warfarin sodium (Coumadin), however, all HMG-CoA reductase inhibitors (statins), including atorvastatin, have been associated with potentiation of warfarin's clinical effect. In patients taking atorvastatin, it may be prudent to monitor the INR at baseline, at initiation of atorvastatin, and after subsequent dosage changes. Adjust warfarin dosage based on INR and clinical response. Once a stable INR is documented, the INR can be monitored at the intervals otherwise recommended based on the indication for anticoagulation and co-existing conditions.
Atovaquone; Proguanil: (Moderate) The anticoagulant effects of warfarin and other coumarin-based anticoagulants may be increased when used concomitantly with proguanil; the mechanism of the interaction is not known. If proguanil is initiated in someone receiving warfarin, monitor the patient closely for an increased INR or symptoms of bleeding.
Avacopan: (Moderate) Closely monitor the INR if coadministration of warfarin with avacopan is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. The R-enantiomer of warfarin is a CYP3A substrate and avacopan is a weak CYP3A inhibitor. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Azathioprine: (Moderate) Azathioprine decreases warfarin serum concentrations and the INR and thus increases warfarin dosage requirements. If azathioprine is discontinued in a patient stabilized on warfarin, an increased risk of bleeding may occur. It is prudent to monitor the INR and response to warfarin prior to azathioprine initiation, frequently following initiation of azathioprine therapy, and again on azathioprine cessation. Adjust warfarin dosage based on INR and clinical response.
Azilsartan; Chlorthalidone: (Moderate) Chlorthalidone has been associated with a decreased anticoagulation response to warfarin. Monitor coagulation parameters and adjust warfarin dosage as needed.
Azithromycin: (Moderate) Carefully monitor the PT/INR in patients who receive warfarin and azithromycin concomitantly. Postmarketing reports suggest that concomitant administration of azithromycin may potentiate the effects of oral warfarin, although the prothrombin time was not affected in the dedicated drug interaction study with azithromycin and warfarin.
Aztreonam: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including aztreonam, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Balsalazide: (Moderate) Increased prothrombin time in patients taking concomitant 5-aminosalicylates and warfarin has been reported. Closely monitor patients PT and INR during and following concomitant balsalazide therapy; dosage adjustments of anticoagulants may be necessary.
Barbiturates: (Moderate) Closely monitor the INR if coadministration of warfarin with barbiturates is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Barbiturates are CYP1A2 and moderate CYP2C9/CYP3A4 inducers and warfarin's enantiomers are substrates of CYP1A2/CYP2C9/CYP3A4. Discontinuation of a barbiturate during warfarin therapy has led to fatal bleeding episodes when the hepatic enzyme-inducing properties of the barbiturate subside. Clinicians should note that warfarin doses will require readjustment if a barbiturate is added or discontinued during warfarin therapy. Dosage adjustments of warfarin may be necessary within 2 weeks of beginning barbiturate treatment, but the effect of the barbiturate on warfarin metabolism may persist for more than a month after discontinuing the barbiturate.
Belumosudil: (Moderate) Closely monitor the INR if coadministration of warfarin with belumosudil is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. The R-enantiomer of warfarin is a CYP3A substrate and belumosudil is a weak CYP3A inhibitor. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Belzutifan: (Moderate) Closely monitor the INR if coadministration of warfarin with belzutifan is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. The R-enantiomer of warfarin is a CYP3A substrate and belzutifan is a CYP3A inducer. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Bempedoic Acid; Ezetimibe: (Moderate) Coadministration with ezetimibe has not demonstrated significant effects on the bioavailability or the anticoagulant effects of warfarin when studied in 12 healthy adult males. However, according to the manufacturer, increases in PT/INR have been reported and accordingly recommends that if ezetimibe is added to warfarin, the INR should be monitored.
Benzhydrocodone; Acetaminophen: (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
Berotralstat: (Moderate) Closely monitor the INR if coadministration of warfarin with berotralstat is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. The R-enantiomer of warfarin is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Betrixaban: (Major) Avoid use of betrixaban with warfarin due to the increased bleeding risk. Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if betrixaban and other anticoagulants are used concomitantly. Coadministration of betrixaban and other anticoagulants may increase the risk of bleeding. Long-term concomitant treatment with betrixaban and other anticoagulants is not recommended; short-term use may be necessary for patients transitioning to or from betrixaban.
Bexarotene: (Moderate) Closely monitor the INR if coadministration of warfarin with bexarotene is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Bexarotene is a moderate CYP3A4 inducer and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Bicalutamide: (Moderate) Closely monitor the PT/INR if coadministration of warfarin with bicalutamide is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. In vitro protein-binding studies have shown that bicalutamide can displace coumarin anticoagulants from binding sites. There have been reports of excessive prolongation of the PT/INR days to weeks after the introduction of bicalutamide in patients who were previously stable on coumarin anticoagulants. Some patients had serious bleeding including intracranial, retroperitoneal, and gastrointestinal requiring blood transfusion and/or administration of vitamin K. Additionally, bicalutamide is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate; the S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Monitor prothrombin time and INR and watch for signs of bleeding with concomitant use of systemic metronidazole and warfarin. Warfarin dose adjustments may be necessary. Metronidazole can potentiate the anticoagulant effect of warfarin, resulting in prolongation of prothrombin time and increased risk of bleeding.
Bismuth Subsalicylate: (Moderate) Coadministration of salicylates and warfarin may result in an increased risk of bleeding. Salicylates may displace warfarin from protein binding sites leading to increased anticoagulation effects. Hypoprothrombinemia, an additional risk factor for bleeding, also has been reported with salicylates. Non-acetylated salicylates do not appear to affect platelet aggregation in the same manner as aspirin and are associated with a lower risk of bleeding when given currently with warfarin. If salicylates and warfarin are coadministered, monitor the patient for signs or symptoms of bleeding.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Coadministration of salicylates and warfarin may result in an increased risk of bleeding. Salicylates may displace warfarin from protein binding sites leading to increased anticoagulation effects. Hypoprothrombinemia, an additional risk factor for bleeding, also has been reported with salicylates. Non-acetylated salicylates do not appear to affect platelet aggregation in the same manner as aspirin and are associated with a lower risk of bleeding when given currently with warfarin. If salicylates and warfarin are coadministered, monitor the patient for signs or symptoms of bleeding. (Moderate) Monitor prothrombin time and INR and watch for signs of bleeding with concomitant use of systemic metronidazole and warfarin. Warfarin dose adjustments may be necessary. Metronidazole can potentiate the anticoagulant effect of warfarin, resulting in prolongation of prothrombin time and increased risk of bleeding.
Bivalirudin: (Minor) Based on the pharmacology of warfarin, other anticoagulants cause additive risk of bleeding when given concurrently with warfarin. Bivalirudin affects the International Normalized Ratio (INR). INR measurements made in patients being treated with bivalirudin may not be useful for determining the appropriate warfarin dose.
Blinatumomab: (Moderate) No drug interaction studies have been performed with blinatumomab. The drug may cause a transient release of cytokines leading to an inhibition of CYP450 enzymes. The interaction risk with CYP450 substrates is likely the highest during the first 9 days of the first cycle and the first 2 days of the second cycle. Monitor patients receiving concurrent CYP450 substrates that have a narrow therapeutic index (NTI) such as warfarin. The dose of the concomitant drug may need to be adjusted.
Bosentan: (Moderate) Closely monitor the INR if coadministration of warfarin with bosentan is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Bosentan is a moderate CYP2C9/CYP3A4 inducer and the enantiomers of warfarin are substrates of CYP2C9/CYP3A4. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Brigatinib: (Moderate) Closely monitor the INR if coadministration of warfarin with brigatinib is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Brigatinib is a weak CYP3A4 inducer and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Brodalumab: (Moderate) Closely monitor the INR if coadministration of warfarin with brodalumab is necessary due to the potential for decreased warfarin efficacy; adjust the dose of warfarin as necessary. Inhibition of IL-17 signaling by brodalumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic indie, such as warfarin, may have fluctuations in drug levels and therapeutic effect when brodalumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping brodalumab.
Bupivacaine; Meloxicam: (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs). To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients.
Bupropion: (Moderate) When bupropion is used for smoking cessation, be aware that changes in the INR may occur in patients previously stabilized on warfarin as tobacco smoking is reduced or halted, as smoking affects CYP1A2, one of the enzymes involved in warfarin metabolism. Physiological changes resulting from smoking cessation, with or without treatment with bupropion, may alter the pharmacokinetics or pharmacodynamics of certain drugs (e.g.,warfarin) for which dosage adjustment may be necessary. A case report of potential interaction with warfarin and bupropion used for depression has been reported; when bupropion was abruptly halted in the patient prior to surgery, the patient's INR increased to 8.0. The authors could not discern a probable mechanism for the potential interaction, but the patient was also reducing his daily tobacco smoking status, Patients who are receiving warfarin with bupropion should be carefully monitored if the patient is also altering their smoking status.
Bupropion; Naltrexone: (Moderate) When bupropion is used for smoking cessation, be aware that changes in the INR may occur in patients previously stabilized on warfarin as tobacco smoking is reduced or halted, as smoking affects CYP1A2, one of the enzymes involved in warfarin metabolism. Physiological changes resulting from smoking cessation, with or without treatment with bupropion, may alter the pharmacokinetics or pharmacodynamics of certain drugs (e.g.,warfarin) for which dosage adjustment may be necessary. A case report of potential interaction with warfarin and bupropion used for depression has been reported; when bupropion was abruptly halted in the patient prior to surgery, the patient's INR increased to 8.0. The authors could not discern a probable mechanism for the potential interaction, but the patient was also reducing his daily tobacco smoking status, Patients who are receiving warfarin with bupropion should be carefully monitored if the patient is also altering their smoking status.
Butabarbital: (Moderate) Closely monitor the INR if coadministration of warfarin with barbiturates is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Barbiturates are CYP1A2 and moderate CYP2C9/CYP3A4 inducers and warfarin's enantiomers are substrates of CYP1A2/CYP2C9/CYP3A4. Discontinuation of a barbiturate during warfarin therapy has led to fatal bleeding episodes when the hepatic enzyme-inducing properties of the barbiturate subside. Clinicians should note that warfarin doses will require readjustment if a barbiturate is added or discontinued during warfarin therapy. Dosage adjustments of warfarin may be necessary within 2 weeks of beginning barbiturate treatment, but the effect of the barbiturate on warfarin metabolism may persist for more than a month after discontinuing the barbiturate.
Butalbital; Acetaminophen: (Moderate) Closely monitor the INR if coadministration of warfarin with barbiturates is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Barbiturates are CYP1A2 and moderate CYP2C9/CYP3A4 inducers and warfarin's enantiomers are substrates of CYP1A2/CYP2C9/CYP3A4. Discontinuation of a barbiturate during warfarin therapy has led to fatal bleeding episodes when the hepatic enzyme-inducing properties of the barbiturate subside. Clinicians should note that warfarin doses will require readjustment if a barbiturate is added or discontinued during warfarin therapy. Dosage adjustments of warfarin may be necessary within 2 weeks of beginning barbiturate treatment, but the effect of the barbiturate on warfarin metabolism may persist for more than a month after discontinuing the barbiturate. (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
Butalbital; Acetaminophen; Caffeine: (Moderate) Closely monitor the INR if coadministration of warfarin with barbiturates is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Barbiturates are CYP1A2 and moderate CYP2C9/CYP3A4 inducers and warfarin's enantiomers are substrates of CYP1A2/CYP2C9/CYP3A4. Discontinuation of a barbiturate during warfarin therapy has led to fatal bleeding episodes when the hepatic enzyme-inducing properties of the barbiturate subside. Clinicians should note that warfarin doses will require readjustment if a barbiturate is added or discontinued during warfarin therapy. Dosage adjustments of warfarin may be necessary within 2 weeks of beginning barbiturate treatment, but the effect of the barbiturate on warfarin metabolism may persist for more than a month after discontinuing the barbiturate. (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Closely monitor the INR if coadministration of warfarin with barbiturates is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Barbiturates are CYP1A2 and moderate CYP2C9/CYP3A4 inducers and warfarin's enantiomers are substrates of CYP1A2/CYP2C9/CYP3A4. Discontinuation of a barbiturate during warfarin therapy has led to fatal bleeding episodes when the hepatic enzyme-inducing properties of the barbiturate subside. Clinicians should note that warfarin doses will require readjustment if a barbiturate is added or discontinued during warfarin therapy. Dosage adjustments of warfarin may be necessary within 2 weeks of beginning barbiturate treatment, but the effect of the barbiturate on warfarin metabolism may persist for more than a month after discontinuing the barbiturate. (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Co-administration of aspirin and warfarin is associated with an increased risk of bleeding. Consider alternate therapy for aspirin for analgesic or antipyretic uses. If aspirin and warfarin are coadministered, monitor the patient for signs or symptoms of bleeding. Gastrointestinal irritation and impaired hemostasis secondary to platelet inhibition have been observed with relatively small doses of aspirin. In addition, aspirin may displace warfarin from protein binding sites leading to increased anticoagulation effects. Large doses (more than 3 to 4 g/day) of aspirin can cause hypoprothrombinemia, an additional risk factor for bleeding; hypoprothrombinemia has also been reported with aspirin doses less than 2 g/day. Lower doses (less than 100 mg) of aspirin are recommended for use in combination with aspirin for the prevention of cardiovascular events in specific cases, including in patients with mechanical mitral or aortic valve or atrial fibrillation after percutaneous coronary intervention or revascularization. The addition of warfarin to aspirin and a P2Y12 inhibitor in patients after ST-elevation myocardial infarction should be limited to situations where the risk of systemic or venous thromboembolism or stent thrombosis is considered to exceed that of bleeding. Data regarding the benefit vs. risk of combination therapy for other cardiovascular conditions remains unclear. (Moderate) Closely monitor the INR if coadministration of warfarin with barbiturates is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Barbiturates are CYP1A2 and moderate CYP2C9/CYP3A4 inducers and warfarin's enantiomers are substrates of CYP1A2/CYP2C9/CYP3A4. Discontinuation of a barbiturate during warfarin therapy has led to fatal bleeding episodes when the hepatic enzyme-inducing properties of the barbiturate subside. Clinicians should note that warfarin doses will require readjustment if a barbiturate is added or discontinued during warfarin therapy. Dosage adjustments of warfarin may be necessary within 2 weeks of beginning barbiturate treatment, but the effect of the barbiturate on warfarin metabolism may persist for more than a month after discontinuing the barbiturate.
Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Moderate) Closely monitor the INR if coadministration of warfarin with famotidine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Famotidine is a CYP1A2 inhibitor and the R-enantiomer of warfarin is a CYP1A2 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Canakinumab: (Moderate) Closely monitor the INR and adjust warfarin dosage as appropriate based on response if coadministration of warfarin and canakinumab is necessary. Concurrent use may decrease warfarin exposure and reduce its efficacy. Canakinumab therapy may normalize the expression of CYP enzymes that are involved in the metabolism of warfarin which are often suppressed during chronic inflammation.
Cannabidiol: (Moderate) Closely monitor the INR if coadministration of warfarin with cannabidiol is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Cannabidiol is a CYP2C9 and weak CYP1A2 inhibitor. The R-enantiomer of warfarin is a CYP1A2 substrate and generally has a slower clearance than the S-enantiomer. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer and is metabolized by CYP2C9.
Capecitabine: (Major) Closely monitor the INR if coadministration of warfarin with capecitabine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Coadministration of warfarin and capecitabine has been reported to cause altered coagulation parameters and bleeding, including death. The effects of the interaction may occur within days to several months after starting or 1 month after stopping capecitabine therapy. Capecitabine is a weak CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. Additionally, age greater than 60 and a diagnosis of cancer independently predispose patients to an increased risk of coagulopathy.
Caplacizumab: (Major) Avoid concomitant use of caplacizumab and anticoagulants when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Capmatinib: (Moderate) Closely monitor the INR if coadministration of warfarin with capmatinib is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. The R-enantiomer of warfarin is a CYP1A2 substrate and capmatinib is a CYP1A2 inhibitor. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Carbamazepine: (Moderate) Closely monitor the INR if coadministration of warfarin with carbamazepine is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Carbamazepine is a CYP1A2, moderate CYP2C9, and strong CYP3A4 inducer and the enantiomers of warfarin are CYP1A2/CYP2C9/CYP3A4 substrates. If carbamazepine is discontinued, dosage reductions of warfarin may be necessary.
Carbidopa; Levodopa; Entacapone: (Moderate) Monitoring of the INR is recommended when entacapone treatment is initiated or when the dose is increased for patients receiving warfarin. Cases of significantly increased INR in patients concomitantly using warfarin have been reported during the postapproval use of entacapone. Entacapone has affinity for CYP2C9. In an interaction study in healthy volunteers, entacapone did not significantly change the plasma levels of S-warfarin while the AUC for R-warfarin increased on average by 18% (Cl 90 11% to 26%), and the INR values increased on average by 13% (Cl 90 6% to 19%).
Cefaclor: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Cefadroxil: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Cefazolin: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Cefdinir: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Cefepime: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Cefiderocol: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Cefixime: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Cefotaxime: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Cefotetan: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Cefoxitin: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Cefpodoxime: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Cefprozil: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Ceftaroline: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Ceftazidime: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Ceftazidime; Avibactam: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Ceftolozane; Tazobactam: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Ceftriaxone: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Cefuroxime: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Celecoxib: (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs). To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients.
Celecoxib; Tramadol: (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs). To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients. (Moderate) Monitor prothrombin time and adjust the warfarin dose as needed if administered with tramadol. Advise patients of the increased bleeding risk associated with concomitant use. Alterations in warfarin effect and elevated prothrombin time have been reported rarely following coadministration in postmarketing surveillance.
Cenobamate: (Moderate) Closely monitor the INR if coadministration of warfarin with cenobamate is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Cenobamate is a moderate CYP3A4 inducer and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Cephalexin: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Cephalosporins: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Ceritinib: (Moderate) Closely monitor the INR if coadministration of warfarin with ceritinib is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Ceritinib is a strong CYP3A4 and the R-enantiomer of warfarin is a CYP3A4 substrate. Ceritinib is also a weak CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Chenodiol: (Moderate) Due to its potential for hepatotoxicity, chenodiol may affect the pharmacodynamics of warfarin. Patients with hepatic impairment may require a lower dosage of warfarin due to decreased warfarin metabolism and decreased production of coagulation factors. Coadministration with chenodiol can cause prolongation of the prothrombin time and increase the risk of bleeding. Monitor patients on concomitant therapy carefully. If prolongation of prothrombin time is observed, the warfarin dosage should be adjusted as needed to produce a prothrombin time 1.5 to 2 times normal. If necessary, discontinue chenodiol therapy.
Chlorambucil: (Moderate) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
Chlordiazepoxide: (Moderate) Chlordiazepoxide has been associated with a decreased anticoagulation response to warfarin. Monitor coagulation parameters and adjust warfarin dosage as needed.
Chlordiazepoxide; Amitriptyline: (Moderate) Chlordiazepoxide has been associated with a decreased anticoagulation response to warfarin. Monitor coagulation parameters and adjust warfarin dosage as needed.
Chlordiazepoxide; Clidinium: (Moderate) Chlordiazepoxide has been associated with a decreased anticoagulation response to warfarin. Monitor coagulation parameters and adjust warfarin dosage as needed.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs). To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients.
Chlorthalidone: (Moderate) Chlorthalidone has been associated with a decreased anticoagulation response to warfarin. Monitor coagulation parameters and adjust warfarin dosage as needed.
Chlorthalidone; Clonidine: (Moderate) Chlorthalidone has been associated with a decreased anticoagulation response to warfarin. Monitor coagulation parameters and adjust warfarin dosage as needed.
Cholestyramine: (Major) Cholestyramine can either increase or decrease the hypoprothrombinemic actions of warfarin. Cholestyramine can bind with vitamin K in the diet, impairing vitamin K absorption, which, in turn, may increase warfarin's hypoprothrombinemic effect. Conversely, cholestyramine can bind with warfarin directly and impair warfarin bioavailability. To prevent altering warfarin pharmacokinetics, doses of warfarin and cholestyramine should be staggered by at least 4 to 6 hours. Cholestyramine should be prescribed cautiously to any patient receiving warfarin since cholestyramine may enhance systemic warfarin clearance.
Choline Salicylate; Magnesium Salicylate: (Moderate) Coadministration of salicylates and warfarin may result in an increased risk of bleeding. Salicylates may displace warfarin from protein binding sites leading to increased anticoagulation effects. Hypoprothrombinemia, an additional risk factor for bleeding, also has been reported with salicylates. Non-acetylated salicylates do not appear to affect platelet aggregation in the same manner as aspirin and are associated with a lower risk of bleeding when given currently with warfarin. If salicylates and warfarin are coadministered, monitor the patient for signs or symptoms of bleeding.
Chondroitin; Glucosamine: (Moderate) Case reports have reported a possible interaction between chondroitin; glucosamine and warfarin or other coumarin anticoagulants, resulting in an increase in INR and a need for warfarin dosage adjustment. In one case report, the patient was taking twice the recommended dosage of a popular chondroitin; glucosamine supplement (Cosamin DS). Controlled clinical trials of chondroitin; glucosamine for the treatment of osteoarthritis have not reported drug interactions with oral anticoagulants at typical dosages of up to 1500 mg glucosamine; 1200 mg chondroitin/day PO. However, drug interactions with these supplements have not been specifically studied. Until more is known regarding the potential for chondroitin or glucosamine to interact with warfarin, it may be prudent to closely monitor patients stabilized on warfarin if these dietary supplements are added to their therapy regimen.
Cilostazol: (Moderate) The safety of cilostazol has not been established with concomitant administration of heparin, other anticoagulants, or thrombolytic agents. Because cilostazol is a platelet aggregation inhibitor, concomitant administration with similar acting drugs could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution. While both cilostazol and warfarin are metabolized by cytochrome P450 CYP3A4 and CYP2C19, administration of cilostazol with a single dose of warfarin (25 mg) in healthy volunteers did not affect warfarin metabolism or effect changes in pro-times, bleeding times, or platelet aggregation. However, the effect of concomitant multiple dosing of cilostazol and warfarin has not been evaluated. Patients on anticoagulants should be monitored for changes in response to anticoagulation therapy if cilostazol is administered concurrently. Regularly monitor the INR and other clinical parameters during the chronic concomitant administration of warfarin and cilostazol. Although the risk of bleeding is increased when clopidogrel is used concomitantly with thrombolytic agents, it is common to see patients receive these drugs simultaneously.
Cimetidine: (Moderate) Closely monitor the INR if coadministration of warfarin with cimetidine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Cimetidine is a CYP1A2 and weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP1A2/CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Ciprofloxacin: (Moderate) Closely monitor the INR if coadministration of warfarin with ciprofloxacin is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Ciprofloxacin is a CYP1A2 and moderate CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP1A2/CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. Interactions may be particularly problematic in the elderly.
Cisapride: (Moderate) Data indicate that administration of cisapride to patients receiving oral anticoagulants (e.g., warfarin) may cause a prolongation in the prothrombin time and increase the INR. When using cisapride with warfarin, monitor the coagulation time during the initiation and discontinuation of cisapride. Warfarin dose adjustment may be necessary.
Citalopram: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of citalopram and warfarin. Carefully monitor patients receiving warfarin therapy if citalopram is initiated or discontinued. Although the pharmacokinetics of warfarin were unaffected by citalopram, prothrombin time was increased by 5%; the clinical significance is unknown. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Clarithromycin: (Moderate) Closely monitor the INR if coadministration of warfarin with clarithromycin is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Clarithromycin is a strong CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Clobazam: (Moderate) Closely monitor the INR if coadministration of warfarin with clobazam is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Clobazam is a weak CYP3A4 inducer and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Clofarabine: (Moderate) Due to the thrombocytopenic effects of clofarabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
Clofazimine: (Moderate) Closely monitor the INR if coadministration of warfarin with clofazimine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Clofazimine is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Clopidogrel: (Moderate) Carefully monitor patients for signs and symptoms of bleeding during coadministration of warfarin and clopidogrel. Both agents independently affect hemostasis.
Clozapine: (Moderate) The protein binding of clozapine is 97%; highly protein-bound medications can displace clozapine from its binding sites, predominantly alpha-1-acid glycoprotein. Clozapine, in turn, can increase the serum concentrations of digoxin or warfarin. Closely observe patients on other highly protein-bound drugs for an increased incidence of adverse effects.
Cobicistat: (Moderate) Closely monitor the INR if coadministration of warfarin with cobicistat is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Cobicistat is a strong CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Cocaine: (Moderate) Closely monitor the INR if coadministration of warfarin with cocaine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Cocaine is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Co-Enzyme Q10, Ubiquinone: (Moderate) Co-enzyme Q10, ubiquinone is structurally similar to vitamin K; a decreased response to warfarin has been noted if this dietary supplement is taken. Avoid concurrent use when possible. If co-enzyme Q10 is taken concurrently with warfarin, monitor INR and adjust warfarin dosage to attain clinical and anticoagulant endpoints.
Colesevelam: (Moderate) Cholestyramine can decrease warfarin absorption. Staggering the doses of cholestyramine and warfarin is recommended but this may not completely avoid a drug interaction. Cholestyramine has also been shown to enhance the clearance of IV warfarin. Thus, it is theoretically possible that cholestyramine may interfere with the actions of warfarin after warfarin has been absorbed. Colestipol may be an acceptable alternative to cholestyramine in patients receiving warfarin, although, both cholestyramine and colestipol can decrease vitamin K absorption from the gut, which may indirectly affect the clinical response to warfarin. Colesevelam may also decrease vitamin K absorption from the gut and interfere with the clinical effects of warfarin.
Colestipol: (Major) Colestipol may affect the hypoprothrombinemic actions of warfarin. Colestipol can bind with vitamin K in the diet, impairing vitamin K absorption, which, in turn, may increase warfarin's hypoprothrombinemic effect. Conversely, colestipol can bind with warfarin directly and impair warfarin bioavailability, although the effects of colestipol on warfarin absorption are less pronounced than the ability of cholestyramine to bind with warfarin. To avoid altering warfarin pharmacokinetics, doses of warfarin and colestipol should be staggered by at least 4-6 hours. Colestipol should be prescribed cautiously to any patient receiving warfarin, although colestipol may be an acceptable alternative to cholestyramine in a patient receiving warfarin who also requires therapy with a bile acid sequestrant.
Colistimethate, Colistin, Polymyxin E: (Moderate) The concomitant use of warfarin with many antibiotics, including colistimethate sodium, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Colistin: (Moderate) The concomitant use of warfarin with many antibiotics, including colistimethate sodium, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Collagenase: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
Conivaptan: (Moderate) Closely monitor the INR if coadministration of warfarin with conivaptan is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. The R-enantiomer of warfarin is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Corticosteroids: (Moderate) Monitor the INR if warfarin is administered with corticosteroids. The effect of corticosteroids on warfarin is variable. There are reports of enhanced as well as diminished effects of anticoagulants when given concurrently with corticosteroids; however, limited published data exist, and the mechanism of the interaction is not well described. High-dose corticosteroids appear to pose a greater risk for increased anticoagulant effect. In addition, corticosteroids have been associated with a risk of peptic ulcer and gastrointestinal bleeding.
Crizotinib: (Moderate) Closely monitor the INR if coadministration of warfarin with crizotinib is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Crizotinib is a moderate CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Cyclophosphamide: (Moderate) Monitor the PT/INR in patients receiving cyclophosphamide with warfarin therapy; both increased and decreased warfarin effect have been reported in patients receiving concomitant therapy.
Cyclosporine: (Moderate) Closely monitor the INR if coadministration of warfarin with cyclosporine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Cyclosporine is a moderate CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Cytarabine, ARA-C: (Moderate) Due to the thrombocytopenic effects of pyrimidine analogs, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
Dabigatran: (Major) Avoid use of dabigatran with warfarin due to the increased bleeding risk. Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if dabigatran and other anticoagulants are used concomitantly. Coadministration of dabigatran and other anticoagulants may increase the risk of bleeding. Long-term concomitant treatment with dabigatran and other anticoagulants is not recommended; short-term use may be necessary for patients transitioning to or from dabigatran.
Dabrafenib: (Moderate) Closely monitor the INR if coadministration of warfarin with dabrafenib is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Dabrafenib is a weak CYP2C9 and moderate CYP3A4 inducer and the enantiomers of warfarin are substrates of CYP2C9/CYP3A4. In a drug interaction study, administration of dabrafenib 150 mg twice daily for 15 days with a single 15 mg-dose of warfarin decreased the AUC of S-warfarin (a CYP2C9 substrate) by 37% and decreased the AUC of R-warfarin (a CYP3A4 substrate) by 33%.
Daclatasvir: (Moderate) Fluctuations in International Normalized Ratio (INR) have been observed in warfarin recipients who were also receiving treatment for hepatitis C virus (HCV) infections, including daclatasvir. It is recommended to closely monitor these patients for changes in INR both during and after discontinuation of the HCV treatment regimen.
Dalfopristin; Quinupristin: (Moderate) Closely monitor the INR if coadministration of warfarin with streptogramins, like quinupristin, is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Streptogramins, like quinupristin, are weak CYP3A4 inhibitors and warfarin is a CYP3A4 substrate. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR.
Dalteparin: (Major) An additive risk of bleeding may be seen in patients receiving other anticoagulants (e.g., heparin, warfarin) in combination with dalteparin.
Danazol: (Moderate) Closely monitor the INR if coadministration of warfarin with danazol is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Danazol is a moderate CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Daptomycin: (Moderate) Monitor patients for signs and symptoms of bleeding during coadministration. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary. The concomitant use of warfarin with antibiotics may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. In 16 healthy adults, a 5-day daptomycin course coadministered with a single oral dose of warfarin (25 mg) on the fifth day had no significant effect on the pharmacokinetics of either drug and did not significantly alter the INR; however, there are no data describing concurrent use beyond a single warfarin dose.
Darunavir: (Moderate) Monitor the INR and adjust the dose as necessary if warfarin is coadministered with darunavir. Concurrent use may increase the INR and the risk of bleeding. Darunavir is a CYP3A4 inhibitor and the R-enantiomer of warfarin is a 3A4 substrate. The S-enantiomer exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Darunavir; Cobicistat: (Moderate) Closely monitor the INR if coadministration of warfarin with cobicistat is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Cobicistat is a strong CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. (Moderate) Monitor the INR and adjust the dose as necessary if warfarin is coadministered with darunavir. Concurrent use may increase the INR and the risk of bleeding. Darunavir is a CYP3A4 inhibitor and the R-enantiomer of warfarin is a 3A4 substrate. The S-enantiomer exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Closely monitor the INR if coadministration of warfarin with cobicistat is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Cobicistat is a strong CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. (Moderate) Monitor the INR and adjust the dose as necessary if warfarin is coadministered with darunavir. Concurrent use may increase the INR and the risk of bleeding. Darunavir is a CYP3A4 inhibitor and the R-enantiomer of warfarin is a 3A4 substrate. The S-enantiomer exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Dasatinib: (Moderate) Monitor for evidence of bleeding if coadministration of dasatinib and anticoagulants is necessary. Dasatinib can cause serious and fatal bleeding. Concomitant anticoagulants may increase the risk of hemorrhage.
Dasiglucagon: (Moderate) Caution should be exercised for patients taking warfarin when glucagon will be administered. Monitor the INR as clinically indicated and monitor for evidence of bleeding. Glucagon has been reported to enhance the hypoprothrombinemic response in 8 out of 13 patients receiving warfarin. Clinical bleeding also was reported in 3 patients. These findings - based on data from only 13 patients - were published in 1970 and no subsequent reports have been identified. The mechanism of this interaction is uncertain.
Deferasirox: (Moderate) Closely monitor the INR if coadministration of warfarin with deferasirox is necessary as concurrent use may increase or decrease the exposure of warfarin leading to increased bleeding risk or reduced efficacy. Deferasirox is a CYP1A2 inhibitor and warfarin is a CYP1A2 substrate. Additionally, deferasirox is a weak CYP3A4 inducer and warfarin is a CYP3A4 substrate. Finally, because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when giving with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including anticoagulants.
Defibrotide: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like anticoagulants is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue systemic antithrombotic agents (not including use for routine maintenance or reopening of central venous catheters) prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Delavirdine: (Moderate) Closely monitor the INR if coadministration of warfarin with delavirdine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Delavirdine is a strong CYP3A4 and moderate CYP2C9 inhibitor and the R-enantiomer of warfarin is a CYP3A4/CYP2C9 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Desirudin: (Major) Any agent which may enhance the risk of hemorrhage should generally be discontinued before initiating desirudin therapy, including anticoagulants. If coadministration cannot be avoided, close clinical and laboratory monitoring should be conducted. The concomitant administration of warfarin did not significantly affect the pharmacokinetic effects of desirudin; however, greater inhibition of hemostasis measured by aPTT, PT, and INR was observed with coadministration. If a patient is switched from oral anticoagulants to desirudin therapy or from desirudin to oral anticoagulants, the anticoagulant activity should continue to be closely monitored with appropriate methods. That activity should be taken into account in the evaluation of the overall coagulation status of the patient during the switch.
Desvenlafaxine: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of desvenlafaxine and warfarin. Carefully monitor patients receiving warfarin therapy if desvenlafaxine is initiated or discontinued. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Dextran: (Moderate) Because of the potential effects of certain dextran formulations on bleeding time, use with caution in patients on anticoagulants concurrently.
Dextromethorphan; Bupropion: (Moderate) When bupropion is used for smoking cessation, be aware that changes in the INR may occur in patients previously stabilized on warfarin as tobacco smoking is reduced or halted, as smoking affects CYP1A2, one of the enzymes involved in warfarin metabolism. Physiological changes resulting from smoking cessation, with or without treatment with bupropion, may alter the pharmacokinetics or pharmacodynamics of certain drugs (e.g.,warfarin) for which dosage adjustment may be necessary. A case report of potential interaction with warfarin and bupropion used for depression has been reported; when bupropion was abruptly halted in the patient prior to surgery, the patient's INR increased to 8.0. The authors could not discern a probable mechanism for the potential interaction, but the patient was also reducing his daily tobacco smoking status, Patients who are receiving warfarin with bupropion should be carefully monitored if the patient is also altering their smoking status.
Dextromethorphan; Quinidine: (Moderate) Quinidine may potentiate the anticoagulation effects of warfarin; bleeding has been reported. This interaction is probably due to additive hypoprothrombinemia associated with concomitant administration of warfarin and quinine or quinidine. Close monitoring of the INR is required when either of these agents is added to warfarin therapy.
Diazoxide: (Minor) Diazoxide can displace highly protein-bound drugs from their protein-binding sites, resulting in an increased therapeutic effect. This interaction should be considered when administering diazoxide concomitantly with other highly protein-bound drugs such as warfarin.
Diclofenac: (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs). To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients.
Diclofenac; Misoprostol: (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs). To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients.
Dicloxacillin: (Moderate) Increased monitoring of the INR, especially during initiation and upon discontinuation of dicloxacillin, is suggested with the concomitant use of warfarin. Dicloxacillin may reduce the anticoagulant response to warfarin. A decrease in INR has been demonstrated.
Diflunisal: (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs). To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients.
Diltiazem: (Moderate) Closely monitor the INR if coadministration of warfarin with diltiazem is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Diltiazem is a moderate CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Diphenhydramine; Ibuprofen: (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs). To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients.
Diphenhydramine; Naproxen: (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs). To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients.
Dipyridamole: (Moderate) Because dipyridamole is a platelet inhibitor, there is a potential additive risk for bleeding if dipyridamole is given in combination with other agents that affect hemostasis. Per the manufacturer, dipyridamole does not influence prothrombin time or activity when administered with warfarin; bleeding frequency and severity are similar when dipyridamole is administered with or without warfarin. In rare cases, however, increased bleeding has been observed during or after surgery. Regardless, caution is advised as both anticoagulants including warfarin and platelet inhibitors such as dipyridamole affect hemostasis and combination therapy could increase the risk of bleeding.
Disopyramide: (Minor) A single case of the use of disopyramide with warfarin reported that discontinuation of disopyramide resulted in a drop in the prothrombin time; however, causality was not established and other factors may have contributed to reduction of anticoagulant effect. A direct interaction between disopyramide and warfarin has not been established.
Disulfiram: (Moderate) Closely monitor the INR if coadministration of warfarin with disulfiram is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Disulfiram is a weak CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate. Disulfiram is also a weak CYP1A2 inhibitor and the R-enantiomer of warfarin is a CYP1A2 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Doripenem: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including carbapenems, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Dronabinol: (Major) Use caution if coadministration of dronabinol with warfarin is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence) as well as increased bleeding or an increased PT/INR. Dronabinol is a CYP2C9 and 3A4 substrate; warfarin is a weak inhibitor of CYP2C9 in vitro. Concomitant use may result in elevated plasma concentrations of dronabinol. Dronabinol is also highly bound to plasma proteins and may displace and increase the free fraction of other concomitantly administered protein-bound drugs such as warfarin.
Dronedarone: (Moderate) Closely monitor the INR if coadministration of warfarin with dronedarone is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Dronedarone is a moderate CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) L-methylfolate and warfarin should be used together cautiously. Significant impairment of folate status may occur after 6 months of therapy with warfarin. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
Duloxetine: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of duloxetine and warfarin. Carefully monitor patients receiving warfarin therapy if duloxetine is initiated or discontinued. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding. Although both duloxetine and warfarin are highly protein bound, concurrent use did not significantly change INR or warfarin pharmacokinetics.
Dupilumab: (Moderate) Coadministration of dupilumab may result in altered exposure to warfarin. During chronic inflammation, increased levels of certain cytokines can alter the formation of CYP450 enzymes. Thus, the formation of CYP450 enzymes could be normalized during dupilumab administration. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as warfarin. Monitor the INR if dupilumab is initiated or discontinued in a patient taking warfarin; warfarin dose adjustments may be needed.
Duvelisib: (Moderate) Closely monitor the INR if coadministration of warfarin with duvelisib is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Duvelisib is a moderate CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Echinacea: (Moderate) Warfarin is metabolized by both CYP1A2 and CYP3A4. Echinacea appears to induce hepatic CYP3A4 and have variable effects on CYP1A2. The impact of Echinacea on the safety and efficacy of warfarin therapy are unknown, but studies suggest an interaction is possible. In one single-dose warfarin study, the apparent clearance of (S)-warfarin (90% CI of ratio; 1.01 to 1.18) was significantly higher during concomitant treatment with echinacea but this did not lead to a clinically significant change in INR (90% CI of AUC of INR; 0.91 to 1.31) in this single-dose warfarin study. Close monitoring of the INR and clinical status of the patient may be prudent if echinacea is used with warfarin until more data are available.
Econazole: (Moderate) Coadministation of econazole and warfarin has resulted in enhanced anticoagulant effect. In many of these cases, absorption of econazole may have been increased by applying the drug under occlusion, to the genitals, or over large body surface areas. If these drugs are used in combination, closely monitor the International Normalized Ratio (INR) and/or prothrombin time.
Edoxaban: (Major) Avoid concurrent use of edoxaban with warfarin due to the increased bleeding risk. Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if edoxaban and other anticoagulants are used concomitantly. Coadministration of edoxaban and other anticoagulants may increase the risk of bleeding. Long-term concomitant treatment with edoxaban and other anticoagulants is not recommended; short-term use may be necessary for patients transitioning to or from edoxaban.
Efavirenz: (Moderate) Closely monitor the INR if coadministration of warfarin with efavirenz is necessary as concurrent use may increase or decrease the exposure of warfarin leading to increased bleeding risk or reduced efficacy. Efavirenz is a moderate CYP2C9 inhibitor and warfarin is a CYP2C9 substrate. Additionally, efavirenz is a moderate CYP3A4 inducer and warfarin is a CYP3A4 substrate.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Closely monitor the INR if coadministration of warfarin with efavirenz is necessary as concurrent use may increase or decrease the exposure of warfarin leading to increased bleeding risk or reduced efficacy. Efavirenz is a moderate CYP2C9 inhibitor and warfarin is a CYP2C9 substrate. Additionally, efavirenz is a moderate CYP3A4 inducer and warfarin is a CYP3A4 substrate.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Closely monitor the INR if coadministration of warfarin with efavirenz is necessary as concurrent use may increase or decrease the exposure of warfarin leading to increased bleeding risk or reduced efficacy. Efavirenz is a moderate CYP2C9 inhibitor and warfarin is a CYP2C9 substrate. Additionally, efavirenz is a moderate CYP3A4 inducer and warfarin is a CYP3A4 substrate.
Elagolix: (Moderate) Closely monitor the INR if coadministration of warfarin with elagolix is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Elagolix is a moderate CYP3A4 inducer and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Elagolix; Estradiol; Norethindrone acetate: (Moderate) Closely monitor the INR if coadministration of warfarin with elagolix is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Elagolix is a moderate CYP3A4 inducer and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Elbasvir; Grazoprevir: (Moderate) Closely monitor patients receiving warfarin in combination with elbasvir for changes in International Normalized Ratio (INR) both during and after discontinuation of the hepatitis C virus (HCV) treatment regimen. One study found that when adding an elbasvir containing regimen to patients stable on warfarin anticoagulation, warfarin sensitivity decreased significantly during treatment and returned to baseline after discontinuation of the HCV therapy. More specifically, the mean INR decreased from 2.4 to 1.96 during treatment and recovered to 2.59 after elbasvir treatment. (Moderate) Closely monitor the INR if coadministration of warfarin with grazoprevir is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Grazoprevir is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Elexacaftor; tezacaftor; ivacaftor: (Moderate) Closely monitor the INR if coadministration of warfarin with ivacaftor is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Ivacaftor is a weak CYP3A4 inhibitor and the R-enantiomer is a CYP3A4 substrate. Ivacaftor is also a weak CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9/CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. (Moderate) Closely monitor the INR if coadministration of warfarin with tezacaftor; ivacaftor is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Ivacaftor is a weak CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate. Ivacaftor is also a weak CYP3A4 inhibitor and the R-enantiomer is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Eltrombopag: (Moderate) Use caution when discontinuing eltrombopag in patients receiving anticoagulants (e.g., warfarin, enoxaparin, dabigatran, rivaroxaban). The risk of bleeding and recurrent thrombocytopenia is increased in patients receiving these drugs when eltrombopag is discontinued.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Closely monitor the INR if coadministration of warfarin with cobicistat is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Cobicistat is a strong CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. (Moderate) Closely monitor the INR if coadministration of warfarin with elvitegravir is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Elvitegravir is a weak CYP2C9 inducer and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Closely monitor the INR if coadministration of warfarin with cobicistat is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Cobicistat is a strong CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. (Moderate) Closely monitor the INR if coadministration of warfarin with elvitegravir is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Elvitegravir is a weak CYP2C9 inducer and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Emapalumab: (Moderate) Monitor for decreased efficacy of warfarin and adjust the dose as needed during coadministration with emapalumab. Warfarin is a CYP2C9 substrate with a narrow therapeutic index. Emapalumab may normalize CYP450 activity, which may decrease the efficacy of drugs that are CYP450 substrates due to increased metabolism.
Encorafenib: (Moderate) Closely monitor the INR if coadministration of warfarin with encorafenib is necessary as concurrent use may increase or decrease the exposure of warfarin leading to increased bleeding risk or reduced efficacy. Encorafenib is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate which can lead to increased warfarin exposure and increased bleeding risk. Encorafenib is also a weak CYP3A4 inducer which can lead to decreased warfarin exposure and reduced efficacy.
Enoxaparin: (Major) Whenever possible, discontinue agents which may enhance the risk of hemorrhage, including warfarin, before initiation of enoxaparin therapy. If coadministration is essential, conduct close clinical and laboratory monitoring.
Entacapone: (Moderate) Monitoring of the INR is recommended when entacapone treatment is initiated or when the dose is increased for patients receiving warfarin. Cases of significantly increased INR in patients concomitantly using warfarin have been reported during the postapproval use of entacapone. Entacapone has affinity for CYP2C9. In an interaction study in healthy volunteers, entacapone did not significantly change the plasma levels of S-warfarin while the AUC for R-warfarin increased on average by 18% (Cl 90 11% to 26%), and the INR values increased on average by 13% (Cl 90 6% to 19%).
Enteral Feedings: (Major) Phytonadione, vitamin K1, is a pharmacologic antagonist of warfarin. Occult sources of vitamin K may decrease or reverse the activity of warfarin. Occult sources of vitamin K may include selected enteral feedings. In general, it is recommended that patients avoid large servings or frequent intake of foods that contain substantial amounts of vitamin K. Patients should aim for a stable and non-excessive intake of vitamin K in the diet to ensure stable INRs and appropriate clinical response to warfarin treatment.
Enzalutamide: (Moderate) Closely monitor the INR if coadministration of warfarin with enzalutamide is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Enzalutamide is a moderate CYP2C9 and strong CYP3A4 inducer and warfarin is a CYP2C9/CYP3A4 substrate.
Epoprostenol: (Moderate) When used concurrently with anticoagulants, epoprostenol may increase the risk of bleeding.
Eptifibatide: (Moderate) Concomitant use of eptifibatide and other agents that may affect hemostasis, such as anticoagulants, may be associated with an increased risk of bleeding.
Erdafitinib: (Moderate) Closely monitor the INR and adjust the dose as necessary if warfarin is coadministered with erdafitinib; concurrent use may increase the risk of bleeding or reduce efficacy. Erdafitinib is a time dependent inhibitor and inducer of CYP3A4 and the R-enantiomer is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Erlotinib: (Major) Regularly monitor prothrombin time (PT) or INR in patients taking warfarin. Increased INR and bleeding adverse reactions, in some cases fatal, have been reported in patients receiving concomitant therapy. Dose modifications of erlotinib are not recommended.
Ertapenem: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including carbapenems, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Erythromycin: (Moderate) Closely monitor the INR if coadministration of warfarin with erythromycin is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Erythromycin is a moderate CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Escitalopram: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of escitalopram and warfarin. Carefully monitor patients receiving warfarin therapy if escitalopram is initiated or discontinued. Although the pharmacokinetics of warfarin were unaffected by citalopram, prothrombin time was increased by 5%; the clinical significance is unknown. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Eslicarbazepine: (Moderate) Closely monitor the INR if coadministration of warfarin with eslicarbazepine is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Eslicarbazepine is a moderate CYP3A4 inducer and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Esterified Estrogens; Methyltestosterone: (Moderate) Methyltestosterone can increase the effects of anticoagulants through reduction of procoagulant factor. Patients receiving oral anticoagulant therapy should be closely monitored, especially when methyltestosterone treatment is initiated or discontinued.
Estrogens: (Major) Estrogen-based hormone replacement therapies and contraceptive methods are generally contraindicated in patients with thromboembolic risk. However, per ACOG guidelines, in select patients the benefits of such contraception may outweigh the risks, as long as appropriate anticoagulant therapy is utilized. Combined oral contraceptives (COCs) may inhibit CYP3A4 and CYP1A2, which can rarely influence warfarin pharmacokinetics and the INR value. Isolated case reports have noted altered responses to warfarin in patients receiving combined hormonal contraceptives. Estrogens increase the hepatic synthesis of prothrombin and factors VII, VIII, IX, and X and decrease antithrombin III; estrogens also increase norepinephrine-induced platelet aggregability. A positive relationship of estrogen-containing OCs to thromboembolic disease has been demonstrated. OC products containing 50-mcg or more of ethinyl estradiol are associated with the greatest risk of thromboembolic complications. The addition of certain progestins may influence thromboembolic risks. A positive relationship between estrogen-based HRT and the risk of thromboembolic disease has also been demonstrated in the Women's Health Initiative Trials. Estrogen-based HRT products are generally contraindicated in patients with a current or past history of stroke, cerebrovascular disease, coronary artery disease, coronary thrombosis, thrombophlebitis, thromboembolic disease (including pulmonary embolism and DVT), or valvular heart disease with complications. If concurrent use of an estrogen-based product cannot be avoided, carefully monitor for signs and symptoms of thromboembolic complications. If thromboembolic events occur, discontinue the HRT regimen. Estrogen-based HRT is generally not expected to significantly alter the INR or to affect the metabolism of warfarin. Dosage adjustment of warfarin in a woman taking HRT should be based on the prothrombin time or INR value.
Ethacrynic Acid: (Major) Although data are very limited, there have been reports of increased hypoprothrombinemia when ethacrynic acid was administered to patients receiving warfarin. Ethacrynic acid has been shown to displace warfarin from plasma protein; a reduction in the usual anticoagulant dosage may be required in patients receiving both drugs. Patients should be monitored for changes in the INR when either of these drugs is initiated or discontinued, or if the dosage is changed.
Etidronate: (Moderate) There have been isolated reports of etidronate causing an increased prothrombin time/INR when the drug is given to patients stabilized on warfarin. Although none of the reports have described clinically significant sequelae, it is advisable to monitor the INR periodically in patients taking warfarin who have etidronate therapy added.
Etodolac: (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs). To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients.
Etoposide, VP-16: (Moderate) Frequently measure the PT/INR if coadministration of etoposide with warfarin is necessary; concomitant use can increase the INR.
Etravirine: (Moderate) Closely monitor the INR if coadministration of warfarin with etravirine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. The active metabolite of warfarin, the S-enantiomer, is a CYP2C9 substrate and etravirine is a CYP2C9 inhibitor. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Everolimus: (Moderate) Closely monitor the INR if coadministration of warfarin with everolimus is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Everolimus is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Exenatide: (Moderate) Cases of an increased INR have been reported with the concomitant use of warfarin and exenatide, sometimes associated with bleeding. Monitor for changes in INR and bleeding when these drugs are coadministered. Dosage adjustments of warfarin may be necessary.
Ezetimibe: (Moderate) Coadministration with ezetimibe has not demonstrated significant effects on the bioavailability or the anticoagulant effects of warfarin when studied in 12 healthy adult males. However, according to the manufacturer, increases in PT/INR have been reported and accordingly recommends that if ezetimibe is added to warfarin, the INR should be monitored.
Ezetimibe; Simvastatin: (Moderate) Coadministration with ezetimibe has not demonstrated significant effects on the bioavailability or the anticoagulant effects of warfarin when studied in 12 healthy adult males. However, according to the manufacturer, increases in PT/INR have been reported and accordingly recommends that if ezetimibe is added to warfarin, the INR should be monitored. (Moderate) Per prescribing information for warfarin sodium (Coumadin), all HMG-CoA reductase inhibitors (statins) have been associated with potentiation of warfarin's clinical effect. However, it appears that pravastatin and atorvastatin may be less likely to significantly interact with warfarin based on drug interaction studies. In addition, atorvastatin has been reported to slightly and transiently decrease the anticoagulant activity of warfarin; these effects were not considered clinically significant. In general, it is prudent to monitor INR at baseline, at initiation of these HMG Co-A reductase inhibitors, and after subsequent dosage changes. Adjust warfarin dosage based on INR and clinical response. Once a stable INR is documented, the INR can be monitored at the intervals otherwise recommended based on the indication for anticoagulation and co-existing conditions.
Famotidine: (Moderate) Closely monitor the INR if coadministration of warfarin with famotidine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Famotidine is a CYP1A2 inhibitor and the R-enantiomer of warfarin is a CYP1A2 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Fedratinib: (Moderate) Closely monitor the INR if coadministration of warfarin with fedratinib is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Fedratinib is a moderate CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Fenofibrate: (Moderate) Fenofibrate potentiates the effects of warfarin and other oral anticoagulants, resulting in increased prothrombin times. Fibrates have been shown to decrease vitamin K dependent coagulation factor synthesis. Since these drugs are also highly protein-bound, it is possible that fenofibrate displaces warfarin from protein-binding sites as a potential mechanism. Case reports of significant effects on warfarin exist for all fibrate drugs. Three clinical case reports of fenofibrate and warfarin interactions have been reported in post-marketing surveillance of fenofibrate in the US and Europe. In one case, a 47 year old male who had been stable over a course of 20 weeks on his prescribed warfarin dose was admitted to the hospital one week after beginning treatment for hypertriglyceridemia with fenofibrate 201 mg/day. He presented with epigastric discomfort and hematuria. His INR on admission was > 8.5 (previously stabilized at 2 to 2.5 prior to fenofibrate). The patient received treatment with phytonadione and discontinuation of the medications. He was discharged 2 days later, but agreed to be rechallenged under a controlled protocol to confirm the interaction of the fenofibrate with his warfarin. After stabilization of his warfarin dose for 3 weeks, fenofibrate was restarted, and the patient was rechallenged on 2 occasions. Both times, an increase in INR above the therapeutic range occurred. Patients receiving warfarin in conjunction with fenofibrate should have frequent prothrombin time and INR determinations until it has been determined that the INR has been stabilized. A reduction in warfarin dose may be necessary.
Fenofibric Acid: (Moderate) Fenofibric acid potentiates the effects of warfarin and other oral anticoagulants, resulting in increased prothrombin times. Fibrates have been shown to decrease vitamin K dependent coagulation factor synthesis. Since these drugs are also highly protein-bound, it is possible that fenofibric acid displaces warfarin from protein-binding sites as a potential mechanism. Case reports of significant effects on warfarin exist for all fibrate drugs. Fenofibric acid is the active metabolite of fenofibrate. Three clinical case reports of fenofibrate and warfarin interactions have been reported in post-marketing surveillance of fenofibrate in the US and Europe. In one case, a male (47 years) who had been stable over a course of 20 weeks on his prescribed warfarin dose was admitted to the hospital one week after beginning treatment for hypertriglyceridemia with fenofibrate 201 mg/day. He presented with epigastric discomfort and hematuria. His INR on admission was > 8.5 (previously stabilized at 2 to 2.5 prior to fenofibrate). The patient received treatment with phytonadione and discontinuation of the medications. He was discharged 2 days later, but agreed to be rechallenged under a controlled protocol to confirm the interaction of the fenofibrate with his warfarin. After stabilization of his warfarin dose for 3 weeks, fenofibrate was restarted, and the patient was rechallenged on 2 occasions. Both times, an increase in INR above the therapeutic range occurred. In order to prevent bleeding complications, patients receiving warfarin concomitantly with fenofibric acid should have frequent INR determinations until it has been determined that the INR has been stabilized. A reduction in warfarin dose may be necessary.
Fenoprofen: (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs). To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients.
Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
Flavocoxid, Flavocoxid; Citrated Zinc Bisglycinate: (Moderate) In vitro, flavocoxid, flavocoxid; citrated zinc bisglycinate demonstrated a 23% inhibition of CYP1A2 isoenzymes. This inhibition could potentially be clinically relevant, especially when flavocoxid, flavocoxid; citrated zinc bisglycinate is coadministered with CYP1A2 substrates that have a narrow therapeutic index such as warfarin. Until more data are available, it may be prudent to monitor for potential adverse effects of warfarin when coadministered with flavocoxid, flavocoxid; citrated zinc bisglycinate.
Flaxseed: (Moderate) Flaxseed fiber can impair the absorption of oral drugs when administered concomitantly. However, no drug interaction studies have been performed to assess the degree to which the absorption of oral drugs may be altered. Based on interactions of other plant seed fiber (e.g., psyllium) used as a bulk-forming laxative, flaxseed fiber may adsorb oral anticoagulants (e.g., warfarin). Administration of prescribed oral agents should be separated from the administration of flaxseed fiber by at least 2 hours.
Floxuridine: (Moderate) Closely monitor the INR if coadministration of warfarin with floxuridine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Floxuridine is a CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Fluconazole: (Moderate) Closely monitor the INR if coadministration of warfarin with fluconazole is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Fluconazole is a moderate CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. Fluconazole is also a moderate CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Fluorouracil, 5-FU: (Moderate) Closely monitor the INR if coadministration of warfarin with fluorouracil is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Fluorouracil is a CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Fluoxetine: (Moderate) Closely monitor the INR if coadministration of warfarin with fluoxetine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Fluoxetine is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. Fluoxetine is also a weak CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate. An increased risk of bleeding, including gastrointestinal bleeding, has been reported with drugs that interfere with serotonin reuptake; thus, concurrent use of fluoxetine and warfarin may result in an additive risk of bleeding events. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Fluphenazine: (Moderate) Closely monitor the INR if coadministration of warfarin with fluphenazine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Fluphenazine is a CYP1A2 inhibitor and the R-enantiomer of warfarin is a CYP1A2 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Flurbiprofen: (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs). To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients.
Flutamide: (Moderate) Prothrombin times and/or INRs have increased in patients receiving long-term warfarin therapy who are given flutamide. Adjustment of the warfarin dose may be required during flutamide therapy.
Fluvastatin: (Moderate) Closely monitor the INR if coadministration of warfarin with fluvastatin is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Fluvastatin is a weak CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Fluvoxamine: (Moderate) Closely monitor the INR if coadministration of warfarin with fluvoxamine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Fluvoxamine is a moderate CYP3A4 and weak CYP1A2 inhibitor and the R-enantiomer of warfarin is a CYP3A4/CYP1A2 substrate. Fluvoxamine is also a weak CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate. An increased risk of bleeding, including gastrointestinal bleeding, has been reported with drugs that interfere with serotonin reuptake; thus, concurrent use of fluoxetine and warfarin may result in an additive risk of bleeding events. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Fondaparinux: (Major) Discontinue warfarin before starting fondaparinux due to the increased bleeding risk, unless these agents are essential, such as in the early treatment of deep venous thrombosis or pulmonary embolism. If coadministration is necessary, monitor patients closely and promptly evaluate any signs or symptoms of bleeding.
Food: (Major) Advise patients to avoid cannabis use during warfarin treatment. The net effect of concomitant use is difficult to predict and may vary based on cannabis's route of administration and frequency of use. Warfarin efficacy and overall exposure may be reduced; cannabis use induces CYP1A2 and warfarin is a CYP1A2 substrate. The induction potential of cannabis is greatest with chronic inhalation. Other routes of administration or sporadic use may have less of an effect. Case reports have also described increases in INR and bleeding events following cannabis use. (Major) Interactions with warfarin and cranberry juice (cranberry, Vaccinium macrocarpon Ait.) have been reported, but the data are controversial. Some case reports have reported increased INR or other clinically significant events, while limited and small controlled clinical research data do not support an interaction. It is not clear if warfarin would interact with cranberry supplements (e.g., dried extracts); caution is advised until further data are available; patients should likely have consistent cranberry intake, including intake of cranberry capsules and concentrates, if on warfarin therapy. (Major) Phytonadione, vitamin K1, is a pharmacologic antagonist of warfarin; it is often administered to reverse elevated INR from warfarin overdose. Exogenous administration or occult sources of vitamin K may decrease or reverse the activity of warfarin. Response to warfarin usually returns after stopping the vitamin K-containing product. Occult sources of vitamin K include enteral feedings, certain multivitamins, and many food products. Foods that contain large amounts of vitamin K include green tea, brussel sprouts, and kale. Other foods that contain moderate-high quantities of vitamin K include asparagus, avocado, broccoli, cabbage, cauliflower, collard greens, lettuce, liver, soy products (including soy milk, soybeans or soybean oil), lentils, peas, mustard greens, turnip greens, parsley, green scallions, and spinach. Medical products that contain soybean oil such as intravenous lipid emulsions or propofol, may decrease warfarin anticoagulation. Intravenous lipids may interfere with warfarin anticoagulation in many ways including enhancing the production of clotting factors, facilitating platelet aggregation, supplying vitamin K, and enhancing warfarin binding to albumin. In general, it is recommended that patients avoid large servings or frequent intake of foods that contain substantial amounts of vitamin K. (Moderate) The regular use of chamomile teas or other chamomile products should be approached with caution in patients taking warfarin. A case report noted an enhanced effect of warfarin, resulting in an elevated international normalized ratio (INR) and associated bleeding, when a patient increased her ingestion of chamomile tea (chamomile, Matricaria recutita); this is the only known formal report of an interaction. Various chamomile species are known to contain coumarin related compounds that may have an additive effect with warfarin. No pharmacokinetic alterations in warfarin were evident from this case report. The authors recommend that patients limit and not greatly alter their chamomile use while taking warfarin therapy. Educate patients on the potential risks of the ingestion of nutritional supplements and herbal remedies, and the importance of dietary intake. Monitor the patient clinically for adverse events and regularly monitor the patient's INR.
Fosamprenavir: (Moderate) Closely monitor the INR if coadministration of warfarin with fosamprenavir is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. The R-enantiomer of warfarin is a CYP3A substrate and fosamprenavir is a moderate CYP3A inhibitor. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Fostamatinib: (Moderate) Closely monitor the INR if coadministration of warfarin with fostamatinib is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Fostamatinib is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Garlic, Allium sativum: (Moderate) Garlic produces clinically significant antiplatelet effects so additive risk of bleeding may occur if anticoagulants are given in combination. Avoid concurrent use of herbs which interact with anticoagulants when possible. If garlic dietary supplements are taken, monitor the INR or other appropriate parameters to attain clinical and anticoagulant endpoints. In regard to warfarin, published data are limited to a random case report; however, the product labeling for warfarin includes garlic as having potential for interaction due to additive pharmacologic activity. A case of spontaneous spinal epidural hematoma, attributed to dysfunctional platelets from excessive garlic use in a patient not receiving concomitant anticoagulation, has been reported.
Gefitinib: (Moderate) Regularly monitor INR regularly and watch carefully for signs and symptoms of bleeding if gefitinib and warfarin are used concomitantly. Elevated INR and/or hemorrhage have been reported in some patients taking warfarin while on gefitinib therapy.
Gemfibrozil: (Moderate) Closely monitor the INR if coadministration of warfarin with gemfibrozil is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Gemfibrozil is a weak CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Gemifloxacin: (Moderate) There have been postmarketing reports of increases in the INR, prothrombin time (PT), and/or clinical episodes of bleeding in patients receiving quinolones, including gemifloxacin, with warfarin or its derivatives. In addition, infectious disease and its accompanying inflammatory process,, and the age and health status of the patient are risk factors for increased anticoagulation activity. Therefore, the PT, INR or other suitable coagulation test should be closely monitored. Monitor for bleeding.
Gentamicin: (Mo derate) The concomitant use of warfarin with many classes of antibiotics, including aminoglycosides, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Ginger, Zingiber officinale: (Moderate) Additive bleeding may occur if anticoagulants are given in combination with ginger, zingiber officinale. Ginger inhibits thromboxane synthetase (platelet aggregation inducer) and is a prostacyclin agonist. Patients taking ginger and an anticoagulant should be monitored closely for bleeding.
Ginkgo, Ginkgo biloba: (Moderate) Monitor for signs or symptoms of bleeding with coadministration of ginkgo biloba and warfarin as an increased bleeding risk may occur. Although data are mixed, ginkgo biloba is reported to inhibit platelet aggregation and several case reports describe bleeding complications with ginkgo biloba, with or without concomitant drug therapy. Ginkgo may also interact with warfarin metabolism as its overall effects on CYP3A are not well defined.
Ginseng, Panax ginseng: (Major) Interactions have been reported clinically between ginseng and warfarin. With regard to warfarin, one case report is noted of a decreased INR (reduced anticoagulant effect) after the addition of ginseng (Ginsana) in a patient stabilized on warfarin, followed by a return to the desired INR after ginseng was discontinued. In another report, ginseng was implicated in a life-threatening case of valve thrombosis in a patient with an inability to maintain a therapeutic INR on warfarin after he began using a commercial ginseng product. The effect of ginseng on warfarin has been evaluated in a double-blind, placebo-controlled trial of 4 weeks duration in healthy volunteers. The subjects (n= 20) received warfarin (5 mg/day PO x 3 days/week). Beginning in week two, 12 of the subjects took ginseng powder (2 g/day PO in capsules); 8 subjects took placebo capsules. Compared with the placebo group, the ginseng group had significantly reduced INR values, warfarin AUCs, and peak plasma warfarin concentrations after 2 weeks. Concurrent use of ginseng and warfarin is not recommended; clinicians should discuss ginseng use with patients. Ginseng (Panax ginseng) also exerts antiplatelet activity and theoretically may interact with other drugs that exhibit antiplatelet effects or anticoagulant activity; however, data are not available to confirm or deny clinical interactions.
Givosiran: (Moderate) Closely monitor the INR if coadministration of warfarin with givosiran is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Givosiran may moderately reduce hepatic CYP1A2 inhibitor enzyme activity because of its pharmacological effects on the hepatic heme biosynthesis pathway and the R-enantiomer of warfarin is a CYP1A2 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Glecaprevir; Pibrentasvir: (Moderate) Fluctuations in International Normalized Ratio (INR) have been observed in warfarin recipients who were also receiving treatment for hepatitis C virus (HCV) infections, including glecaprevir. It is recommended to closely monitor these patients for changes in INR both during and after discontinuation of the HCV treatment regimen. (Moderate) Fluctuations in International Normalized Ratio (INR) have been observed in warfarin recipients who were also receiving treatment for hepatitis C virus (HCV) infections, including pibrentasvir. It is recommended to closely monitor these patients for changes in INR both during and after discontinuation of the HCV treatment regimen.
Glucagon: (Moderate) Caution should be exercised for patients taking warfarin when glucagon will be administered. Monitor the INR as clinically indicated and monitor for evidence of bleeding. Glucagon has been reported to enhance the hypoprothrombinemic response in 8 out of 13 patients receiving warfarin. Clinical bleeding also was reported in 3 patients. These findings - based on data from only 13 patients - were published in 1970 and no subsequent reports have been identified. The mechanism of this interaction is uncertain.
Glucosamine: (Moderate) Case reports have reported a possible interaction between chondroitin; glucosamine and warfarin or other coumarin anticoagulants, resulting in an increase in INR and a need for warfarin dosage adjustment. In one case report, the patient was taking twice the recommended dosage of a popular chondroitin; glucosamine supplement (Cosamin DS). Controlled clinical trials of chondroitin; glucosamine for the treatment of osteoarthritis have not reported drug interactions with oral anticoagulants at typical dosages of up to 1500 mg glucosamine; 1200 mg chondroitin/day PO. However, drug interactions with these supplements have not been specifically studied. Until more is known regarding the potential for chondroitin or glucosamine to interact with warfarin, it may be prudent to closely monitor patients stabilized on warfarin if these dietary supplements are added to their therapy regimen.
Glycerol Phenylbutyrate: (Moderate) Closely monitor the INR if coadministration of warfarin with glycerol phenylbutyrate is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. The R-enantiomer of warfarin is a CYP3A substrate and glycerol phenylbutyrate is a CYP3A inducer. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Glycylcyclines: (Moderate) In healthy subjects receiving tigecycline (repeated dosing) and warfarin (25 mg single dose) concomitantly, the clearance of R-warfarin and S-warfarin was decreased by 40% and 23%, the Cmax increased by 38% and 43%, and the AUC increased by 68% and 29%, respectively. Tigecycline did not significantly alter the effects of warfarin on the INR in this single-dose study. Warfarin did not affect the pharmacokinetic profile of tigecycline. However, it is recommended that the prothrombin time or other suitable anticoagulation test (i.e., INR) be monitored if tigecycline is administered with warfarin.
Golimumab: (Moderate) If golimumab is initiated or discontinued in a patient taking warfarin, monitor the INR; warfarin dose adjustment may be needed. The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines (e.g., TNF-alpha) during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during golimumab receipt. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as warfarin, and alter the clinical response to warfarin treatment.
Grapefruit juice: (Moderate) Closely monitor the INR if coadministration of warfarin with grapefruit/grapefruit juice is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Grapefruit/grapefruit juice is a strong CYP3A4 and moderate CYP2C9 inhibitor and the R-enantiomer of warfarin is a CYP3A4/CYP2C9 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Green Tea: (Moderate) Green tea has demonstrated antiplatelet and fibrinolytic actions in animals. It is possible that the use of green tea may increase the risk of bleeding if co-administered with anticoagulants (e.g., enoxaparin, heparin, warfarin, and others), thrombolytic agents, or platelet inhibitors (e.g., aspirin, clopidogrel, cilostazol and others). Caution and careful monitoring of clinical and/or laboratory parameters are warranted if green tea is coadministered with any of these agents. Exogenous administration or occult sources of vitamin K may decrease or reverse the activity of warfarin; stability of the diet can be an important factor in maintaining anticoagulation goals. Occult sources of vitamin K include green tea and green tea dietary supplements. Published data are limited in regard to this interaction. A patient with previous INRs of 3.2 and 3.79 on a dose of 7.5mg daily of warfarin (goal INR 2.5 to 3.5) had an INR of 1.37. One month later, the patient's INR was 1.14. The patient admitted that he had started consuming 0.51 gallon of green tea daily approximately one week prior to the INR of 1.37. The patient denied noncompliance and other changes in diet, medications, or health. The patient discontinued green tea and one week later his INR was 2.55. While the amount of vitamin K in a single cup of brewed green tea may not be high (0.03 mcg/100 g), the actual amount may vary from cup to cup depending on the amount of tea leaves used, the length of time the tea bags are allowed to brew, and the volume of tea consumed. Additionally, if a patient drinks multiple cups of tea per day, the amount of vitamin K could reach significance. It is recommended that patients on warfarin maintain a stable intake of green tea.
Griseofulvin: (Major) The anticoagulant effect of warfarin can be decreased if griseofulvin is used concurrently. The griseofulvin-warfarin drug interaction is one of the most well-documented warfarin drug interactions. The mechanism of this interaction is unclear. It is commonly believed that griseofulvin enhances the hepatic metabolism of warfarin. The interaction between warfarin and griseofulvin may require up to 12 weeks to fully manifest and may be more significant with the ultramicrocrystalline formulation of griseofulvin. The international normalized ratio (INR) should be monitored closely if griseofulvin is either added to or discontinued from warfarin therapy.
Haloperidol: (Moderate) Haloperidol can decrease the anticoagulation effects of warfarin. If these drugs are coadministered, monitor INR and adjust warfarin doses as needed.
Hemin: (Major) Because hemin has exhibited transient, mild anticoagulant effects during clinical studies, concurrent use of anticoagulants should be avoided. The extent and duration of the hypocoagulable state induced by hemin has not been established.
Heparin: (Major) An additive risk of bleeding may be seen in patients receiving other anticoagulants in combination with heparin. Heparin and warfarin therapies often overlap with no serious sequelae, although the risk of bleeding is nonetheless increased. It should be noted that heparin also can prolong prothrombin time. When heparin and warfarin are administered concomitantly, wait at least 5 hours after the last IV heparin dose or 24 hours after the last subcutaneous heparin dose before drawing blood to obtain prothrombin time.
Hydantoins: (Moderate) Closely monitor the INR if coadministration of warfarin with hydantoins is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Hydantoins are CYP1A2, moderate CYP2C9, and strong CYP3A4 inducers and the enantiomers of warfarin are substrates of CYP1A2/CYP2C9/CYP3A4. Additionally, an immediate interaction may occur as phenytoin can displace warfarin from protein binding sites causing rapid increases in the INR. Warfarin dosage adjustments may also be necessary on discontinuation of the anticonvulsant.
Hydrocodone; Ibuprofen: (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs). To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients.
Ibritumomab Tiuxetan: (Major) During and after therapy, avoid the concomitant use of Yttrium (Y)-90 ibrutumomab tiuxetan with drugs that interfere with coagulation such as anticoagulants; the risk of bleeding may be increased. If coadministration with anticoagulants is necessary, monitor platelet counts more frequently for evidence of thrombocytopenia.
Ibrutinib: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as warfarin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
Ibuprofen: (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs). To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients.
Ibuprofen; Famotidine: (Moderate) Closely monitor the INR if coadministration of warfarin with famotidine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Famotidine is a CYP1A2 inhibitor and the R-enantiomer of warfarin is a CYP1A2 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs). To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients.
Ibuprofen; Oxycodone: (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs). To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients.
Ibuprofen; Pseudoephedrine: (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs). To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients.
Icosapent ethyl: (Moderate) Icosapent ethyl is an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA). Because omega-3 fatty acids inhibit platelet aggregation, caution is advised when icosapent ethyl is used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 36 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant icosapent ethyl therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
Idelalisib: (Moderate) Closely monitor the INR if coadministration of warfarin with idelalisib is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Idelalisib is a strong CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Iloprost: (Moderate) When used concurrently with anticoagulants, inhaled iloprost may increase the risk of bleeding.
Imatinib: (Moderate) Due to the thrombocytopenic effects of imatinib an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, as well as thrombolytic agents. In addition, large doses of salicylates (3 to 4 g/day and greater) can cause hypoprothrombinemia, an additional risk factor for bleeding. The manufacturer recommends that patients who require anticoagulation while receiving imatinib should receive low-molecular weight heparin or standard heparin instead of warfarin. Coagulation parameters should be monitored closely if warfarin therapy is continued during imatinib therapy. Imatinib is a moderate inhibitor of CYP3A4 and the R-enantiomer is a CYP3A4 substrate, and therefore has potential to increase serum concentrations of warfarin. Since both imatinib and warfarin are highly protein bound (95% and 99%, respectively), displacement from plasma proteins may also occur. In a phase II trial of imatinib, a patient with Philadelphia positive chronic myelogenous leukemia in chronic phase developed cerebral and urinary tract bleeding while receiving imatinib 400 mg daily in combination with warfarin (dose not available). Although a significantly prolonged prothrombin time may have been the result of an increase in the patient's warfarin dose in the days preceding the bleeding, a drug interaction cannot be excluded.
Imipenem; Cilastatin: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including carbapenems, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Imipenem; Cilastatin; Relebactam: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including carbapenems, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Indinavir: (Moderate) Monitor the INR and adjust the dose as necessary if warfarin is coadministered with indinavir. Concurrent use may increase the INR and the risk of bleeding. Indinavir is a CYP3A4 inhibitor and the R-enantiomer of warfarin is a 3A4 substrate. The S-enantiomer exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Indomethacin: (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs). To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients.
Infliximab: (Moderate) The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines (e.g., TNF-alpha) during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during infliximab receipt. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as warfarin. If infliximab is initiated or discontinued in a patient taking warfarin, check the INR; warfarin dose adjustment may be needed.
Inotersen: (Moderate) Use caution with concomitant use of inotersen and anticoagulants due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of anticoagulants in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Insulin Glargine; Lixisenatide: (Moderate) Concomitant administration of 25 mg of warfarin with repeated dosing of lixisenatide 20 mcg delayed warfarin Tmax by approximately 7 hours and reduced Cmax by 19%. No clinically relevant effects on AUC or INR were observed. Although increased INR has not been reported in patients receiving warfarin and lixisenatide, cases of an increased INR have been reported with the concomitant use of warfarin and exenatide. Clinicians should closely monitor patients for changes in INR and bleeding when these drugs are coadministered. Dosage adjustments of warfarin may be necessary.
Intravenous Lipid Emulsions: (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly. (Moderate) Monitor coagulation parameters closely during coadministration. Anticoagulant activity of warfarin may be counteracted by coadministration of intravenous lipid emulsions due to the natural vitamin K content of soybean and olive oils contained in the product.
Intravenous Lipid Emulsions: (Moderate) Monitor coagulation parameters closely during coadministration. Anticoagulant activity of warfarin may be counteracted by coadministration of intravenous lipid emulsions due to the natural vitamin K content of soybean and olive oils contained in the product.
Isavuconazonium: (Moderate) Closely monitor the INR if coadministration of warfarin with isavuconazonium is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Isavuconazonium is a moderate CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Isoniazid, INH: (Moderate) Closely monitor the INR if coadministration of warfarin with isoniazid is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Isoniazid is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Closely monitor the INR if coadministration of warfarin with isoniazid is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Isoniazid is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Isoniazid, INH; Rifampin: (Moderate) Closely monitor the INR if coadministration of warfarin with isoniazid is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Isoniazid is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Isotretinoin: (Moderate) Isotretinoin can decrease the anticoagulation effects of warfarin. If these drugs are coadministered, monitor INR and adjust warfarin doses as needed.
Istradefylline: (Moderate) Closely monitor the INR if coadministration of warfarin with istradefylline is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Istradefylline is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Itraconazole: (Moderate) Closely monitor the INR if coadministration of warfarin with itraconazole is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Itraconazole is a strong CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Ivacaftor: (Moderate) Closely monitor the INR if coadministration of warfarin with ivacaftor is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Ivacaftor is a weak CYP3A4 inhibitor and the R-enantiomer is a CYP3A4 substrate. Ivacaftor is also a weak CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9/CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Ivermectin: (Moderate) Concurrent administration of warfarin and oral ivermectin has been associated with postmarketing reports of elevated INR. In 1 case report, a patient who was previously stable on warfarin developed supratherapeutic INR concentrations (greater than 20) and subsequent hematoma after receiving two 3 mg oral ivermectin doses. Although data are limited, ivermectin has been shown to antagonize vitamin K-dependent clotting factors II, VII, IX, and X.
Ivosidenib: (Moderate) Closely monitor the INR if coadministration of warfarin with ivosidenib is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Ivosidenib is a weak CYP2C9/CYP3A4 inducer and the enantiomers of warfarin are substrates of CYP2C9/CYP3A4.
Ketoconazole: (Moderate) Closely monitor the INR if coadministration of warfarin with ketoconazole is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Ketoconazole is a strong CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Ketoprofen: (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs). To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients.
Ketorolac: (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs). To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients.
Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) Closely monitor the INR if coadministration of warfarin with clarithromycin is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Clarithromycin is a strong CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. (Moderate) The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Lapatinib: (Moderate) Closely monitor the INR if coadministration of warfarin with lapatinib is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Lapatinib is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Larotrectinib: (Moderate) Closely monitor the INR if coadministration of warfarin with larotrectinib is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Larotrectinib is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Ledipasvir; Sofosbuvir: (Moderate) Fluctuations in International Normalized Ratio (INR) have been observed in warfarin recipients who were also receiving treatment for hepatitis C virus (HCV) infections, including ledipasvir. It is recommended to closely monitor these patients for changes in INR both during and after discontinuation of the HCV treatment regimen. (Moderate) Fluctuations in International Normalized Ratio (INR) have been observed in warfarin recipients who were also receiving treatment for hepatitis C virus (HCV) infections, including sofosbuvir. It is recommended to closely monitor these patients for changes in INR both during and after discontinuation of the HCV treatment regimen.
Lefamulin: (Moderate) Closely monitor the INR if coadministration of warfarin with lefamulin is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Lefamulin is a moderate CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Leflunomide: (Moderate) Closely monitor the INR if coadministration of warfarin with leflunomide is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Leflunomide is metabolized to teriflunomide, which is responsible for almost all of leflunomide's activity in vivo. Teriflunomide is a CYP1A2 inducer and the R-enantiomer of warfarin is a CYP1A2 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. Teriflunomide may decrease peak INR by approximately 25%. The mechanism is uncertain but, during pharmacokinetic studies, teriflunomide did not affect the pharmacokinetics of S-warfarin (a CYP2C9 substrate).
Lenacapavir: (Moderate) Closely monitor the INR if coadministration of warfarin with lenacapavir is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. The R-enantiomer of warfarin is a CYP3A substrate and lenacapavir is a moderate CYP3A inhibitor. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Lenalidomide: (Minor) Close monitoring of PT levels and INR in patients with multiple myeloma who require both lenalidomide and warfarin is recommended. According to the manufacturer, the use of warfarin in patients with blood dyscrasias is contraindicated. Therefore, to minimize the bleeding risk, warfarin should be used cautiously in patients receiving antineoplastic agents that cause myelosuppression or blood dyscrasias. In addition, effects of antineoplastic agents on protein synthesis as well as protein binding may lead to transient changes in a patient's INR while receiving warfarin. The INR may increase and/or decrease throughout the chemotherapy cycle leading to supra- or sub-therapeutic values; monitor warfarin therapy closely. There was no change in pharmacokinetic parameters for either agent when a single dose of warfarin 25 mg PO was administered following multiple oral doses of lenalidomide 10 mg/day. Expected PT and INR changes from warfarin use occurred.
Leniolisib: (Moderate) Closely monitor the INR if coadministration of warfarin with leniolisib is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. The R-enantiomer of warfarin is a CYP1A2 substrate and leniolisib is a CYP1A2 inhibitor. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Lesinurad: (Moderate) Closely monitor the INR if coadministration of warfarin with lesinurad is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Lesinurad is a weak CYP3A4 inducer and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Lesinurad; Allopurinol: (Moderate) Closely monitor the INR if coadministration of warfarin with allopurinol is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. The R-enantiomer of warfarin is a CYP1A2 substrate and allopurinol is a CYP1A2 inhibitor. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. (Moderate) Closely monitor the INR if coadministration of warfarin with lesinurad is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Lesinurad is a weak CYP3A4 inducer and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Letermovir: (Moderate) Closely monitor the INR if coadministration of warfarin with letermovir is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Letermovir is a moderate CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Levamlodipine: (Moderate) Closely monitor the INR if coadministration of warfarin with amlodipine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Amlodipine is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Levocarnitine: (Moderate) Closely monitor the INR if coadministration of warfarin with levocarnitine is necessary. Concomitant use has resulted in increased INR levels in case reports. The mechanism of this interaction has not been identified.
Levofloxacin: (Moderate) Closely monitor the INR and for evidence of bleeding if levofloxacin is administered concomitantly with warfarin. There have been postmarketing reports that levofloxacin enhances the effects of warfarin. Elevations of prothrombin time in the setting of concomitant levofloxacin and warfarin use have been associated with episodes of bleeding.
Levoketoconazole: (Moderate) Closely monitor the INR if coadministration of warfarin with ketoconazole is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Ketoconazole is a strong CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Levomefolate: (Moderate) L-methylfolate and warfarin should be used together cautiously. Significant impairment of folate status may occur after 6 months of therapy with warfarin. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.
Levomilnacipran: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of levomilnacipran and warfarin. Carefully monitor patients receiving warfarin therapy if levomilnacipran is initiated or discontinued. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Lincomycin: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including aminoglycosides, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Lixisenatide: (Moderate) Concomitant administration of 25 mg of warfarin with repeated dosing of lixisenatide 20 mcg delayed warfarin Tmax by approximately 7 hours and reduced Cmax by 19%. No clinically relevant effects on AUC or INR were observed. Although increased INR has not been reported in patients receiving warfarin and lixisenatide, cases of an increased INR have been reported with the concomitant use of warfarin and exenatide. Clinicians should closely monitor patients for changes in INR and bleeding when these drugs are coadministered. Dosage adjustments of warfarin may be necessary.
Lomitapide: (Major) Coadministration of warfarin and lomitapide results in increased serum concentrations of warfarin. Monitor the INR regularly, especially after dose adjustments of lomitapide and adjust the warfarin dose as clinically indicated during concurrent use. Lomitapide increases the plasma concentrations of both R-warfarin and S-warfarin by approximately 30% and the INR by 22%. In the lomitapide clinical trials, difficulty controlling INR led to early discontinuation in 1 of 5 patients receiving concomitant warfarin therapy.
Lomustine, CCNU: (Moderate) Due to the bone marrow suppressive and thrombocytopenic effects of lomustine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
Lonafarnib: (Major) Avoid coadministration of lonafarnib and warfarin; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. Concurrent use may also increase warfarin exposure leading to increased bleeding risk. If coadministration is unavoidable, closely monitor INR and for adverse reactions of both drugs. Lonafarnib is a CYP2C9 substrate and strong CYP3A4 inhibitor; warfarin is a CYP3A4 substrate and CYP2C9 inhibitor.
Lopinavir; Ritonavir: (Moderate) Closely monitor the INR if coadministration of warfarin with ritonavir is necessary as concurrent use may alter the exposure of warfarin leading to increased bleeding risk or reduced efficacy. Warfarin is a substrate of CYP3A4, CYP2C9, and CYP1A2 and ritonavir is a strong CYP3A4 inhibitor as well as a CYP1A4, CYP2C9, and CYP3A4 inducer.
Lorlatinib: (Moderate) Closely monitor the INR if coadministration of warfarin with lorlatinib is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Lorlatinib is a moderate CYP3A4 inducer and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Lovastatin: (Moderate) Monitor INR carefully in patients taking warfarin when lovastatin is initiated or a lovastatin dosage adjustment is made. Lovastatin's influence on warfarin's clinical effects is unclear. Bleeding and/or prolonged prothrombin time have been reported in a few patients when lovastatin was taken concurrently with coumarin anticoagulants. However, one small clinical trial found no effect on prothrombin time when lovastatin was given to patients receiving warfarin. Another HMG-CoA reductase inhibitor was found to increase the INR by < 2 seconds in healthy subjects taking low doses of warfarin. Alternatively, it appears that pravastatin and atorvastatin may be less likely to significantly interact with warfarin based on drug interaction studies.
Luliconazole: (Moderate) Theoretically, luliconazole may increase the side effects of warfarin, which is a CYP2C19 and a CYP3A4 substrate. Monitor patients for adverse effects of warfarin, such as increased bleeding, PT, and INR. In vitro, therapeutic doses of luliconazole inhibit the activity of CYP2C19 and CYP3A4 and small systemic concentrations may be noted with topical application, particularly when applied to patients with moderate to severe tinea cruris. No in vivo drug interaction trials were conducted prior to the approval of luliconazole.
Lumacaftor; Ivacaftor: (Moderate) Closely monitor the INR if coadministration of warfarin with ivacaftor is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Ivacaftor is a weak CYP3A4 inhibitor and the R-enantiomer is a CYP3A4 substrate. Ivacaftor is also a weak CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9/CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Lumacaftor; Ivacaftor: (Moderate) Closely monitor the INR if coadministration of warfarin with lumacaftor; ivacaftor is necessary as concurrent use may decrease or increase the exposure of warfarin leading to reduced efficacy or increased bleeding risk. Lumacaftor is a moderate CYP3A4 inducer, ivacaftor is a weak CYP3A4 inhibitor, and the R-enantiomer of warfarin is a CYP3A4 substrate. Ivacaftor is also a weak CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate.
Magnesium Salicylate: (Moderate) Coadministration of salicylates and warfarin may result in an increased risk of bleeding. Salicylates may displace warfarin from protein binding sites leading to increased anticoagulation effects. Hypoprothrombinemia, an additional risk factor for bleeding, also has been reported with salicylates. Non-acetylated salicylates do not appear to affect platelet aggregation in the same manner as aspirin and are associated with a lower risk of bleeding when given currently with warfarin. If salicylates and warfarin are coadministered, monitor the patient for signs or symptoms of bleeding.
Maribavir: (Moderate) Closely monitor the INR if coadministration of warfarin with maribavir is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. The R-enantiomer of warfarin is a CYP3A substrate and maribavir is a weak CYP3A inhibitor. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Mavacamten: (Moderate) Closely monitor the INR if coadministration of warfarin with mavacamten is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. The active metabolite of warfarin, the S-enantiomer, is a CYP2C9 substrate and mavacamten is a CYP2C9 inducer. The R-enantiomer of warfarin is a CYP3A substrate and mavacamten is a CYP3A inducer. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Meclofenamate Sodium: (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs). To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients.
Mefenamic Acid: (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs). To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients.
Mefloquine: (Moderate) Mefloquine has been reported to increase the effects of warfarin in patients stabilized on warfarin therapy. For patients who are stabilized on warfarin therapy and require mefloquine malaria prophylaxis, it is recommended that steady state mefloquine concentrations be achieved prior to leaving for malarial areas. This allows for prothrombin time monitoring and warfarin dosage adjustments.
Megestrol: (Moderate) At high doses, megestrol may be associated alterations in warfarin pharmacokinetics that may increase warfarin exposure. Carefully monitor the INR when these drugs are used together. Lower doses of warfarin may be necessary when megestrol is given. In one study, a small change in the rate of warfarin clearance was see with concomitant administration of high doses of megestrol; a minor decrease observed in warfarin clearance may be of clinical importance. Additionally, a 71% increase in warfarin's half-life was seen.
Meloxicam: (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs). To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients.
Meprobamate: (Moderate) Meprobamate has been associated with a decreased anticoagulation response to warfarin. Monitor coagulation parameters and adjust warfarin dosage as needed.
Mercaptopurine, 6-MP: (Major) The concomitant use of mercaptopurine and warfarin may decrease the anticoagulant effectiveness of warfarin. If concurrent use is required, monitor prothrombin time or INR and adjust the warfarin dose to maintain the desired level of anticoagulation.
Meropenem: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including carbapenems, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Meropenem; Vaborbactam: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including carbapenems, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Mesalamine, 5-ASA: (Moderate) Mesalamine may alter the anticoagulant effects of warfarin. Closely monitor a patient's PT and INR during and following concomitant mesalamine therapy; dosage adjustments of anticoagulants may be necessary. In elderly patients taking mesalamine with anticoagulants, consider regularly monitoring complete blood cell counts and platelet counts, as an increased risk for blood dyscrasia has been reported in geriatric adults. In a published case study, a decreased effect of warfarin was reported when mesalamine was prescribed. Iincreased prothrombin time (PT) in patients taking concomitant warfarin has been reported during mesalamine treatment.
Methimazole: (Moderate) The interaction between thioamine antithyroid agents and warfarin is variable. The effects of warfarin can be enhanced due to the vitamin K antagonistic properties of methimazole or propylthiouracil, PTU. Isolated cases have reported hypoprothrombinemia due to methimazole or propylthiouracil, which may be additive with warfarin. In addition, as hyperthyroidism is corrected, the anticoagulant effect of warfarin can diminish due to a change in the clearance rate of endogenous clotting factors. Thus, administration of antithyroid agents such as methimazole or PTU can also reduce the effectiveness of warfarin. INRs should be monitored closely whenever methimazole is added or discontinued during warfarin therapy or when the thyroid status of a patient is expected to change. Warfarin dosage should be adjusted accordingly based on the INR and the clinical goals for the patient.
Methohexital: (Moderate) Closely monitor the INR if coadministration of warfarin with barbiturates is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Barbiturates are CYP1A2 and moderate CYP2C9/CYP3A4 inducers and warfarin's enantiomers are substrates of CYP1A2/CYP2C9/CYP3A4. Discontinuation of a barbiturate during warfarin therapy has led to fatal bleeding episodes when the hepatic enzyme-inducing properties of the barbiturate subside. Clinicians should note that warfarin doses will require readjustment if a barbiturate is added or discontinued during warfarin therapy. Dosage adjustments of warfarin may be necessary within 2 weeks of beginning barbiturate treatment, but the effect of the barbiturate on warfarin metabolism may persist for more than a month after discontinuing the barbiturate.
Methotrexate: (Major) Avoid concomitant use of methotrexate and warfarin due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Methotrexate is approximately 50% protein bound; warfarin is highly protein-bound. Coadministration may displace methotrexate from its protein binding sites, increasing methotrexate plasma concentrations.
Methoxsalen: (Minor) Agents, such as anticoagulants, that decrease clotting could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
Methylphenidate Derivatives: (Moderate) A dose adjustment of warfarin and more frequent INR monitoring may be required when initiating or discontinuing methylphenidate derivatives. Case reports suggest a potential interaction between methylphenidate derivatives and coumarin anticoagulants. Human pharmacologic studies have shown that methylphenidate derivatives may inhibit the metabolism of warfarin. The mechanism of the potential interaction is not clear. A dose adjustment of warfarin and more frequent monitoring of the INR may be required when initiating or discontinuing methylphenidate derivatives.
Methylsulfonylmethane, MSM: (Moderate) Increased effects from concomitant anticoagulant drugs such as increased bruising or blood in the stool have been reported in patients taking methylsulfonylmethane, MSM. Although these effects have not been confirmed in published medical literature or during clinical studies, clinicians should consider using methylsulfonylmethane, MSM with caution in patients who are taking anticoagulants such as warfarin until data confirming the safety of MSM in patients taking these drugs are available. During one of the available, published clinical trials in patients with osteoarthritis, those patients with bleeding disorders or using anticoagulants or antiplatelets were excluded from enrollment. Patients who choose to consume methylsulfonylmethane, MSM while receiving warfarin should be observed for increased bleeding.
Methyltestosterone: (Moderate) Methyltestosterone can increase the effects of anticoagulants through reduction of procoagulant factor. Patients receiving oral anticoagulant therapy should be closely monitored, especially when methyltestosterone treatment is initiated or discontinued.
Metreleptin: (Moderate) Upon initiation or discontinuation of metreleptin in a patient receiving warfarin, more frequent INR monitoring should be performed; warfarin dosage adjustments may be necessary. Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with a narrow therapeutic index, such as warfarin.
Metronidazole: (Moderate) Monitor prothrombin time and INR and watch for signs of bleeding with concomitant use of systemic metronidazole and warfarin. Warfarin dose adjustments may be necessary. Metronidazole can potentiate the anticoagulant effect of warfarin, resulting in prolongation of prothrombin time and increased risk of bleeding.
Mexiletine: (Moderate) Closely monitor the INR if coadministration of warfarin with mexiletine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Mexiletine is a CYP1A2 inhibitor and the R-enantiomer of warfarin is a CYP1A2 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Miconazole: (Moderate) Concomitant administration of miconazole and warfarin has resulted in enhancement of anticoagulant effect. Closely monitor prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests if miconazole is administered concomitantly with warfarin. Also monitor for evidence of bleeding. Miconazole is a known inhibitor of CYP2C9 and CYP3A4. The systemic absorption of buccal miconazole is minimal and plasma concentrations of miconazole are substantially lower than when given intravenously. However, there have been reported cases of bleeding and bruising with orally administered miconazole. (Moderate) Concomitant administration of miconazole and warfarin has resulted in enhancement of anticoagulant effect. Closely monitor prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests if topical or vaginal miconazole is administered concomitantly with warfarin. Also monitor for evidence of bleeding. Miconazole is a known inhibitor of CYP2C9 and CYP3A4. The systemic absorption of miconazole following vaginal or topical administration is minimal and plasma concentrations of miconazole are substantially lower than when given intravenously. However, there have been reported cases of bleeding and bruising following the concomitant use of warfarin and topical or intravaginal miconazole.
Miconazole; Petrolatum; Zinc Oxide: (Moderate) Concomitant administration of miconazole and warfarin has resulted in enhancement of anticoagulant effect. Closely monitor prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests if topical or vaginal miconazole is administered concomitantly with warfarin. Also monitor for evidence of bleeding. Miconazole is a known inhibitor of CYP2C9 and CYP3A4. The systemic absorption of miconazole following vaginal or topical administration is minimal and plasma concentrations of miconazole are substantially lower than when given intravenously. However, there have been reported cases of bleeding and bruising following the concomitant use of warfarin and topical or intravaginal miconazole.
Mifepristone: (Major) When mifepristone is used for the termination of pregnancy, concurrent use of anticoagulants is contraindicated due to the risk of serious bleeding. Use with caution in other circumstances due to increased warfarin exposure. Closely monitor the INR if coadministration of warfarin with mifepristone is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Mifepristone is a moderate CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate. Mifepristone is a strong CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. The lowest effective dose of warfarin should be used. Due to the slow elimination of mifepristone from the body, such an interaction may be observed for a prolonged period after its administration.
Miglitol: (Moderate) The manufacturer has stated that miglitol does not appear to affect the pharmacokinetics or pharmacodynamics of warfarin. There has been, however, one case report published of an interaction between warfarin and acarbose published. The mechanism or incidence of the interaction has not been established. INRs should be closely observed during the first month of acarbose or miglitol therapy.
Milnacipran: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of milnacipran and warfarin. Carefully monitor patients receiving warfarin therapy if milnacipran is initiated or discontinued. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding. At steady-state, milnacipran did not affect the INR or pharmacokinetics of a single dose of warfarin 25 mg.
Miltefosine: (Moderate) Caution is advised when administering miltefosine with anticoagulants, as use of these drugs together may increase risk for bleeding. Miltefosine, when administered f or the treatment of visceral leishmaniasis, has been associated with thrombocytopenia; monitor platelet counts in patients receiving treatment for this indication. In addition, monitor closely for increased bleeding if use in combination with an anticoagulant.
Mineral Oil: (Moderate) Since vitamin K absorption may be theoretically decreased by the use of mineral oil, patients on chronic stable doses of warfarin should be monitored closely for changes in coagulation parameters when mineral oil is prescribed for regular use. This interaction is more theoretical than of practical concern, as evidence of this interaction is lacking, particularly since administration of mineral oil is likely to be on an 'as needed' intermittent basis. It would be prudent to monitor the response to warfarin (e.g., INR) regularly in patients who report concurrent use of mineral oil.
Mirabegron: (Moderate) When given in combination, mirabegron increased the mean warfarin (S- and R-warfarin) Cmax by approximately 4% and the AUC by approximately 9% when administered as a single dose of 25 mg warfarin after multiple doses of 100 mg mirabegron. Following a single dose administration of 25 mg warfarin, mirabegron had no effect on INR and prothrombin time. However, the effect of mirabegron on multiple doses of warfarin and on warfarin pharmacodynamic end points such as INR and prothrombin time has not been fully investigated. Therefore, careful monitoring and dose adjustment may be necessary.
Mirtazapine: (Moderate) In a study of 16 healthy subjects, concurrent use of mirtazapine (30 mg/day) and warfarin resulted in a small (0.20) but statistically significant increase in INR. The mechanism of this interaction has not been described. Until further information becomes available, it is advisable to carefully monitor the INR during concurrent use of mirtazapine and warfarin.
Mitapivat: (Moderate) Closely monitor the INR if coadministration of warfarin with mitapivat is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. The active metabolite of warfarin, the S-enantiomer, is a CYP2C9 substrate and mitapivat is a CYP2C9 inducer. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Mitotane: (Moderate) Closely monitor the INR if coadministration of warfarin with mitotane is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Mitotane is a strong CYP3A4 inducer and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Mobocertinib: (Moderate) Closely monitor the INR if coadministration of warfarin with mobocertinib is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. The R-enantiomer of warfarin is a CYP3A substrate and mobocertinib is a weak CYP3A inducer. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Modafinil: (Moderate) Closely monitor the INR if coadministration of warfarin with modafinil is necessary as concurrent use may increase or decrease the exposure of warfarin leading to increased bleeding risk or reduced efficacy. Modafinil is a weak CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate. Additionally, modafinil is a CYP1A2 inducer and warfarin is a CYP1A2 substrate.
Montelukast: (Moderate) Closely monitor the INR if coadministration of warfarin with montelukast is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. The R-enantiomer of warfarin is a CYP1A2 substrate and montelukast is CYP1A2 inducer. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Moxifloxacin: (Moderate) Quinolones, including moxifloxacin, have been reported to enhance the anticoagulant effects of warfarin or its derivatives. In addition, infectious disease and its accompanying inflammatory process, age, and general status of the patient are risk factors for increased anticoagulant activity. Therefore closely monitor the prothrombin time (PT), INR, or other suitable anticoagulation tests if moxifloxacin is administered concomitantly with warfarin. Monitor for bleeding.
Mycophenolate: (Moderate) Mycophenolate may causes thrombocytopenia and increase the risk for bleeding. Agents which may lead to an increased incidence of bleeding in patients with thrombocytopenia include anticoagulants.
Nabumetone: (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs). To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients.
Nafcillin: (Moderate) Closely monitor the INR if coadministration of warfarin with nafcillin is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Nafcillin is a moderate CYP3A4 inducer and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. High-dose (e.g., 12 g/day IV) nafcillin added to established warfarin therapy may warrant a 2- to 5-fold increase in warfarin dosage within 2 weeks of starting therapy. The dosage of warfarin may be reduced to pretreatment levels within 4 weeks of discontinuing nafcillin therapy.
Naproxen: (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs). To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients.
Naproxen; Esomeprazole: (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs). To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients.
Naproxen; Pseudoephedrine: (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs). To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients.
Nefazodone: (Moderate) Closely monitor the INR if coadministration of warfarin with nefazodone is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Nefazodone is a strong CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Nelarabine: (Moderate) Due to the thrombocytopenic effects of nelarabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
Nelfinavir: (Moderate) Monitor the INR and adjust the dose as necessary if warfarin is coadministered with nelfinavir. Concurrent use may increase the INR and the risk of bleeding. Nelfinavir is a CYP3A4 inhibitor and the R-enantiomer of warfarin is a 3A4 substrate. The S-enantiomer exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Neomycin: (Moderate) Oral administration of neomycin inhibits vitamin K-synthesizing intestinal bacteria and can potentiate the effects of warfarin.
Netupitant, Fosnetupitant; Palonosetron: (Moderate) Closely monitor the INR if coadministration of warfarin with netupitant is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Netupitant is a moderate CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Nevirapine: (Moderate) Closely monitor the INR if coadministration of warfarin with nevirapine is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. The R-enantiomer of warfarin is a CYP3A substrate and nevirapine is a CYP3A inducer. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Niacin, Niacinamide: (Moderate) Niacin (nicotinic acid) is occasionally associated with small but statistically significant increases (mean 4%) in prothrombin time. While rare, there is a possibility that an interaction would occur in some patients stabilized on warfarin. It appears prudent to monitor the INR periodically.
Niacin; Simvastatin: (Moderate) Niacin (nicotinic acid) is occasionally associated with small but statistically significant increases (mean 4%) in prothrombin time. While rare, there is a possibility that an interaction would occur in some patients stabilized on warfarin. It appears prudent to monitor the INR periodically. (Moderate) Per prescribing information for warfarin sodium (Coumadin), all HMG-CoA reductase inhibitors (statins) have been associated with potentiation of warfarin's clinical effect. However, it appears that pravastatin and atorvastatin may be less likely to significantly interact with warfarin based on drug interaction studies. In addition, atorvastatin has been reported to slightly and transiently decrease the anticoagulant activity of warfarin; these effects were not considered clinically significant. In general, it is prudent to monitor INR at baseline, at initiation of these HMG Co-A reductase inhibitors, and after subsequent dosage changes. Adjust warfarin dosage based on INR and clinical response. Once a stable INR is documented, the INR can be monitored at the intervals otherwise recommended based on the indication for anticoagulation and co-existing conditions.
Nicardipine: (Moderate) Closely monitor the INR if coadministration of warfarin with nicardipine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Nicardipine is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Nifedipine: (Minor) Concurrent administration of highly protein-bound agents such as nifedipine can theoretically displace warfarin from its binding sites, with potential for increased anticoagulation effects. The manufacturer of nifedipine reports rare cases of increased prothrombin time when nifedipine was administered to patients taking warfarin; the relationship to nifedipine is uncertain.
Nilotinib: (Moderate) Closely monitor the INR if coadministration of warfarin with nilotinib is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Nilotinib is a moderate CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Nilutamide: (Moderate) Nilutamide inhibits the activity of hepatic cytochrome P450 isoenzymes and may reduce the metabolism of drugs by these enzymes. Drugs with a low therapeutic margin, such as warfarin, could have a delayed elimination and corresponding increase in serum half-life. Warfarin dose may need to be modified if administered concomitantly with nilutamide.
Nintedanib: (Moderate) Nintedanib is a VEGFR inhibitor and may increase the risk of bleeding. Monitor patients who are taking anticoagulants closely and adjust anticoagulation therapy as necessary. Use nintedanib in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.
Nirmatrelvir; Ritonavir: (Moderate) Closely monitor the INR if coadministration of warfarin with ritonavir is necessary as concurrent use may alter the exposure of warfarin leading to increased bleeding risk or reduced efficacy. Warfarin is a substrate of CYP3A4, CYP2C9, and CYP1A2 and ritonavir is a strong CYP3A4 inhibitor as well as a CYP1A4, CYP2C9, and CYP3A4 inducer.
Nitazoxanide: (Moderate) No interactions with other drugs have been reported by patients using nitazoxanide. The active metabolite of nitazoxanide, tizoxanide, is highly bound to plasma proteins (> 99%). The manufacturer has reported that nitazoxanide does not affect the pharmacokinetics or anticoagulant effects of warfarin in healthy volunteers. No studies have been performed to determine if there are interactions with other drugs that exhibit high protein binding (e.g., hydantoins like phenytoin or fosphenytoin, the sulfonylureas, or salicylates). Therefore, caution should be exercised when administering nitazoxanide concurrently with other highly plasma protein-bound drugs with narrow therapeutic indices because competition for binding sites may occur. No other clinical studies have been conducted to specifically exclude the possibility of interactions between nitazoxanide and other medicinal products which are not highly-protein bound.
Nitisinone: (Moderate) Closely monitor the INR if coadministration of warfarin with nitisinone is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Nitisinone is a weak CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Nitrofurantoin: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including nitrofurantoin, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Nonsteroidal antiinflammatory drugs: (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs). To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients.
Obeticholic Acid: (Moderate) Closely monitor the INR if coadministration of warfarin with obeticholic acid is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. The R-enantiomer of warfarin is a CYP1A2 substrate and obeticholic acid is a CYP1A2 inhibitor. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. Concomitant use of 25 mg warfarin as a single dose with obeticholic acid 10 mg once daily resulted in a 13% increase in systemic exposure to S-warfarin and an 11% decrease in maximum INR.
Obinutuzumab: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
Odevixibat: (Moderate) Closely monitor the INR if coadministration of warfarin with odevixibat is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. The R-enantiomer of warfarin is a CYP3A substrate and odevixibat is a weak CYP3A inducer. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Ofloxacin: (Moderate) Some quinolones have been reported to enhance the effects of the oral anticoagulant warfarin or its derivatives. Therefore, if ofloxacin is administered concomitantly with warfarin, the prothrombin time (PT), INR, or other suitable coagulation test should be closely monitored. Monitor for evidence of bleeding.
Olanzapine; Fluoxetine: (Moderate) Closely monitor the INR if coadministration of warfarin with fluoxetine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Fluoxetine is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. Fluoxetine is also a weak CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate. An increased risk of bleeding, including gastrointestinal bleeding, has been reported with drugs that interfere with serotonin reuptake; thus, concurrent use of fluoxetine and warfarin may result in an additive risk of bleeding events. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Closely monitor the INR if coadministration of warfarin with amlodipine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Amlodipine is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Olsalazine: (Moderate) Olsalazine does not interfere with the protein binding of warfarin, however increased prothrombin time (PT) in patients taking concomitant warfarin has been reported. Closely monitor a patient's PT and INR during and following concomitant olsalazine therapy; dosage adjustments of anticoagulants may be necessary. In elderly patients taking olsalazine with anticoagulants, consider regularly monitoring complete blood cell counts and platelet counts, as an increased risk for blood dyscrasia has been reported in geriatric adults.
Olutasidenib: (Moderate) Closely monitor the INR if coadministration of warfarin with olutasidenib is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. The R-enantiomer of warfarin is a CYP3A substrate and olutasidenib is a CYP3A inducer. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Omacetaxine: (Major) Avoid the concomitant use of omacetaxine and anticoagulants when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
Omaveloxolone: (Moderate) Closely monitor the INR if coadministration of warfarin with omaveloxolone is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. The R-enantiomer of warfarin is a CYP3A substrate and omaveloxolone is a CYP3A inducer. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Omeprazole; Amoxicillin; Rifabutin: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Omidubicel: (Moderate) Because of the potential effects of certain dextran formulations on bleeding time, use with caution in patients on anticoagulants concurrently.
Oritavancin: (Moderate) Closely monitor the INR if coadministration of warfarin with oritavancin is necessary as concurrent use may increase or decrease the exposure of warfarin leading to increased bleeding risk or reduced efficacy. Oritavancin is a weak CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate. Additionally, oritavancin is a weak CYP3A4 inducer and warfarin is a CYP3A4 substrate.
Orlistat: (Moderate) Warfarin therapy can be affected by changes in dietary intake of vitamin K. Since vitamin K absorption may be affected by orlistat, patients on chronic stable doses of warfarin should be monitored closely for changes in coagulation parameters when orlistat is prescribed; some experts recommend that the INR be monitored weekly during the first month of orlistat therapy. Reports of decreased prothrombin, increased INR and unbalanced anticoagulant treatment resulting in change of hemostatic parameters have been reported in patients treated concomitantly with orlistat and anticoagulants. Orlistat 120 mg PO 3 times per day administered orally for 16 days in 12 normal-weight subjects did not appear to alter vitamin K nutritional status. No changes in the pharmacokinetics or pharmacodynamics (PT and serum Factor VII) of warfarin were noted following a single 30 mg dose of warfarin in a placebo-controlled, randomized, third-party blind, 2-way crossover study. However, vitamin K levels decreased.
Osilodrostat: (Moderate) Closely monitor the INR if coadministration of warfarin with osilodrostat is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Osilodrostat is a moderate CYP1A2 inhibitor and weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP1A2 and CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Ospemifene: (Moderate) Administer warfarin with ospemifene with considerable caution. The effect of ospemifene on clotting time such as the International Normalized Ratio (INR) or prothrombin time (PT) has not been studied. Repeated administration of ospemifene had no effect on the pharmacokinetics of a single 10 mg dose of warfarin. However, no study was conducted with multiple doses of warfarin.
Oxacillin: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Oxaliplatin: (Moderate) Increase the frequency of PT/INR monitoring in patients who are receiving concomitant therapy with oxaliplatin and warfarin. Prolonged PT/INR occasionally associated with hemorrhage have been reported in patients who received oxaliplatin in combination with fluorouracil/leucovorin while on anticoagulants.
Oxandrolone: (Moderate) An increased effect of anticoagulants may occur with oxandrolone; the anticoagulant dosage may need adjustment downward with oxandrolone initiation or adjustment upward with oxandrolone discontinuation to maintain the desired clinical effect. Oxandrolone suppresses clotting factors II, V, VII, and X, which results in an increased prothrombin time. An increase in plasminogen-activator activity, and serum concentrations of plasminogen, protein C, and antithrombin III have occurred with several 17-alpha-alkylated androgens. For example, concurrent use of oxandrolone and warfarin may result in unexpectedly large increases in the INR or prothrombin time (PT). A multidose study of oxandrolone (5 or 10 mg PO twice daily) in 15 healthy individuals concurrently treated with warfarin resulted in significant increases in warfarin half-life and AUC; a 5.5-fold decrease in the mean warfarin dosage from 6.13 mg/day to 1.13 mg/day (approximately 80 to 85% dose reduction) was necessary to maintain a target INR of 1.5. According to the manufacturer, if oxandrolone therapy is initiated in a patient already receiving warfarin, the dose of warfarin may need to be decreased significantly to reduce the potential for excessive INR elevations and associated risk of serious bleeding events. The patient should be closely monitored with frequent evaluation of the INR and clinical parameter, and the dosage of warfarin should be adjusted as necessary until a stable target INR is achieved. Careful monitoring of the INR and necessary adjustment of the warfarin dosage are also recommended when the androgen therapy is changed or discontinued.
Oxaprozin: (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs). To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients.
Oxcarbazepine: (Moderate) Closely monitor the INR if coadministration of warfarin with oxcarbazepine is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Oxcarbazepine is a weak CYP3A4 inducer and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Oxymetholone: (Moderate) Concomitant use of anabolic steroids such as oxymetholone and oral anticoagulants such as warfarin may increase INR or prothrombin time (PT) and the anticoagulant dosage may need to be decreased. Anabolic steroids may suppress clotting factors II, V, VII, and X and increase PT. In patients receiving warfarin, closely monitor the INR and PT when initiating oxymetholone therapy or when subsequently changing the dosage or discontinuing oxymetholone therapy; adjust the warfarin dose as necessary to maintain a therapeutic INR and PT. Monitor patients for signs and symptoms of bleeding.
Pacritinib: (Moderate) Closely monitor the INR if coadministration of warfarin with pacritinib is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Pacritinib is a weak CYP3A4 and CYP1A2 inhibitor and the R-enantiomer of warfarin is both a CYP3A4 and CYP1A2 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Palbociclib: (Moderate) Closely monitor the INR if coadministration of warfarin with palbociclib is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Palbociclib is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Paromomycin: (Moderate) A small rise in warfarin-induced hypoprothrombinemia may occur, possibly due to interference in absorption of dietary vitamin K by paromomycin.
Paroxetine: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of paroxetine and warfarin. Carefully monitor patients receiving warfarin therapy if paroxetine is initiated or discontinued. Some data suggest there may be a pharmacodynamic interaction that causes increased bleeding without a change in prothrombin time. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Pazopanib: (Moderate) Closely monitor the INR if coadministration of warfarin with pazopanib is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Pazopanib is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Peginterferon Alfa-2b: (Moderate) Closely monitor the INR if coadministration of warfarin with peginterferon alfa-2b is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Peginterferon alfa-2b is a CYP1A2 inhibitor and the R-enantiomer of warfarin is a CYP1A2 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Penicillin G Benzathine: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Penicillin G Benzathine; Penicillin G Procaine: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Penicillin G Procaine: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Penicillin G: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Penicillin V: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Pentobarbital: (Moderate) Closely monitor the INR if coadministration of warfarin with barbiturates is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Barbiturates are CYP1A2 and moderate CYP2C9/CYP3A4 inducers and warfarin's enantiomers are substrates of CYP1A2/CYP2C9/CYP3A4. Discontinuation of a barbiturate during warfarin therapy has led to fatal bleeding episodes when the hepatic enzyme-inducing properties of the barbiturate subside. Clinicians should note that warfarin doses will require readjustment if a barbiturate is added or discontinued during warfarin therapy. Dosage adjustments of warfarin may be necessary within 2 weeks of beginning barbiturate treatment, but the effect of the barbiturate on warfarin metabolism may persist for more than a month after discontinuing the barbiturate.
Pentosan: (Major) Pentosan is a weak anticoagulant. Pentosan has 1/15 the anticoagulant activity of heparin. An additive risk of bleeding may be seen in patients receiving warfarin in combination with pentosan. In a study of healthy subjects who received pentosan 100 mg or placebo every 8 hours for 7 days and received warfarin at a dose to achieve a target INR of 1.4-1.8, the pharmacokinetic parameters of S- and R-warfarin and the INR were similar with and without pentosan.
Pentoxifylline: (Moderate) Pentoxifylline interacts with warfarin by increasing the inhibition of platelet aggregation when the drugs are administered together. Prolonged prothrombin times have been reported when pentoxifylline and oral anticoagulants have been used concomitantly. Therefore, careful monitoring of prothrombin time, signs of bleeding, and hematocrit/hemoglobin should be done periodically.
Perindopril; Amlodipine: (Moderate) Closely monitor the INR if coadministration of warfarin with amlodipine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Amlodipine is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Pexidartinib: (Moderate) Closely monitor the INR if coadministration of warfarin with pexidartinib is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Pexidartinib is a CYP3A4 inducer and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Phenicol Derivatives: (Moderate) Closely monitor the INR if coadministration of warfarin with a phenicol derivative, such as chloramphenicol, is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Phenicol derivatives are strong CYP3A4 inhibitors and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Phenobarbital: (Moderate) Closely monitor the INR if coadministration of warfarin with barbiturates is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Barbiturates are CYP1A2 and moderate CYP2C9/CYP3A4 inducers and warfarin's enantiomers are substrates of CYP1A2/CYP2C9/CYP3A4. Discontinuation of a barbiturate during warfarin therapy has led to fatal bleeding episodes when the hepatic enzyme-inducing properties of the barbiturate subside. Clinicians should note that warfarin doses will require readjustment if a barbiturate is added or discontinued during warfarin therapy. Dosage adjustments of warfarin may be necessary within 2 weeks of beginning barbiturate treatment, but the effect of the barbiturate on warfarin metabolism may persist for more than a month after discontinuing the barbiturate.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Closely monitor the INR if coadministration of warfarin with barbiturates is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Barbiturates are CYP1A2 and moderate CYP2C9/CYP3A4 inducers and warfarin's enantiomers are substrates of CYP1A2/CYP2C9/CYP3A4. Discontinuation of a barbiturate during warfarin therapy has led to fatal bleeding episodes when the hepatic enzyme-inducing properties of the barbiturate subside. Clinicians should note that warfarin doses will require readjustment if a barbiturate is added or discontinued during warfarin therapy. Dosage adjustments of warfarin may be necessary within 2 weeks of beginning barbiturate treatment, but the effect of the barbiturate on warfarin metabolism may persist for more than a month after discontinuing the barbiturate.
Phentermine; Topiramate: (Moderate) Closely monitor the INR if coadministration of warfarin with topiramate is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy; increased bleeding is also possible with the combination. Topiramate is a weak CYP3A4 inducer and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Phytonadione, Vitamin K1: (Major) Phytonadione antagonizes the actions of warfarin. Phytonadione catalyzes the hepatic synthesis of blood-clotting factors including active prothrombin (Factor II), Factor VII, Factor IX, and Factor X. Warfarin inhibits vitamin K-epoxide reductase depleting the reduced form of vitamin K (vitamin KH2), thus preventing the gamma-carboxylation of the vitamin K-dependent coagulant proteins resulting in the synthesis of inactive proteins. S-warfarin affects vitamin K to a greater extent than R-warfarin. The degree of effect on the vitamin K-dependent proteins is related to the dose of warfarin. Phytonadione, in doses proportional to warfarin-induced hypoprothrombinemia, can overcome this effect. Alterations in vitamin K intake influence the response to warfarin. Temporary resistance to warfarin or other prothrombin-depressing anticoagulants occurs after treatment with phytonadione; this may be long-lasting when large doses of phytonadione are used. If relatively large doses of phytonadione have been used, when reinstituting anticoagulant therapy it may be necessary to use somewhat higher doses or to use an anticoagulant that acts by a different mechanism (i.e., heparin).
Piperacillin; Tazobactam: (Moderate) Some penicillins (e.g., piperacillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
Piroxicam: (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs). To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients.
Pirtobrutinib: (Moderate) Closely monitor the INR if coadministration of warfarin with pirtobrutinib is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. The R-enantiomer of warfarin is a CYP3A substrate and pirtobrutinib is a weak CYP3A inhibitor. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Pitavastatin: (Minor) Although no clinically significant interaction has been demonstrated with warfarin and pitavastatin, the manufacturer of pitavastatin recommends patients receiving warfarin have their PT and INR monitored when pitavastatin is added to therapy.
Pitolisant: (Moderate) Closely monitor the INR if coadministration of warfarin with pitolisant is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Pitolisant is a weak CYP3A4 inducer and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Polymyxin B: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including polymyxin B, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Posaconazole: (Moderate) Closely monitor the INR if coadministration of warfarin with posaconazole is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Posaconazole is a strong CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Major) Prasterone (DHEA) is contraindicated for use in patients with active deep vein thrombosis, pulmonary embolism or history of these conditions. Prasterone is also contraindicated in patients with active arterial thromboembolic disease (for example, stroke and myocardial infarction), or a history of these conditions. Thus, patients receiving anticoagulation due to a history of these conditions are not candidates for prasterone treatment. DHEA is converted to androgens and estrogens within the human body and thus may affect hemostasis via androgenic or estrogenic effects. Estrogens increase the production of clotting factors VII, VIII, IX, and X. Androgens, such as testosterone, increase the synthesis of several anticoagulant and fibrinolytic proteins. Because of the potential effects on coagulation, patients receiving prasterone or DHEA concurrently with preventative anticoagulants (e.g., warfarin or heparin) or other platelet inhibitors, including aspirin, ASA should be monitored for side effects or the need for dosage adjustments.
Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Major) Prasterone (DHEA) is contraindicated for use in patients with active deep vein thrombosis, pulmonary embolism or history of these conditions. Prasterone is also contraindicated in patients with active arterial thromboembolic disease (for example, stroke and myocardial infarction), or a history of these conditions. Thus, patients receiving anticoagulation due to a history of these conditions are not candidates for prasterone treatment. DHEA is converted to androgens and estrogens within the human body and thus may affect hemostasis via androgenic or estrogenic effects. Estrogens increase the production of clotting factors VII, VIII, IX, and X. Androgens, such as testosterone, increase the synthesis of several anticoagulant and fibrinolytic proteins. Because of the potential effects on coagulation, patients receiving prasterone or DHEA concurrently with preventative anticoagulants (e.g., warfarin or heparin) or other platelet inhibitors, including aspirin, ASA should be monitored for side effects or the need for dosage adjustments.
Prasugrel: (Moderate) The potential for bleeding is increased when prasugrel and oral anticoagulants, such as warfarin, are coadministered. According to the manufacturer, a significant prolongation of the bleeding time was observed when prasugrel was administered with 15 mg of warfarin. Avoid coadministration of prasugrel and warfarin when possible; monitor for bleeding if prasugrel is given concurrently with warfarin.
Pravastatin: (Moderate) Coadministration of pravastatin (40 mg) has been reported to have no clinically significant effect on prothrombin time in normal elderly subjects previously stabilized on warfarin. However, per prescribing information for warfarin sodium (Coumadin), all HMG-CoA reductase inhibitors (statins), including pravastatin, have been associated with potentiation of warfarin's clinical effect. However, it appears that pravastatin may be less likely to significantly interact with warfarin based on drug interaction studies. In general, it is prudent to monitor INR at baseline, at initiation of pravastatin, and after subsequent dosage changes. Adjust warfarin dosage based on INR and clinical response. Once a stable INR is documented, the INR can be monitored at the intervals otherwise recommended based on the indication for anticoagulation and co-existing conditions.
Primidone: (Moderate) Closely monitor the INR if coadministration of warfarin with barbiturates is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Barbiturates are CYP1A2 and moderate CYP2C9/CYP3A4 inducers and warfarin's enantiomers are substrates of CYP1A2/CYP2C9/CYP3A4. Discontinuation of a barbiturate during warfarin therapy has led to fatal bleeding episodes when the hepatic enzyme-inducing properties of the barbiturate subside. Clinicians should note that warfarin doses will require readjustment if a barbiturate is added or discontinued during warfarin therapy. Dosage adjustments of warfarin may be necessary within 2 weeks of beginning barbiturate treatment, but the effect of the barbiturate on warfarin metabolism may persist for more than a month after discontinuing the barbiturate.
Propafenone: (Major) Concomitant use of propafenone and warfarin results in a significant increase in warfarin plasma levels by 39%, with an increase in prothrombin time of about 25%. Warfarin dosages should be adjusted as needed to attain appropriate INR goals for the individual patient.
Propofol: (Moderate) The administration of high-dose propofol infusions has been associated with the reversal of warfarin anticoagulation. Propofol is emulsified with soybean oil 10%, which contains vitamin K. Close monitoring of the anticoagulation effect of warfarin is recommended for patients requiring concurrent propofol.
Propranolol: (Moderate) Propranolol has been shown to increase warfarin AUC, and concurrent increases in INR values have been reported. Patients should be monitored for changes in anticoagulation parameters during concurrent therapy with propranolol and warfarin.
Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Propranolol has been shown to increase warfarin AUC, and concurrent increases in INR values have been reported. Patients should be monitored for changes in anticoagulation parameters during concurrent therapy with propranolol and warfarin.
Propylthiouracil, PTU: (Moderate) The interaction between thioamine antithyroid agents and warfarin is variable. Administration of propylthiouracil, PTU can reduce the effectiveness of warfarin. Conversely, the effects of warfarin can be enhanced due to the anti-vitamin K properties of propylthiouracil, PTU. Prothrombin times should be monitored closely. Warfarin dosage should be adjusted accordingly based on the INR and the clinical goals for the patient.
Protein C Concentrate, Human: (Major) Concomitant administration of vitamin K antagonists (coumarin anticoagulants such as warfarin) and protein C concentrate should be done with close monitoring. Upon initiation of vitamin K antagonists, patients may experience a transient hypercoagulable state before the desired anticoagulant effect becomes apparent. This transient effect may occur because protein C also is a vitamin K-dependent plasma protein with a much shorter half-life than other vitamin K-dependent proteins such as Factor II, IX and X. Upon initiation of treatment, the activity of protein C is more rapidly suppressed than that of the procoagulant factors. Therefore, if a patient is switched to oral anticoagulants, protein C replacement must be continued until stable anticoagulation is established. In addition, patients with severe congenital protein C deficiency are at a higher risk of developing warfarin-induced skin necrosis. Monitor patients closely during treatment.
Prothrombin Complex Concentrate, Human: (Major) Concomitant administration of vitamin K antagonists (coumarin anticoagulants such as warfarin) and protein C concentrate should be done with close monitoring. Upon initiation of vitamin K antagonists, patients may experience a transient hypercoagulable state before the desired anticoagulant effect becomes apparent. This transient effect may occur because protein C also is a vitamin K-dependent plasma protein with a much shorter half-life than other vitamin K-dependent proteins such as Factor II, IX and X. Upon initiation of treatment, the activity of protein C is more rapidly suppressed than that of the procoagulant factors. Therefore, if a patient is switched to oral anticoagulants, protein C replacement must be continued until stable anticoagulation is established. In addition, patients with severe congenital protein C deficiency are at a higher risk of developing warfarin-induced skin necrosis. Monitor patients closely during treatment.
Proton pump inhibitors: (Moderate) Monitor the INR in patients receiving warfarin with proton pump inhibitors. Increases in INR may lead to abnormal bleeding. Adjust the warfarin dose to maintain the target INR.
Psyllium: (Moderate) Psyllium can interfere with the absorption of certain oral drugs if administered concomitantly. For example, psyllium fiber is theorized to adsorb oral anticoagulants (e.g., warfarin); although, response to a single dose of warfarin was not affected by repeated administration (every 2 hours) of psyllium in a group (n=6) of healthy subjects. Per the psyllium manufacturers, administration of other prescribed oral drugs should be separated from the administration of psyllium by at least 2 hours.
Quinidine: (Moderate) Quinidine may potentiate the anticoagulation effects of warfarin; bleeding has been reported. This interaction is probably due to additive hypoprothrombinemia associated with concomitant administration of warfarin and quinine or quinidine. Close monitoring of the INR is required when either of these agents is added to warfarin therapy.
Quinine: (Moderate) Closely monitor the INR if coadministration of warfarin with quinine is necessary as concurrent use may increase or decrease the exposure of warfarin leading to increased bleeding risk or reduced efficacy. Quinine is a weak CYP3A4 inhibitor and warfarin is a CYP3A4 substrate. Quinine is also a CYP1A2 inducer and warfarin is a CYP1A2 substrate.
Raloxifene: (Moderate) Monitor INR closely when warfarin is coadministered with raloxifene. Raloxifene may decrease prothrombin time.
Ranolazine: (Moderate) Closely monitor the INR if coadministration of warfarin with ranolazine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Ranolazine is a weak CYP3A4 inhibitor and warfarin is a CYP3A4 substrate.
Red Yeast Rice: (Contraindicated) Per prescribing information for warfarin sodium (Coumadin), all HMG-CoA reductase inhibitors (statins) have been associated with potentiation of warfarin's clinical effect. However, it appears that pravastatin and atorvastatin may be less likely to significantly interact with warfarin based on drug interaction studies. In addition, atorvastatin has been reported to slightly and transiently decrease the anticoagulant activity of warfarin; these effects were not considered clinically significant. In general, it is prudent to monitor INR at baseline, at initiation of these HMG Co-A reductase inhibitors, and after subsequent dosage changes. Adjust warfarin dosage based on INR and clinical response. Once a stable INR is documented, the INR can be monitored at the intervals otherwise recommended based on the indication for anticoagulation and co-existing conditions. Since compounds in red yeast rice claim to have HMG-CoA reductase inhibitor activity, red yeast rice should not be used in combination with warfarin.
Regorafenib: (Moderate) Closely monitor the INR if coadministration of warfarin with regorafenib is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Regorafenib is a weak CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Reteplase, r-PA: (Contraindicated) Based on the pharmacology of warfarin, other thrombolytic agents could cause additive risk of bleeding when given concurrently with warfarin. Pre-treatment with oral anticoagulants is reported to be an independent risk factor for intracranial hemorrhage in thrombolytic-treated patients. Prothrombin times stabilized during administration of both agents will change slightly when heparin is discontinued.
Ribociclib: (Moderate) Closely monitor the INR if coadministration of warfarin with ribociclib is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Ribociclib is a strong CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Ribociclib; Letrozole: (Moderate) Closely monitor the INR if coadministration of warfarin with ribociclib is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Ribociclib is a strong CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Rifamycins: (Moderate) Closely monitor the INR if coadministration of warfarin with rifamycins is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Rifamycins may induce the hepatic metabolism of warfarin through induction of CYP3A4, CYP2C9, and CYP1A2. A 2- to 3-fold increase in the daily dose of warfarin may be needed within a week of starting rifamycins to maintain appropriate anticoagulation. Once the rifamycin is discontinued, the dose of warfarin will need to be decreased.
Rilonacept: (Moderate) The formation of CYP450 enzymes is suppressed by increased concentrations of cytokines (e.g., IL-1) during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during rilonacept receipt. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as warfarin. If rilonacept is initiated in a patient taking warfarin, check the INR; warfarin dose adjustment may be needed.
Ritlecitinib: (Moderate) Closely monitor the INR if coadministration of warfarin with ritlecitinib is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. The R-enantiomer of warfarin is a CYP1A2 and CYP3A substrate and ritlecitinib is a moderate CYP1A2 and CYP3A inhibitor. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Ritonavir: (Moderate) Closely monitor the INR if coadministration of warfarin with ritonavir is necessary as concurrent use may alter the exposure of warfarin leading to increased bleeding risk or reduced efficacy. Warfarin is a substrate of CYP3A4, CYP2C9, and CYP1A2 and ritonavir is a strong CYP3A4 inhibitor as well as a CYP1A4, CYP2C9, and CYP3A4 inducer.
Rivaroxaban: (Major) Avoid use of rivaroxaban with warfarin due to the increased bleeding risk. Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if rivaroxaban and other anticoagulants are used concomitantly. Coadministration of rivaroxaban and other anticoagulants may increase the risk of bleeding. Long-term concomitant treatment with rivaroxaban and other anticoagulants is not recommended; short-term use may be necessary for patients transitioning to or from rivaroxaban.
Rolapitant: (Major) Avoid the concurrent use of warfarin and rolapitant if possible; if coadministration is necessary, monitor INR and prothrombin time carefully and adjust the dosage of warfarin, as needed to maintain the target INR range. In vitro, warfarin is a CYP2D6 substrate, and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
Romidepsin: (Major) Prolongation of PT and elevation of INR have been observed in a patient receiving romidepsin and warfarin. Carefully monitor PT and INR in patients receiving romidepsin and warfarin concomitantly.
Ropinirole: (Moderate) A possible drug interaction between ropinirole and warfarin has been reported clinically, with a resultant increase in the INR. While no signs of bleeding occurred in the reported case, the increase in INR necessitated a warfarin dosage adjustment during concurrent treatment. After ropinirole was discontinued, the warfarin dosage had to be adjusted upward. Closely monitor the INR when starting or stopping ropinirole therapy in a patient stabilized on warfarin.
Rosuvastatin: (Moderate) Addition of rosuvastatin to warfarin therapy has resulted in significant increases in the INR (> 4, baseline 2 to 3), without a change in warfarin plasma concentrations. INR should be monitored at baseline prior to rosuvastatin initiation, and frequently following initiation of rosuvastatin therapy and subsequent dosage changes. Adjust warfarin dosage based on INR and clinical response. Once a stable INR is documented, INR can be monitored at the intervals otherwise recommended based on the indication for anticoagulation and co-existing conditions. Rosuvastatin has not been associated with bleeding or with changes in INR in patients not taking oral anticoagulants.
Rosuvastatin; Ezetimibe: (Moderate) Addition of rosuvastatin to warfarin therapy has resulted in significant increases in the INR (> 4, baseline 2 to 3), without a change in warfarin plasma concentrations. INR should be monitored at baseline prior to rosuvastatin initiation, and frequently following initiation of rosuvastatin therapy and subsequent dosage changes. Adjust warfarin dosage based on INR and clinical response. Once a stable INR is documented, INR can be monitored at the intervals otherwise recommended based on the indication for anticoagulation and co-existing conditions. Rosuvastatin has not been associated with bleeding or with changes in INR in patients not taking oral anticoagulants. (Moderate) Coadministration with ezetimibe has not demonstrated significant effects on the bioavailability or the anticoagulant effects of warfarin when studied in 12 healthy adult males. However, according to the manufacturer, increases in PT/INR have been reported and accordingly recommends that if ezetimibe is added to warfarin, the INR should be monitored.
Rucaparib: (Moderate) Closely monitor the INR if coadministration of warfarin with rucaparib is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Rucaparib is a weak CYP3A4/CYP2C9/CYP1A2 inhibitor and warfarin is a CYP3A4/CYP2C9/CYP1A2 substrate. /> Salsalate: (Moderate) Coadministration of salicylates and warfarin may result in an increased risk of bleeding. Salicylates may displace warfarin from protein binding sites leading to increased anticoagulation effects. Hypoprothrombinemia, an additional risk factor for bleeding, also has been reported with salicylates. Non-acetylated salicylates do not appear to affect platelet aggregation in the same manner as aspirin and are associated with a lower risk of bleeding when given currently with warfarin. If salicylates and warfarin are coadministered, monitor the patient for signs or symptoms of bleeding.
Saquinavir: (Moderate) Monitor the INR and adjust the dose as necessary if warfarin is coadministered with saquinavir. Concurrent use may increase the INR and the risk of bleeding. Saquinavir is a CYP3A4 inhibitor and the R-enantiomer of warfarin is a 3A4 substrate. The S-enantiomer exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Sarilumab: (Moderate) Monitor the INR if sarilumab is coadministered with warfarin due to the potential for decreased warfarin efficacy; adjust the dose of warfarin as necessary. Inhibition of IL-6 signaling by sarilumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as warfarin, may have fluctuations in drug levels and therapeutic effect when sarilumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping sarilumab.
Secobarbital: (Moderate) Closely monitor the INR if coadministration of warfarin with barbiturates is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Barbiturates are CYP1A2 and moderate CYP2C9/CYP3A4 inducers and warfarin's enantiomers are substrates of CYP1A2/CYP2C9/CYP3A4. Discontinuation of a barbiturate during warfarin therapy has led to fatal bleeding episodes when the hepatic enzyme-inducing properties of the barbiturate subside. Clinicians should note that warfarin doses will require readjustment if a barbiturate is added or discontinued during warfarin therapy. Dosage adjustments of warfarin may be necessary within 2 weeks of beginning barbiturate treatment, but the effect of the barbiturate on warfarin metabolism may persist for more than a month after discontinuing the barbiturate.
Secukinumab: (Moderate) Closely monitor the INR if coadministration of warfarin with secukinumab is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Secukinumab is a moderate CYP3A4/CYP2C9/CYP1A2 inhibitor and warfarin is a CYP3A4/CYP2C9/CYP1A2 substrate.
Selpercatinib: (Moderate) Closely monitor the INR if coadministration of warfarin with selpercatinib is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Selpercatinib is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Selumetinib: (Moderate) Closely monitor the INR and for bleeding if coadministration of warfarin and selumetinib is necessary as concurrent use may increase the bleeding risk; adjust the warfarin dose as appropriate. Selumetinib contains vitamin E which can inhibit platelet aggregation and antagonize vitamin K-dependent clotting factors.
Semaglutide: (Moderate) Consider additional warfarin monitoring during concomitant use of oral semaglutide. Oral semaglutide delays gastric emptying and has been observed to increase warfarin overall exposure. Advise patients to take oral semaglutide 30 minutes before other oral medications. This interaction is not expected with subcutaneous semaglutide.
Sertraline: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of sertraline and warfarin. Carefully monitor the INR. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding. Additionally, monitor for sertraline-related adverse effects. Reduce the sertraline or warfarin dose as necessary. Sertraline is highly bound to plasma protein and concomitant use with another drug that is highly bound to plasma protein, like warfarin, may increase free plasma concentrations of sertraline or the other tightly bound drug.
Sevoflurane: (Minor) Sevoflurane may increase the effects of warfarin. Another halogenated anesthetic, halothane, has been associated with an increase in activity of warfarin. The trifluoroacetic acid metabolite of halothane appears to displace warfarin from plasma proteins, which may increase the free-fraction of warfarin. The effects of sevoflurane on the displacement of drugs from serum and tissue proteins have not been investigated.
Siltuximab: (Moderate) Monitor the INR if siltuximab is coadministered with warfarin due to the potential for decreased warfarin efficacy; adjust the dose of warfarin as necessary. Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as warfarin, may have fluctuations in drug levels and therapeutic effect when siltuximab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping siltuximab.
Simvastatin: (Moderate) Per prescribing information for warfarin sodium (Coumadin), all HMG-CoA reductase inhibitors (statins) have been associated with potentiation of warfarin's clinical effect. However, it appears that pravastatin and atorvastatin may be less likely to significantly interact with warfarin based on drug interaction studies. In addition, atorvastatin has been reported to slightly and transiently decrease the anticoagulant activity of warfarin; these effects were not considered clinically significant. In general, it is prudent to monitor INR at baseline, at initiation of these HMG Co-A reductase inhibitors, and after subsequent dosage changes. Adjust warfarin dosage based on INR and clinical response. Once a stable INR is documented, the INR can be monitored at the intervals otherwise recommended based on the indication for anticoagulation and co-existing conditions.
Sodium Iodide: (Moderate) Anticoagulants may alter sodium iodide I-131 pharmacokinetics and dynamics for up to 1 week after administrations.
Sodium Phenylbutyrate; Taurursodiol: (Moderate) Closely monitor the INR if coadministration of warfarin with taurursodiol is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. The R-enantiomer of warfarin is a CYP3A and CYP1A2 substrate and taurursodiol is a CYP3A and CYP1A2 inducer. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Sofosbuvir: (Moderate) Fluctuations in International Normalized Ratio (INR) have been observed in warfarin recipients who were also receiving treatment for hepatitis C virus (HCV) infections, including sofosbuvir. It is recommended to closely monitor these patients for changes in INR both during and after discontinuation of the HCV treatment regimen.
Sofosbuvir; Velpatasvir: (Moderate) Fluctuations in International Normalized Ratio (INR) have been observed in warfarin recipients who were also receiving treatment for hepatitis C virus (HCV) infections, including sofosbuvir. It is recommended to closely monitor these patients for changes in INR both during and after discontinuation of the HCV treatment regimen. (Moderate) Fluctuations in International Normalized Ratio (INR) have been observed in warfarin recipients who were also receiving treatment for hepatitis C virus (HCV) infections, including velpatasvir. It is recommended to closely monitor these patients for changes in INR both during and after discontinuation of the HCV treatment regimen.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Fluctuations in International Normalized Ratio (INR) have been observed in warfarin recipients who were also receiving treatment for hepatitis C virus (HCV) infections, including sofosbuvir. It is recommended to closely monitor these patients for changes in INR both during and after discontinuation of the HCV treatment regimen. (Moderate) Fluctuations in International Normalized Ratio (INR) have been observed in warfarin recipients who were also receiving treatment for hepatitis C virus (HCV) infections, including velpatasvir. It is recommended to closely monitor these patients for changes in INR both during and after discontinuation of the HCV treatment regimen. (Moderate) Fluctuations in International Normalized Ratio (INR) have been observed in warfarin recipients who were also receiving treatment for hepatitis C virus (HCV) infections, including voxilaprevir. It is recommended to closely monitor these patients for changes in INR both during and after discontinuation of the HCV treatment regimen.
Sorafenib: (Moderate) Monitor for an increased risk of bleeding and regularly monitor the PT/INR of patients taking sorafenib concomitantly with warfarin. Infrequent bleeding or elevations in the INR have been reported in some patients taking warfarin while on sorafenib.
Sotorasib: (Moderate) Closely monitor the INR if coadministration of warfarin with sotorasib is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Sotorasib is a CYP3A4 inducer and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Sparsentan: (Moderate) Closely monitor the INR if coadministration of warfarin with sparsentan is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. The active metabolite of warfarin, the S-enantiomer, is a CYP2C9 substrate and sparsentan is a CYP2C9 inducer. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Spironolactone: (Moderate) Closely monitor the INR if coadministration of warfarin with spironolactone is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Spironolactone is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Closely monitor the INR if coadministration of warfarin with spironolactone is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Spironolactone is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
St. John's Wort, Hypericum perforatum: (Moderate) Closely monitor the INR if coadministration of warfarin with St. John's Wort is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. St. John's Wort is a CYP1A2, moderate CYP2C9, and strong CYP3A4 inducer and the enantiomers of warfarin are substrates of CYP1A2/CYP2C9/CYP3A4. In one report, a decreased INR occurred in 7 patients previously stabilized on warfarin. The interactions occurred within 1 week to 1 month of St. John's wort coadministration. Conversely, if St. John's wort is discontinued in a patient stabilized on warfarin, frequent monitoring and dosage adjustment may be necessary to avoid an increased INR or risk of bleeding.
Stiripentol: (Moderate) Closely monitor the INR if coadministration of warfarin with stiripentol is necessary as concurrent use may increase or decrease the exposure of warfarin leading to increased bleeding risk or reduced efficacy. Stiripentol is a CYP1A2 and weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP1A2/CYP3A4 substrate. Additionally, stiripentol is a CYP1A2 and weak CYP3A4 inducer, which may decrease the INR.
Streptogramins: (Moderate) Closely monitor the INR if coadministration of warfarin with streptogramins, like quinupristin, is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Streptogramins, like quinupristin, are weak CYP3A4 inhibitors and warfarin is a CYP3A4 substrate. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR.
Streptomycin: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including aminoglycosides, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Sucralfate: (Moderate) Sucralfate has been reported to interfere with warfarin absorption. While isolated reports have shown that sucralfate can inhibit warfarin oral absorption, other studies have shown no clinical effect.
Sulfonamides: (Moderate) Closely monitor the INR if coadministration of warfarin with sulfonamides is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Warfarin doses may need to be adjusted when sulfonamide therapy is discontinued. Sulfonamides, including sulfathiazole, sulfamethoxazole, and sulfisoxazole, potentiate the anticoagulant effect of warfarin. Sulfonamides are known to inhibit the hepatic metabolism of S-warfarin and have, in some cases, doubled the hypoprothrombinemic effect of warfarin. A protein-binding interaction also may be possible, with sulfonamides displacing warfarin from protein binding sites.
Sulfonylureas: (Moderate) The interaction between oral anticoagulants and oral sulfonylureas is complex; both enhancement or reduction of hypoprothrombinemic response to oral anticoagulants has been reported in various literature accounts along with a potential for altered hypoglycemic response to the sulfonylurea. One proposed mechanism may be related to displacement of the drugs from plasma protein binding sites. Dicumarol has been reported to inhibit the metabolism of chlorpropamide and tolbutamide, however, warfarin did not exhibit a similar effect on tolbutamide kinetics. Glyburide has been reported to augment the hypoprothrombinemic response to warfarin, although other reports have showed no interaction. Warfarin appears less likely to interact with sulfonylureas than dicumarol. In clinical trials, glimepiride therapy resulted in a slight, but statistically significant decrease in pharmacodynamic response to warfarin. The reductions in effect are unlikely to be clinically important in most cases. Nevertheless, it would be wise for clinicians to use warfarin and sulfonylureas together cautiously until the combined effects of the drugs are known. Monitor the INR as indicated and be alert for altered blood sugar control when either of these drugs is added or discontinued.
Sulindac: (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs). To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients.
Sumatriptan; Naproxen: (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs). To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients.
Tamoxifen: (Major) Closely monitor PT/INR if coadministration of warfarin with tamoxifen for the treatment of metastatic breast cancer or as adjuvant therapy is necessary; a marked increase in anticoagulant effect may occur. Tamoxifen is contraindicated with warfarin therapy if the indication for tamoxifen is reduction of breast cancer incidence in high-risk patients or risk reduction of invasive breast cancer after treatment of DCIS.
Tazemetostat: (Moderate) Closely monitor the INR if coadministration of warfarin with tazemetostat is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Tazemetostat is a CYP3A4 inducer and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Tecovirimat: (Moderate) Closely monitor the INR if coadministration of warfarin with tecovirimat is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Tecovirimat is a weak CYP3A4 inducer and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Tedizolid: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including tedizolid, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Teduglutide: (Moderate) Although an interaction is possible, these drugs may be used together. Teduglutide may increase the actions of warfarin. Your prescriber will monitor your therapy closely. Report any unusual effects to your prescriber.
Telavancin: (Moderate) Telavancin has no effect on coagulation or platelet aggregation; however, caution is advised when administering telavancin concurrently with other anticoagulants as telavancin may interfere with laboratory tests used in monitoring these medications. The coagulation tests affected by telavancin include prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (aPTT), activated clotting time, and coagulation-based factor Xa tests. When measured shortly after completion of a telavancin infusion, the results of these tests are increased; however, the effects of telavancin on these tests dissipate over time as plasma concentrations of telavancin decrease. Therefore, when administering telavancin in conjunction with anticoagulants ensure that blood samples for these coagulation tests are collected as close as possible to the patient's next telavancin dose. Additionally, the concomitant use of warfarin with many antibiotics may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Telmisartan: (Minor) The coadministration of telmisartan and warfarin may lead to a decrease in the anticoagulation effects of warfarin.
Telmisartan; Amlodipine: (Moderate) Closely monitor the INR if coadministration of warfarin with amlodipine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Amlodipine is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. (Minor) The coadministration of telmisartan and warfarin may lead to a decrease in the anticoagulation effects of warfarin.
Telmisartan; Hydrochlorothiazide, HCTZ: (Minor) The coadministration of telmisartan and warfarin may lead to a decrease in the anticoagulation effects of warfarin.
Telotristat Ethyl: (Moderate) Closely monitor the INR if coadministration of warfarin with telotristat is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Telotristat is a weak CYP3A4 inducer and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Tenecteplase: (Contraindicated) Based on the pharmacology of warfarin, other thrombolytic agents could cause additive risk of bleeding when given concurrently with warfarin. Pre-treatment with oral anticoagulants is reported to be an independent risk factor for intracranial hemorrhage in thrombolytic-treated patients. Prothrombin times stabilized during administration of both agents will change slightly when heparin is discontinued.
Terbinafine: (Minor) Terbinafine has been associated with an increase in the activity of warfarin.
Teriflunomide: (Moderate) Closely monitor the INR if coadministration of warfarin with teriflunomide is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. The R-enantiomer of warfarin is a CYP1A2 substrate and teriflunomide is CYP1A2 inducer. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. Teriflunomide may decrease peak INR by approximately 25%. The mechanism is uncertain but, during pharmacokinetic studies, teriflunomide did not affect the pharmacokinetics of S-warfarin (a CYP2C9 substrate).
Testolactone: (Moderate) When used concomitantly, testolactone may increase the effects of oral anticoagulants such as warfarin. The INR should be monitored closely and the patient observed for signs and symptoms of bleeding; the dose of warfarin should be adjusted as necessary.
Testosterone: (Moderate) Testosterone can increase the anticoagulant action of warfarin. Serious bleeding has been reported in some patients with this drug-drug interaction. Although the mechanism is unclear, testosterone may reduce procoagulant factors. Reduction of warfarin dosage may be necessary if testosterone therapy is coadministered. More frequent monitoring of INR and prothrombin time in patients taking such oral anticoagulants is recommneded, especially at the initiation and termination of androgen therapy. It is unclear if testosterone can augment the anticoagulant response to heparin therapy or if testosterone alters the effect of other non-coumarin oral anticoagulants in a similar manner.
Tetracyclines: (Moderate) Tetracyclines may increase the action of warfarin and other oral anticoagulants by either impairing prothrombin utilization or, possibly, decreasing production of vitamin K because of its antiinfective action on gut bacteria. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Tezacaftor; Ivacaftor: (Moderate) Closely monitor the INR if coadministration of warfarin with ivacaftor is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Ivacaftor is a weak CYP3A4 inhibitor and the R-enantiomer is a CYP3A4 substrate. Ivacaftor is also a weak CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9/CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. (Moderate) Closely monitor the INR if coadministration of warfarin with tezacaftor; ivacaftor is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Ivacaftor is a weak CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate. Ivacaftor is also a weak CYP3A4 inhibitor and the R-enantiomer is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Thrombolytic Agents: (Contraindicated) Based on the pharmacology of warfarin, other thrombolytic agents could cause additive risk of bleeding when given concurrently with warfarin. Pre-treatment with oral anticoagulants is reported to be an independent risk factor for intracranial hemorrhage in thrombolytic-treated patients. Prothrombin times stabilized during administration of both agents will change slightly when heparin is discontinued.
Thyroid hormones: (Moderate) The concurrent use of thyroid hormones and warfarin potentiates anticoagulation effects of warfarin. The mechanism of this interaction may be the increased catabolism of vitamin K clotting factors as the hypothyroid state is corrected. As a result, the hypoprothrombinemic response to warfarin occurs earlier and to a greater degree. Dextrothyroxine has been shown to potentiate the effects of warfarin. Dextrothyroxine may increase the affinity of warfarin for its receptor sites in addition to increasing the catabolism of vitamin K dependent clotting factors. A reduction in the dosage of warfarin is recommended with concomitant therapy.
Ticagrelor: (Moderate) Closely monitor the INR if coadministration of warfarin with ticagrelor is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Ticagrelor is a weak CYP3A4 inhibitor and warfarin is a CYP3A4 substrate. Also, because ticagrelor inhibits platelet aggregation, additive risk for bleeding is possible when given in combination with anticoagulants such as warfarin.
Ticlopidine: (Moderate) Closely monitor patients for increased bleeding and monitor their INR if coadministration of warfarin with ticlopidine is necessary; concurrent use may increase the exposure of warfarin. Ticlopidine is a CYP1A2 inhibitor and the R-enantiomer of warfarin is a CYP1A2 substrate. Also, because ticlopidine inhibits platelet aggregation, additive risk for bleeding is possible when ticlopidine is given in combination with anticoagulants such as warfarin. It has been reported that the concomitant use of warfarin and ticlopidine may be associated with cholestatic hepatitis. Per the manufacturer of ticlopidine, if a patient is switched from an anticoagulant or a thrombolytic agent to ticlopidine, the former drug should be discontinued prior to the administration of ticlopidine.
Tinidazole: (Moderate) The warfarin dose may need to be adjusted during tinidazole coadministration and for up to 8 days after stopping therapy. Tinidazole may enhance the effect of warfarin resulting in a prolongation of prothrombin time.
Tipranavir: (Moderate) Monitor the INR and adjust the dose as necessary if warfarin is coadministered with tipranavir; concurrent use may increase the risk of bleeding or reduce efficacy. Tipranavir is a CYP3A4 inhibitor as well as CYP1A2 inducer. Warfarin is a substrate of CYP3A4 and CYP1A2.
Tirofiban: (Moderate) Concomitant use of tirofiban and other agents that effect hemostasis, such as anticoagulants, may be associated with an increased risk of bleeding.
Tirzepatide: (Moderate) Monitor for changes in INR and bleeding when tirzepatide is coadministered with warfarin. Dosage adjustments of warfarin may be necessary. Tirzepatide delays gastric emptying, and thereby has the potential to impact the absorption of warfarin.
Tobacco: (Major) Advise patients to avoid smoking tobacco while taking warfarin. Smoking tobacco has been observed to enhance warfarin clearance by 13% and may decrease efficacy. R-warfarin is a CYP1A2 substrate and smoking tobacco induces CYP1A2.
Tobramycin: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including aminoglycosides, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Tocilizumab: (Moderate) Monitor the INR if tocilizumab is coadministered with warfarin due to the potential for decreased warfarin efficacy; adjust the dose of warfarin as necessary. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. Therefore, CYP450 substrates with a narrow therapeutic index, such as warfarin, may have fluctuations in drug levels and therapeutic effect when tocilizumab therapy is started or discontinued. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab.
Tolcapone: (Minor) Although evidence for an interaction is lacking, the affinity of tolcapone for CYP2C9 may result in enhanced anticoagulation with warfarin, a substrate for CYP2C9. Clinical studies with sensitive CYP2C9 substrates did not indicate a major effect of tolcapone on CYP2C9-induced drug metabolism. However, since data are limited regarding warfarin, the manufacturer recommends that the INR be monitored with tolcapone initation and at dose changes to ensure proper patient INR goals.
Tolmetin: (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs). To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients.
Tolterodine: (Moderate) Increased INR values have been reported with concurrent use of warfarin and tolterodine. In two case reports, patients stabilized on warfarin experienced elevated INR values 10-14 days after beginning tolterodine treatment. Careful monitoring of the INR should be considered.
Topiramate: (Moderate) Closely monitor the INR if coadministration of warfarin with topiramate is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy; increased bleeding is also possible with the combination. Topiramate is a weak CYP3A4 inducer and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Toremifene: (Moderate) Closely monitor the INR if coadministration of warfarin with toremifene is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Toremifene is a weak CYP2C9 inhibitor and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate.
Torsemide: (Moderate) Use caution and frequently monitor the PT/INR of patients receiving concomitant therapy with warfarin and torsemide; adjust the dose of warfarin as appropriate. S-warfarin is a CYP2C9 substrate; torsemide is a CYP2C9 inhibitor. Coadministration may result in increases in PT/INR response.
Tramadol: (Moderate) Monitor prothrombin time and adjust the warfarin dose as needed if administered with tramadol. Advise patients of the increased bleeding risk associated with concomitant use. Alterations in warfarin effect and elevated prothrombin time have been reported rarely following coadministration in postmarketing surveillance.
Tramadol; Acetaminophen: (Moderate) Monitor prothrombin time and adjust the warfarin dose as needed if administered with tramadol. Advise patients of the increased bleeding risk associated with concomitant use. Alterations in warfarin effect and elevated prothrombin time have been reported rarely following coadministration in postmarketing surveillance. (Minor) Although acetaminophen is routinely considered safer than aspirin and agent of choice when a mild analgesic/antipyretic is necessary for a patient receiving therapy with warfarin, acetaminophen has also been shown to augment the hypoprothrombinemic response to warfarin. Concomitant acetaminophen ingestion may result in increases in the INR in a dose-related fashion. Clinical bleeding has been reported. Single doses or short (i.e., several days) courses of treatment with acetaminophen are probably safe in most patients taking warfarin. Clinicians should be alert for an increased INR if acetaminophen is administered in large daily doses for longer than 10 to 14 days.
Trandolapril; Verapamil: (Moderate) Closely monitor the INR if coadministration of warfarin with verapamil is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Verapamil is a CYP1A2 and moderate CYP3A4 inhibitor and warfarin is a CYP1A2/CYP3A4 substrate.
Trazodone: (Moderate) Patients should be instructed to monitor for signs and symptoms of bleeding while taking trazodone concurrently with anticoagulants and to promptly report any bleeding events to the practitioner. Serotonergic agents may increase the risk of bleeding when combined with anticoagulants via inhibition of serotonin uptake by platelets; however, the absolute risk is not known. It would be prudent for clinicians to monitor the INR and patient's clinical status closely if trazodone is added to or removed from the regimen of a patient stabilized on anticoagulant therapy.
Treprostinil: (Moderate) When used concurrently with anticoagulants, treprostinil may increase the risk of bleeding.
Triclabendazole: (Moderate) Monitor PT/INR if triclabendazole is initiated or discontinued in a patient taking warfarin; warfarin dose adjustments may be needed. Coadministration of triclabendazole and warfarin may result in increased warfarin concentrations; however, this elevation may be transient due to the short treatment duration of triclabendazole. Triclabendazole is an inhibitor of CYP2C19 in vitro and warfarin is partially metabolized by CYP2C19.
Trofinetide: (Moderate) Closely monitor the INR if coadministration of warfarin with trofinetide is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. The R-enantiomer of warfarin is a CYP3A substrate and trofinetide is a weak CYP3A inhibitor. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Tucatinib: (Moderate) Closely monitor the INR if coadministration of warfarin with tucatinib is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Tucatinib is a strong CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Ustekinumab: (Moderate) The formation of CYP450 enzymes may be altered during chronic inflammation; the formation of CYP450 enzymes could be normalized during ustekinumab receipt. For CYP450 substrates that have a narrow therapeutic index such as warfarin, consider monitoring the warfarin concentration if ustekinumab is initiated or discontinued; warfarin dose adjustment may be needed.
Valdecoxib: (Moderate) Monitor patients for signs or symptoms of bleeding during concurrent use of warfarin and nonsteroidal antiinflammatory drugs (NSAIDs). To minimize the potential for GI bleeding, use the lowest effective NSAID dose for the shortest possible duration. If signs or symptoms of bleeding occur, promptly evaluate and treat. Systemic hematological effects may also occur with the use of topical NSAIDs. NSAIDs inhibit platelet aggregation and may prolong bleeding time in some patients.
Valproic Acid, Divalproex Sodium: (Moderate) Closely monitor the INR if coadministration of warfarin with valproic acid is necessary as concurrent use may increase or decrease the exposure of warfarin leading to increased bleeding risk or reduced efficacy. Valproic acid is a weak CYP3A4 and moderate CYP2C9 inhibitor and warfarin is a CYP3A4/CYP2C9 substrate. Additionally, valproic acid is a weak CYP3A4 inducer and warfarin is a CYP3A4 substrate.
Vancomycin: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including aminoglycosides, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Vemurafenib: (Moderate) Closely monitor the INR if coadministration of warfarin with vemurafenib is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Vemurafenib is a CYP1A2 and CYP2C9 inhibitor; warfarin is a CYP1A2 and CYP2C9 substrate. Coadministration of vemurafenib and S-warfarin increased the AUC of S-warfarin by 18%.
Venetoclax: (Major) The concomitant use of venetoclax and warfarin may increase the concentration and exposure of warfarin and increase the risk of bleeding. If these agents are used together, monitor the international normalized ratio (INR) more frequently and adjust the dosage of warfarin as necessary. In a drug-drug interaction study, the R- and S-warfarin Cmax and AUC values increased by 18% to 28% when a single 400-mg dose of venetoclax was co-administered with a single 5-mg dose of warfarin.
Venlafaxine: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of venlafaxine and warfarin. Carefully monitor patients receiving warfarin therapy, including coagulation parameters such as the INR and/or prothrombin time, if venlafaxine is initiated or discontinued. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Verapamil: (Moderate) Closely monitor the INR if coadministration of warfarin with verapamil is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Verapamil is a CYP1A2 and moderate CYP3A4 inhibitor and warfarin is a CYP1A2/CYP3A4 substrate.
Verteporfin: (Moderate) Use caution if coadministration of verteporfin with anticoagulants is necessary due to the risk of decreased verteporfin efficacy. Verteporfin is a light-activated drug. Once activated, local damage to neovascular endothelium results in a release of procoagulant and vasoactive factors resulting in platelet aggregation, fibrin clot formation, and vasoconstriction. Concomitant use of drugs that decrease clotting could decrease the efficacy of verteporfin therapy.
Vigabatrin: (Moderate) Vigabatrin is not significantly metabolized; however, it is an inducer of CYP2C9. In theory, decreased exposure of drugs that are extensively metabolized by CYP2C9, such as warfarin, may occur during concurrent use of vigabatrin.
Vilazodone: (Moderate) Patients should be instructed to monitor for signs and symptoms of bleeding while taking vilazodone concurrently with anticoagulants and to promptly report any bleeding events to the practitioner. Serotonergic agents may increase the risk of bleeding when combined with anticoagulants via inhibition of serotonin uptake by platelets; however, the absolute risk is not known. In addition, both vilazodone and warfarin are highly protein bound, which may result in displacement of warfarin from protein binding sites and an increased anticoagulant effect. It would be prudent for clinicians to monitor the INR and clinical status of the patient closely if vilazodone is added to or removed from the regimen of a patient stabilized on warfarin.
Viloxazine: (Moderate) Closely monitor the INR if coadministration of warfarin with viloxazine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. The R-enantiomer of warfarin is a CYP1A2 and CYP3A substrate; viloxazine is a strong CYP1A2 and weak CYP3A inhibitor. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Vismodegib: (Moderate) Elevated INR values up to 9.5 occurred when vismodegib was added to a medication regimen that included warfarin in a 78-year old man with recurrent basal-cell carcinoma and recurrent deep vein thrombosis. Therefore, use these drugs together with caution; consider increased INR monitoring. Using the Drug Interaction Probability Scale (DIPS), a score of 7 indicated a probable warfarin-vismodegib interaction. CYP isoenzyme inhibition (i.e., CYP2C9) and/or warfarin displacement from protein binding (as both drugs are highly protein bound) are possible reasons for this drug-drug interaction per the authors of this case report. The patient had been stable on warfarin therapy for 9 months prior to starting vismodegib; the medical chart listed no other medication changes and the patient reported no change alcohol consumption, smoking, or diet and denied symptoms of diarrhea or vomiting. His INR increased from 2.3 to 4.6 about 3 weeks after starting vismodegib 150 mg PO once daily. After skipping one dose and resuming warfarin therapy at the previous dose (total dose of 55 mg/week) for 3 weeks, the patient's INR was 9.5. Warfarin therapy was held for 5 days and then resumed at a 31.8% decrease in weekly dose (to a total dose of 37.5 mg/week). Within one week, warfarin therapy was again held and resumed at a lower dose (total of a 36% decrease in weekly dose from the original dose), his INR level was 2.9 one week later. Within 2 weeks of the last warfarin dosage change, the patient was admitted to the hospital with altered mental status and loss of consciousness unrelated to warfarin therapy; the INR level was 4.7 on admission and warfarin and vismodegib were discontinued. The patient died in the hospital for reasons not caused by an elevated INR.
Vitamin E: (Moderate) Vitamin E should be used cautiously in patients receiving warfarin. While the mechanism is unclear, it is believed that concomitant administration of large doses of vitamin E (e.g., more than 400 units per day) with warfarin potentiates hypoprothrombinemia due to the vitamin K antagonistic activity of vitamin E.
Vonoprazan; Amoxicillin: (Moderate) Closely monitor the INR if coadministration of warfarin with vonoprazan is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. The R-enantiomer of warfarin is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. (Moderate) The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Vonoprazan; Amoxicillin; Clarithromycin: (Moderate) Closely monitor the INR if coadministration of warfarin with clarithromycin is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Clarithromycin is a strong CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. (Moderate) Closely monitor the INR if coadministration of warfarin with vonoprazan is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. The R-enantiomer of warfarin is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. (Moderate) The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Vorapaxar: (Major) Avoid concomitant use of vorapaxar and warfarin or other anticoagulants. Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as anticoagulants.
Voriconazole: (Moderate) Closely monitor the INR if coadministration of warfarin with voriconazole is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Voriconazole is a strong CYP3A4 and moderate CYP2C9 inhibitor and warfarin is a CYP3A4/CYP2C9 substrate.
Vorinostat: (Moderate) Use vorinostat and warfarin together with caution; concomitant use may result in prolonged prothrombin time (PT) and International Normalized Ratio (INR) and an increased risk of bleeding. Monitor PT and INR more frequently if use of both drugs is required. Prolonged PT and INR have occurred in patients who received vorinostat in combination with coumarin-derivative anticoagulants.
Vortioxetine: (Moderate) Platelet aggregation may be impaired by vortioxetine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving anticoagulants. Bleeding events related to drugs that inhibit serotonin reuptake have ranged from ecchymosis to life-threatening hemorrhages. Patients should be instructed to monitor for signs and symptoms of bleeding while taking vortioxetine concurrently with anticoagulants and to promptly report any bleeding events to the practitioner. Co-administration of vortioxetine and warfarin has not been shown to significantly affect the pharmacokinetics of either agent.
Voxelotor: (Moderate) Closely monitor the INR if coadministration of warfarin with voxelotor is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. The R-enantiomer of warfarin is a CYP3A substrate and voxelotor is a moderate CYP3A inhibitor. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Zafirlukast: (Moderate) Closely monitor the INR if coadministration of warfarin with zafirlukast is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Zafirlukast is a weak CYP3A4/CYP2C9/CYP1A2 inhibitor and warfarin is a CYP3A4/CYP2C9/CYP1A2 substrate.
Zanubrutinib: (Moderate) Closely monitor the INR if coadministration of warfarin with zanubrutinib is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Zanubrutinib is a weak CYP3A4 inducer and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Zileuton: (Moderate) Closely monitor the INR if coadministration of warfarin with zileuton is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. The R-enantiomer of warfarin is a CYP1A2 substrate and zileuton is a CYP1A2 inhibitor. Concomitant use has been observed to increase R-warfarin AUC by 22%. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.

Coumadin/Jantoven/Warfarin/Warfarin Sodium Oral Tab: 1mg, 2mg, 2.5mg, 3mg, 4mg, 5mg, 6mg, 7.5mg, 10mg

Warfarin has a narrow therapeutic index (see Therapeutic Drug Monitoring section). The maximum dosage is individualized based on INR monitoring and assessment of efficacy and safety parameters (see specific indications for target INR goals).

Warfarin inhibits the synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X and anticoagulant proteins C and S. Specifically, warfarin inhibits the C1 subunit of the vitamin K epoxide reductase (VKORC1) enzyme, which reduces the regeneration of vitamin K epoxide. Vitamin K is a cofactor for the carboxylation of glutamate residues to gamma-carboxyglutamates on the N-terminal regions of vitamin K-dependent proteins. Carboxylation allows the coagulation proteins to undergo a conformational change, which is necessary for their activation. Warfarin exerts its anticoagulant effect by inhibiting vitamin K epoxide reductase and possibly vitamin K reductase. This results in depletion of the reduced form of vitamin K (vitamin KH2) and limits the gamma-carboxylation of the vitamin K-dependent coagulant proteins. The degree of effect on the vitamin K-dependent proteins is dependent upon the dose of warfarin and, to some extent, the patient's VKORC1 genotype. The anticoagulant effects of warfarin are stereoselective; the S-isomer of warfarin is 3—5 times more potent than the R-isomer. Therapeutic doses of warfarin decrease the total amount of active vitamin K-dependent clotting factors produced by the liver by 30—50%.
 
Since warfarin does not affect the activity of synthesized coagulation factors, depletion of these mature factors through normal catabolism and replacement by newly synthesized dysfunctional vitamin K-dependent clotting factors must occur before therapeutic effects of warfarin are seen. Each factor differs in its degradation half-life; factor II 60 hours, factor VII 4—6 hours, factor IX 24 hours, and factor X 48—72 hours. The half-lives of proteins C and S are approximately 8 and 30 hours, respectively. As a result, 3—4 days of therapy may be required before a complete clinical response to any one dosage is seen. Since warfarin reduces the activity of anticoagulant proteins C and S, a hypercoagulable state may be induced for a short period of time after treatment with warfarin is started. The rapid loss of protein C temporarily shifts the balance in favor of clotting until sufficient time has passed for warfarin to decrease the activity of coagulant factors.
 
Warfarin prolongs the prothrombin time (PT), which is responsive to depression of three of the four vitamin K-dependent coagulation factors (factors II, VII, and X). These factors are reduced by warfarin at a rate proportionate to their respective half-lives. During the first 2—5 days of warfarin therapy, the PT primarily reflects the depression of factor VII. With subsequent warfarin treatment, the PT is prolonged by depression of factors II and X. Prothrombin time ratio results can be affected by the responsiveness of the thromboplastin to warfarin. The International Normalized Ratio (INR) has been developed and adopted as a method to standardize monitoring of oral anticoagulant therapy. The PT and INR are related based upon the ISI value (International Sensitivity Index value). The ISI is a measure of the responsiveness of a given thromboplastin to reduction of the vitamin K-dependent coagulation factors compared to the first World Health Organization international reference preparation (IRP). At an ISI value of 0.1, the PT ratio is identical to the INR. As the ISI value of the thromboplastin increases, the INR for a given PT ratio also increases. Therefore, a lower ISI is associated with a more responsive reagent. The INR is less reliable as a measure of anticoagulation in the early course of warfarin therapy; however, it is more reliable than the PT or PT ratio for clinical management.
 
Warfarin does not affect established thrombus and does not reverse ischemic tissue damage. Warfarin therapy prevents further extension of the clot and prevents secondary thromboembolic complications. The antithrombotic effect of warfarin is generally thought to reflect its anticoagulant effects, mediated through its ability to inhibit thrombin generation by reducing levels of vitamin K-dependent coagulation factors. However, there is evidence that the reduction of prothrombin (factor II), and possibly factor X, is more important than the reduction of factors VII and IX for the antithrombotic effect of warfarin. Reduction in prothrombin levels may results in a decrease in the amount of thrombin that can be generated and bound to fibrin, thereby reducing the thrombogenicity of the clot. If the antithrombotic effect of warfarin is reflected by its ability to lower prothrombin levels, this provides a rationale for overlapping heparin with warfarin in the treatment of patients with thrombotic disease until the prothrombin level is lowered into the therapeutic range. In contrast to heparin, warfarin has no anticoagulant effect in vitro. Warfarin does not affect prostaglandin-mediated platelet aggregation.
 
The action of warfarin may be overcome by the administration of vitamin K or by transfusion of plasma proteins that contain clotting factors. Hereditary resistance to warfarin has been described. Affected patients may require doses that are 5- to 20-fold higher than average to achieve an anticoagulant effect. This is thought to be due to altered affinity of the receptor for warfarin. There are also anecdotal reports of acquired resistance to warfarin. Acquired resistance to warfarin could be due to poor patient compliance, drug interactions that alter the response to warfarin, exogenous consumption of vitamin K, decreased absorption of warfarin, or increased clearance of warfarin.
 
Effects of warfarin on bone metabolism: Gamma-carboxyglutamate (Gla) proteins synthesized in bone include osteocalcin, protein S, and matrix Gla protein. Warfarin interferes with the carboxylation of these proteins and inhibits the action of vitamin K in osteoblasts. These effects may be responsible for bone abnormalities that can occur in neonates when women are treated with warfarin during pregnancy. There is no evidence, however, that warfarin adversely affects bone metabolism when administered to children or adults, including post-menopausal women.

Warfarin is administered via the oral route. Warfarin is highly bound (about 97%) to plasma protein, mainly albumin. The high degree of protein binding is one of several mechanisms whereby other drugs interact with it. Warfarin is distributed to the liver, lungs, spleen, and kidneys but does not appear to be distributed into breast milk in significant amounts. It crosses the placenta and is a known teratogen. The terminal half-life of warfarin after a single dose is 7 days; however, the clinically effective half-life ranges from 20 to 60 hours (mean 40 hours) depending upon the rate of catabolism of activated clotting factors. The clearance of R-warfarin is generally half that of S-warfarin, and thus, the half-life of R-warfarin is longer than that of S-warfarin. The half-life of R-warfarin ranges from 37 to 89 hours, while that of S-warfarin ranges from 21 to 43 hours. Inactive metabolites are excreted in the urine and to a lesser extent in the bile. Up to 92% of the orally administered dose is recovered in the urine, primarily as metabolites.
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP2C9, CYP2C19, CYP2C8, CYP2C18, CYP1A2
Warfarin is stereoselectively metabolized by hepatic cytochrome P450 (CYP) isoenzymes to inactive hydroxylated metabolites (predominant route) and by reductases to reduced metabolites (warfarin alcohols). Warfarin alcohols have minimal anticoagulant activity. The CYP isoenzymes involved in the metabolism of warfarin include 2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. CYP2C9 is the primary enzyme that metabolizes S-warfarin and modulates the in vivo activity of warfarin. CYP1A2 and CYP3A4, and to a lesser extent CYP2C19, metabolize the R-isomer. Genetic polymorphism of CYP2C9 may play a role in the interpatient variability of response to warfarin and predisposition to drug interactions. The variant alleles, CYP2C9*2 and CYP2C9*3, result in decreased hydroxylation of S-warfarin and decrease S-warfarin clearance; the presence of more than 1 of the CYP2C9 variant alleles further decreases clearance. For example, patients with CYP2C9 genotypes *1/*2 or *1/*3 have a clearance of 0.041 mL/minute/kg vs. 0.065 mL/minute/kg in patients with CYP2C9 genotypes *1/*1. Additionally, patients with CYP2C9 genotypes *2/*2, *2/*3, or *3/*3 have a clearance of 0.02 mL/minute/kg. In White patients, the frequency of the CYP2C9*2 variant is 8% to 20%, while the frequency of the CYP2C9*3 variant is 6% to 10%. . The presence of CYP2C9*2 and *3 variant alleles in Black patients and Asian patients are much lower (0% to 4%); other CYP2C9 alleles that may decrease warfarin metabolism occur at lower frequencies in all races. Poor CYP2C9 metabolizers are more dependent on the metabolism of S-warfarin via the CYP3A4 pathway. Drugs that affect any of the enzymes involved in the metabolism of warfarin may alter the anticoagulation response. As a result, drugs that preferentially induce the metabolism of S-warfarin impair coagulation to a greater extent than those that induce R-warfarin metabolism.

Oral Route

Orally administered warfarin is well absorbed from the GI tract, but individual brands of warfarin can exhibit different rates or degrees of absorption. Administration with food may delay the rate but not the extent of absorption. Although warfarin plasma concentrations are detectable within 1 hour of oral administration, anticoagulation effects are dependent on the gradual catabolism of circulating activated clotting factors; requiring up to 4 days for complete clinical effect. Therefore, loading doses (7.5 to 10 mg) do not provide more rapid complete anticoagulation and may be associated with development of a hypercoagulable state. It takes roughly 4 days to return to normal blood coagulation parameters following discontinuation of the drug.

Topical Route

Warfarin is also readily absorbed through the skin, and systemic manifestations are possible with significant exposure to rodenticides.

Pregnancy

Warfarin was not present in human milk from mothers treated with warfarin from a limited published study. Human data are available; based on published data in 15 breast-feeding mothers, warfarin was not detected in human milk. Among the 15 full-term newborns, 6 nursing infants had documented prothrombin times within the expected range. Prothrombin times were not obtained for the other 9 nursing infants. Effects in premature infants have not been evaluated. Because of the potential for serious adverse reactions, including bleeding in a breast-fed infant, consider the developmental and health benefits of breast-feeding along with the mother's clinical need for warfarin and any potential adverse effects on the breast-fed infant from warfarin or the underlying maternal condition. Previous American Academy of Pediatrics considered warfarin as usually compatible with breast-feeding. Monitor breast-feeding infants for bleeding or bruising.