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  • CLASSES

    Factor Xa Inhibitors

    BOXED WARNING

    Geriatric, nonvalvular atrial fibrillation in patients with a CrCl greater than 95 mL/min, renal failure, renal impairment

    Edoxaban is not to be used for nonvalvular atrial fibrillation in patients with a CrCl greater than 95 mL/min. In the ENGAGE AF-TIMI 48 study, the efficacy of edoxaban was reduced and there was an increased rate of ischemic stroke in patients with nonvalvular atrial fibrillation patients with a CrCl greater than 95 mL/min treated with edoxaban 60 mg PO once daily compared to patients treated with warfarin. Use another anticoagulant in this population. The use of edoxaban is not recommended in patients with renal failure or severe renal impairment, defined as CrCl less than 15 mL/min. Dose reductions are required in patients with CrCl 15 to 50 mL/min. According to the Beers Criteria, the dose of edoxaban should be reduced in geriatric patients with a creatinine clearance in the range of 30 mL/min to 50 mL/min due to an increased risk of bleeding. The Beers expert panel recommends avoiding edoxaban in geriatric patients with a creatinine clearance less than 30 mL/min or greater than 95 mL/min. The creatinine clearance thresholds for which the Beers expert panel recommends avoiding use of edoxaban are based on clinical trial exclusion criteria and may not be the same as those in the product labeling.

    Abrupt discontinuation

    Avoid the abrupt discontinuation of edoxaban in the absence of adequate alternative anticoagulation. Discontinuing edoxaban puts patients at an increased risk of thrombotic events. If edoxaban must be discontinued for reasons other than pathological bleeding or completion of a course of therapy, consider administering another anticoagulant.

    Epidural anesthesia, lumbar puncture, spinal anesthesia, surgery

    Discontinue edoxaban at least 24 hours before invasive or surgical procedures due to an increased risk of bleeding. If surgery cannot be delayed, the risk of bleeding should be weighed against the urgency of the intervention. Edoxaban can be restarted after the procedure as soon as adequate hemostasis has been established noting that the time to onset of pharmacodynamic effect is 1 to 2 hours. If oral medication cannot be taken during or after surgical intervention, administer a parenteral anticoagulant and then switch to oral edoxaban. Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis. Epidural or spinal hematomas that may result in long-term or permanent paralysis may occur in patients who are anticoagulated and are receiving neuraxial anesthesia or undergoing spinal puncture. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include use of indwelling epidural catheters; concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants; a history of spinal deformity or spinal surgery; and traumatic or repeated epidural or spinal puncture. Do not remove an indwelling epidural catheter or intrathecal catheter earlier than 12 hours after the last administration of edoxaban, and do not administer the next edoxaban dose earlier than 2 hours after the catheter removal. The optimal timing between the administration of edoxaban and neuraxial procedures is not known. If epidural anesthesia, lumbar puncture, or spinal anesthesia is employed, monitor patients frequently for signs and symptoms of neurological impairment (e.g., numbness or weakness of legs, bowel or bladder dysfunction). Instruct patients to immediately report if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment.

    DEA CLASS

    Rx

    DESCRIPTION

    Oral anticoagulant
    For risk reduction of stroke and systemic embolism in atrial fibrillation unrelated to valvular heart disease and for treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) after initial injectable therapy
    Dose reduction required for patients treated for DT or PE and also receiving P-gp inhibitors

    COMMON BRAND NAMES

    Savaysa

    HOW SUPPLIED

    Savaysa Oral Tab: 15mg, 30mg, 60mg

    DOSAGE & INDICATIONS

    For stroke prophylaxis and systemic embolism prophylaxis in patients with nonvalvular atrial fibrillation (NVAF).
    NOTE: Reduce dose to 30 mg once daily in patients with CrCL 15 to 50 mL/min. Edoxaban should not be used in patients with NVAF with CrCl > 95 mL/min because of increased risk of ischemic stroke compared to warfarin.
    Oral dosage
    Adults

    60 mg PO once daily.

    For the treatment of deep venous thrombosis (DVT) or pulmonary embolism.
    Oral dosage
    Adults > 60 kg

    60 mg PO once daily following 5 to 10 days of initial therapy with a parenteral anticoagulant.

    Adults <= 60 kg

    30 mg PO once daily following 5 to 10 days of initial therapy with a parenteral anticoagulant.

    MAXIMUM DOSAGE

    Adults

    60 mg/day PO.

    Geriatric

    60 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Mild impairment (Child-Pugh Class A): No dose adjustment needed.
    Moderate impairment (Child-Pugh Class B): Use not recommended.
    Severe impairment (Child-Pugh Class C): Use not recommended.

    Renal Impairment

    CrCl 15—50 mL/min: 30 mg PO once daily.
    CrCl < 15 mL/min: Use not recommended.

    ADMINISTRATION

    Oral Administration

    May be taken without regard to food.

    Oral Solid Formulations

    For patients unable to swallow the tablet whole, tablets may be crushed and mixed with 2 to 3 ounces of water and immediately administered by mouth or gastric tube. Crushed tablets may also be mixed into applesauce for immediate administration by mouth.

    STORAGE

    Savaysa:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Bleeding

    Edoxaban is contraindicated in patients with active pathological bleeding. Edoxaban increases the risk of bleeding and can cause serious and potentially fatal bleeding. Patients should be monitored for signs or symptoms of bleeding; evaluate signs or symptoms of blood loss promptly. Discontinue edoxaban in patients with active pathological bleeding. The risk of bleeding may be increased with concomitant use of drugs affecting hemostasis, such as aspirin and other antiplatelet agents, other antithrombotic agents, fibrinolytic therapy, chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs). There is no established way to reverse the anticoagulant effects of edoxaban, which can be expected to persist for approximately 24 hours after the last dose. The anticoagulant effect of edoxaban cannot be reliably monitored with standard laboratory testing. A specific reversal agent for edoxaban is not available. Hemodialysis does not significantly contribute to edoxaban clearance. Protamine sulfate, vitamin K, and tranexamic acid are not expected to reverse the anticoagulant activity of edoxaban. The use of prothrombin complex concentrates (PCC) or other procoagulant reversal agents such as activated prothrombin complex concentrate (APCC) or recombinant factor VIIa may be considered to reverse the anticoagulant activity of edoxaban; however, outcomes have not been evaluated in clinical studies. If PCCs are utilized, monitoring for the anticoagulation effect of edoxaban using clotting test (PT, INR, or aPTT) or anti-factor Xa activity is not useful and is not recommended.

    Geriatric, nonvalvular atrial fibrillation in patients with a CrCl greater than 95 mL/min, renal failure, renal impairment

    Edoxaban is not to be used for nonvalvular atrial fibrillation in patients with a CrCl greater than 95 mL/min. In the ENGAGE AF-TIMI 48 study, the efficacy of edoxaban was reduced and there was an increased rate of ischemic stroke in patients with nonvalvular atrial fibrillation patients with a CrCl greater than 95 mL/min treated with edoxaban 60 mg PO once daily compared to patients treated with warfarin. Use another anticoagulant in this population. The use of edoxaban is not recommended in patients with renal failure or severe renal impairment, defined as CrCl less than 15 mL/min. Dose reductions are required in patients with CrCl 15 to 50 mL/min. According to the Beers Criteria, the dose of edoxaban should be reduced in geriatric patients with a creatinine clearance in the range of 30 mL/min to 50 mL/min due to an increased risk of bleeding. The Beers expert panel recommends avoiding edoxaban in geriatric patients with a creatinine clearance less than 30 mL/min or greater than 95 mL/min. The creatinine clearance thresholds for which the Beers expert panel recommends avoiding use of edoxaban are based on clinical trial exclusion criteria and may not be the same as those in the product labeling.

    Abrupt discontinuation

    Avoid the abrupt discontinuation of edoxaban in the absence of adequate alternative anticoagulation. Discontinuing edoxaban puts patients at an increased risk of thrombotic events. If edoxaban must be discontinued for reasons other than pathological bleeding or completion of a course of therapy, consider administering another anticoagulant.

    Epidural anesthesia, lumbar puncture, spinal anesthesia, surgery

    Discontinue edoxaban at least 24 hours before invasive or surgical procedures due to an increased risk of bleeding. If surgery cannot be delayed, the risk of bleeding should be weighed against the urgency of the intervention. Edoxaban can be restarted after the procedure as soon as adequate hemostasis has been established noting that the time to onset of pharmacodynamic effect is 1 to 2 hours. If oral medication cannot be taken during or after surgical intervention, administer a parenteral anticoagulant and then switch to oral edoxaban. Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis. Epidural or spinal hematomas that may result in long-term or permanent paralysis may occur in patients who are anticoagulated and are receiving neuraxial anesthesia or undergoing spinal puncture. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include use of indwelling epidural catheters; concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants; a history of spinal deformity or spinal surgery; and traumatic or repeated epidural or spinal puncture. Do not remove an indwelling epidural catheter or intrathecal catheter earlier than 12 hours after the last administration of edoxaban, and do not administer the next edoxaban dose earlier than 2 hours after the catheter removal. The optimal timing between the administration of edoxaban and neuraxial procedures is not known. If epidural anesthesia, lumbar puncture, or spinal anesthesia is employed, monitor patients frequently for signs and symptoms of neurological impairment (e.g., numbness or weakness of legs, bowel or bladder dysfunction). Instruct patients to immediately report if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment.

    Mechanical heart valves, mitral stenosis

    The safety and efficacy of edoxaban have not been studied in patients with mechanical heart valves or moderate to severe mitral stenosis. Therefore, the use of edoxaban is not recommended in these patients.

    Labor, obstetric delivery, pregnancy

    Available data are insufficient to determine whether there are drug-associated risks with edoxaban use in pregnancy. No adverse developmental effects were seen when edoxaban was administered to pregnant rats and rabbits during organogenesis at up to 16-times and 8-times, respectively, the human exposure when based on body surface area and AUC, respectively. Increased postimplantation loss and embryofetal and maternal toxicities in rats and rabbits, respectively, occurred at doses 49-times and more than 20-times, respectively, the human exposure. The use of anticoagulants, including edoxaban, may increase the risk of bleeding in the fetus and neonate. Monitor neonates for bleeding. Edoxaban use during labor or obstetric delivery in women who are receiving neuraxial anesthesia may result in epidural or spinal hematomas. Consider use of a shorter acting anticoagulant as delivery approaches.

    Breast-feeding

    There are no data on the presence of edoxaban in human milk, or its effect on the breast-feeding infant or on milk production. Edoxaban was present in the milk of lactating rats. Due to the potential for serious adverse reactions (e.g., hemorrhage) in breast-feeding infants, advise women that breast-feeding is not recommended during edoxaban therapy. If pharmacotherapy is necessary, previous American Academy of Pediatrics (AAP) recommendations consider warfarin to be usually compatible with breast-feeding. Low-molecular weight heparins and heparin have relatively high molecular weights ; therefore, these drugs are not expected to be excreted into human milk to a clinically significant degree.

    Intramuscular injections

     Intramuscular injections of other medications should not be administered to patients receiving edoxaban. IM injections may cause bleeding, bruising, or hematomas.

    ADVERSE REACTIONS

    Severe

    GI bleeding / Delayed / 1.8-4.2
    intracranial bleeding / Delayed / 0.1-0.5
    pulmonary fibrosis / Delayed / 0.2-0.2

    Moderate

    anemia / Delayed / 1.7-9.6
    vaginal bleeding / Delayed / 9.0-9.0
    elevated hepatic enzymes / Delayed / 4.8-7.8
    hematuria / Delayed / 2.2-2.2
    bleeding / Early / Incidence not known

    Mild

    rash (unspecified) / Early / 3.6-3.7
    epistaxis / Delayed / 4.7

    DRUG INTERACTIONS

    Abciximab: (Major) Coadministration of edoxaban and platelet inhibitors should be avoided due to an increased risk of bleeding during concurrent use. Occasionally, short-term coadministration may be necessary in patients transitioning to and from edoxaban. Long-term coadminstration is not recommended. Promptly evaluate any signs or symptoms of blood loss in patients on concomitant therapy.
    Acetaminophen; Aspirin, ASA; Caffeine: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and edoxaban should be monitored closely for bleeding.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and edoxaban should be monitored closely for bleeding.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and edoxaban should be monitored closely for bleeding.
    Ado-Trastuzumab emtansine: (Major) Use caution if coadministration of anticoagulants such as antithrombin III, apixaban, argatroban, bivalirudin, dabigatran, dalteparin, danaparoid, desirudin, enoxaparin, fondaparinux, heparin, lepirudin, rivaroxaban, and warfarin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anticoagulant therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Alteplase, tPA: (Major) Coadministration of edoxaban and thrombolytic agents should be avoided due to an increased risk of bleeding during concurrent use. Occasionally, short-term coadministration may be necessary in patients transitioning to and from edoxaban. Long-term coadminstration is not recommended. Promptly evaluate any signs or symptoms of blood loss in patients on concomitant therapy.
    Altretamine: (Moderate) Due to the thrombocytopenic effects of altretamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Aminosalicylate sodium, Aminosalicylic acid: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and edoxaban should be monitored closely for bleeding.
    Amiodarone: (Moderate) Coadministration of edoxaban and amiodarone may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and amiodarone is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of amiodarone; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Reduce the dose of edoxaban to 30 mg/day PO in patients being treated for deep venous thrombosis (DVT) or pulmonary embolism and receiving concomitant therapy with clarithromycin. No dosage adjustment is required in patients with atrial fibrillation. Edoxaban is a P-glycoprotein (P-gp) substrate and clarithromycin is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of clarithromycin; monitor for increased adverse effects of edoxaban. (Moderate) Coadministration of edoxaban and lansoprazole may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and lansoprazole is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of lansoprazole; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Reduce the dose of edoxaban to 30 mg/day PO in patients being treated for deep venous thrombosis (DVT) or pulmonary embolism and receiving concomitant therapy with clarithromycin. No dosage adjustment is required in patients with atrial fibrillation. Edoxaban is a P-glycoprotein (P-gp) substrate and clarithromycin is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of clarithromycin; monitor for increased adverse effects of edoxaban. (Moderate) Coadministration of edoxaban and omeprazole may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and omeprazole is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of omeprazole; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Anagrelide: (Major) Coadministration of edoxaban and platelet inhibitors should be avoided due to an increased risk of bleeding during concurrent use. Occasionally, short-term coadministration may be necessary in patients transitioning to and from edoxaban. Long-term coadminstration is not recommended. Promptly evaluate any signs or symptoms of blood loss in patients on concomitant therapy.
    Anthracyclines: (Moderate) Due to the thrombocytopenic effects of anthracyclines, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. In addition, rivaroxaban is a mild P-glycoprotein (P-gp) inhibitor and doxorubicin is a major substrate of P-gp. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of P-gp, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of rivaroxaban and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Antithrombin III: (Major) Avoid concurrent use of edoxaban with antithrombin III 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.
    Antithymocyte Globulin: (Moderate) Drugs that can cause thrombocytopenia, such as antithymocyte globulin, may lead to an increased risk of bleeding when given concurrently with anticoagulants.
    Apixaban: (Major) Avoid concurrent use of edoxaban with apixaban 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. If switching from apixaban to another anticoagulant, discontinue apixaban and start the other anticoagulant at the usual time of the next dose of apixaban. If switching from another anticoagulant to apixaban, discontinue the other anticoagulant and start apixaban at the usual time of the next dose of the other anticoagulant. 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.
    Ardeparin: (Major) Avoid concurrent use of edoxaban with low molecular weight heparins 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.
    Argatroban: (Major) Avoid concurrent use of edoxaban with thrombin inhibitors 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.
    Arsenic Trioxide: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Aspirin, ASA: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and edoxaban should be monitored closely for bleeding.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and edoxaban should be monitored closely for bleeding.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and edoxaban should be monitored closely for bleeding.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and edoxaban should be monitored closely for bleeding.
    Aspirin, ASA; Carisoprodol: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and edoxaban should be monitored closely for bleeding.
    Aspirin, ASA; Carisoprodol; Codeine: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and edoxaban should be monitored closely for bleeding.
    Aspirin, ASA; Dipyridamole: (Major) Coadministration of edoxaban and platelet inhibitors should be avoided due to an increased risk of bleeding during concurrent use. Occasionally, short-term coadministration may be necessary in patients transitioning to and from edoxaban. Long-term coadminstration is not recommended. Promptly evaluate any signs or symptoms of blood loss in patients on concomitant therapy. (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and edoxaban should be monitored closely for bleeding.
    Aspirin, ASA; Omeprazole: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and edoxaban should be monitored closely for bleeding. (Moderate) Coadministration of edoxaban and omeprazole may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and omeprazole is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of omeprazole; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Aspirin, ASA; Oxycodone: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and edoxaban should be monitored closely for bleeding.
    Aspirin, ASA; Pravastatin: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and edoxaban should be monitored closely for bleeding.
    Atazanavir; Cobicistat: (Moderate) Coadministration of edoxaban and cobicistat may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and cobicistat is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of cobicistat; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Atomoxetine: (Major) Coadministration of edoxaban with other drugs that affect hemostasis, such as selective norepinephrine reuptake inhibitors (SNRIs), increases the risk of bleeding. If these drugs are administered together, instruct patients to monitor for signs and symptoms of bleeding, and to promptly report any bleeding events to their practitioner.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and edoxaban should be monitored closely for bleeding.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Moderate) Coadministration of edoxaban and phenobarbital may result in decreased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and phenobarbital is a P-gp inducer. Decreased concentrations of edoxaban may occur during concomitant use of phenobarbital; monitor for decreased efficacy of edoxaban.
    Azithromycin: (Major) Reduce the dose of edoxaban to 30 mg/day PO in patients being treated for deep venous thrombosis (DVT) or pulmonary embolism and receiving concomitant therapy with azithromycin. No dosage adjustment is required in patients with atrial fibrillation. Edoxaban is a P-glycoprotein (P-gp) substrate and azithromycin is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of azithromycin; monitor for increased adverse effects of edoxaban.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Coadministration of edoxaban and phenobarbital may result in decreased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and phenobarbital is a P-gp inducer. Decreased concentrations of edoxaban may occur during concomitant use of phenobarbital; monitor for decreased efficacy of edoxaban.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and edoxaban should be monitored closely for bleeding.
    Betrixaban: (Major) Avoid concurrent use of edoxaban with betrixaban 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.
    Bevacizumab: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Bismuth Subsalicylate: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and edoxaban should be monitored closely for bleeding.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and edoxaban should be monitored closely for bleeding.
    Bivalirudin: (Major) Avoid concurrent use of edoxaban with thrombin inhibitors 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.
    Bosutinib: (Moderate) Coadministration of edoxaban and bosutinib may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and in vitro data indicate bosutinib is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of bosutinib; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Bupropion; Naltrexone: (Moderate) Give the extended-release injectable suspension of naltrexone cautiously to patients taking anticoagulants. Steps should be taken to avoid the risk of bleeding and hematoma formation following intramuscular injection.
    Cabozantinib: (Moderate) Coadministration of edoxaban and cabozantinib may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and cabozantinib is a mild P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of cabozantinib; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Canagliflozin: (Moderate) Coadministration of edoxaban and canagliflozin may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and canagliflozin is a mild P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of canagliflozin; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Canagliflozin; Metformin: (Moderate) Coadministration of edoxaban and canagliflozin may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and canagliflozin is a mild P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of canagliflozin; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Carbamazepine: (Moderate) Coadministration of edoxaban and carbamazepine may result in decreased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and carbamazepine is a potent P-gp inducer. Decreased concentrations of edoxaban may occur during concomitant use of carbamazepine; monitor for decreased efficacy of edoxaban.
    Carbenicillin: (Moderate) Some penicillins (e.g., carbenicillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type 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.
    Celecoxib: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Chlorambucil: (Moderate) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Choline Salicylate; Magnesium Salicylate: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and edoxaban should be monitored closely for bleeding.
    Chondroitin; Glucosamine: (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.
    Cilostazol: (Major) Coadministration of edoxaban and platelet inhibitors should be avoided due to an increased risk of bleeding during concurrent use. Occasionally, short-term coadministration may be necessary in patients transitioning to and from edoxaban. Long-term coadminstration is not recommended. Promptly evaluate any signs or symptoms of blood loss in patients on concomitant therapy.
    Clarithromycin: (Major) Reduce the dose of edoxaban to 30 mg/day PO in patients being treated for deep venous thrombosis (DVT) or pulmonary embolism and receiving concomitant therapy with clarithromycin. No dosage adjustment is required in patients with atrial fibrillation. Edoxaban is a P-glycoprotein (P-gp) substrate and clarithromycin is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of clarithromycin; monitor for increased adverse effects of edoxaban.
    Clofarabine: (Moderate) Due to the thrombocytopenic effects of clofarabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Clopidogrel: (Major) Coadministration of edoxaban and platelet inhibitors should be avoided due to an increased risk of bleeding during concurrent use. Occasionally, short-term coadministration may be necessary in patients transitioning to and from edoxaban. Long-term coadminstration is not recommended. Promptly evaluate any signs or symptoms of blood loss in patients on concomitant therapy.
    Cobicistat: (Moderate) Coadministration of edoxaban and cobicistat may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and cobicistat is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of cobicistat; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of edoxaban and cobicistat may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and cobicistat is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of cobicistat; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of edoxaban and cobicistat may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and cobicistat is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of cobicistat; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Cod Liver Oil: (Major) Cod liver oil should be used only with caution and with frequent monitoring in patients on concurrent anticoagulants. In a limited number of patients, the hypoprothrombinemic response to warfarin was increased following large doses of vitamin A. Additionally, omega-3 fatty acids contained in cod liver oil may inhibit platelet aggregation. Theoretically, the risk of bleeding may be increased, but some studies that combined omega-3 fatty acids and anticoagulant 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 to 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 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 cod liver oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly. (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.
    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.
    Crizotinib: (Moderate) Coadministration of edoxaban and crizotinib may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and in vitro data indicate crizotinib is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of crizotinib; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Cyclosporine: (Moderate) Coadministration of edoxaban and cyclosporine may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and cyclosporine is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of cyclosporine; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    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 concurrent use of edoxaban with dabigatran 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.
    Dalteparin: (Major) Avoid concurrent use of edoxaban with low molecular weight heparins 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.
    Darunavir: (Moderate) Coadministration of edoxaban and darunavir may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and darunavir is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of darunavir; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Darunavir; Cobicistat: (Moderate) Coadministration of edoxaban and cobicistat may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and cobicistat is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of cobicistat; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism. (Moderate) Coadministration of edoxaban and darunavir may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and darunavir is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of darunavir; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Coadministration of edoxaban and ritonavir may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and ritonavir is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of ritonavir; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Dasatinib: (Moderate) Due to the thrombocytopenic and possible platelet inhibiting effects of dasatinib, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. In addition, dasatinib is an inhibitor of CYP3A4, and rivaroxaban is a substrate of CYP3A4. Coadministration may result in increases in rivaroxaban exposure and may increase bleeding risk. Caution should be exercised if patients are required to take anticoagulants concomitantly with dasatinib.
    Decitabine: (Moderate) Due to the thrombocytopenic effects of antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Deferasirox: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including anticoagulants.
    Defibrotide: (Severe) 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.
    Denileukin Diftitox: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Desirudin: (Major) Avoid concurrent use of edoxaban with thrombin inhibitors 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.
    Desvenlafaxine: (Major) Platelet aggregation may be impaired by desvenlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving anticoagulants. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Dextran: (Moderate) Because of the potential effects of certain dextran formulations on bleeding time, use with caution in patients on anticoagulants concurrently.
    Dextromethorphan; Quinidine: (Major) Reduce the dose of edoxaban to 30 mg/day PO in patients being treated for deep venous thrombosis (DVT) or pulmonary embolism and receiving concomitant therapy with quinidine. No dosage adjustment is required in patients with atrial fibrillation. Edoxaban is a P-glycoprotein (P-gp) substrate and quinidine is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of quinidine; monitor for increased adverse effects of edoxaban. Similar interactions may occur with dextromethorphan; quinidine.
    Diclofenac: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Diclofenac; Misoprostol: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Diflunisal: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Diltiazem: (Moderate) Coadministration of edoxaban and diltiazem may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and diltiazem is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of diltiazem; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Diphenhydramine; Ibuprofen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Diphenhydramine; Naproxen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Dipyridamole: (Major) Coadministration of edoxaban and platelet inhibitors should be avoided due to an increased risk of bleeding during concurrent use. Occasionally, short-term coadministration may be necessary in patients transitioning to and from edoxaban. Long-term coadminstration is not recommended. Promptly evaluate any signs or symptoms of blood loss in patients on concomitant therapy.
    Dronedarone: (Moderate) Coadministration of edoxaban and dronedarone may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and dronedarone is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of dronedarone; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Drotrecogin Alfa: (Major) Treatment with drotrecogin alfa should be carefully considered in patients who are receiving or have received any anticoagulants. There is an additive risk of beeding.
    Duloxetine: (Major) Platelet aggregation may be impaired by duloxetine 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. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Eliglustat: (Moderate) Coadministration of edoxaban and eliglustat may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and eliglustat is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of eliglustat; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    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.
    Enoxaparin: (Major) Avoid concurrent use of edoxaban with low molecular weight heparins 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.
    Epoprostenol: (Moderate) When used concurrently with anticoagulants, epoprostenol may increase the risk of bleeding.
    Eptifibatide: (Major) Coadministration of edoxaban and platelet inhibitors should be avoided due to an increased risk of bleeding during concurrent use. Occasionally, short-term coadministration may be necessary in patients transitioning to and from edoxaban. Long-term coadminstration is not recommended. Promptly evaluate any signs or symptoms of blood loss in patients on concomitant therapy.
    Erythromycin: (Major) Reduce the dose of edoxaban to 30 mg/day PO in patients being treated for deep venous thrombosis (DVT) or pulmonary embolism and receiving concomitant therapy with erythromycin. No dosage adjustment is required in patients with atrial fibrillation. Edoxaban is a P-glycoprotein (P-gp) substrate and erythromycin is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of erythromycin; monitor for increased adverse effects of edoxaban.
    Erythromycin; Sulfisoxazole: (Major) Reduce the dose of edoxaban to 30 mg/day PO in patients being treated for deep venous thrombosis (DVT) or pulmonary embolism and receiving concomitant therapy with erythromycin. No dosage adjustment is required in patients with atrial fibrillation. Edoxaban is a P-glycoprotein (P-gp) substrate and erythromycin is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of erythromycin; monitor for increased adverse effects of edoxaban.
    Esomeprazole; Naproxen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    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.
    Estramustine: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Etodolac: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Etravirine: (Moderate) Coadministration of edoxaban and etravirine may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and etravirine is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of etravirine; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Ezetimibe; Simvastatin: (Moderate) Coadministration of edoxaban and simvastatin may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and simvastatin is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of simvastatin; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Factor X: (Major) The actions of factor X are likely to be counteracted by direct and indirect factor Xa inhibitors such as apixaban, edoxaban, rivaroxaban, and fondaparinux.
    Famotidine; Ibuprofen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Fenoprofen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    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.
    Floxuridine: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Fluorouracil, 5-FU: (Major) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Flurbiprofen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Folate analogs: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Fondaparinux: (Major) Avoid concurrent use of edoxaban with fondaparinux due to the increased bleeding risk. Discontinue edoxaban before starting fondaparinux, unless these agents are essential. If coadministration is necessary, monitor patients closely and promptly evaluate any signs or symptoms of bleeding. 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.
    Fulvestrant: (Moderate) Because fulvestrant is given intramuscularly, it should not be used or given with caution in patients receiving anticoagulants. Fulvestrant IM injections may cause bleeding, bruising, or hematomas in these patients.
    Garlic, Allium sativum: (Moderate) Garlic produces clinically significant antiplatelet effects so additive bleeding may occur if anticoagulants are given in combination with garlic, allium sativum. In regard to warfarin, no substantial clinical data are available to support or deny a potential for interaction; the data are limited to a random case report. 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. Avoid concurrent use of herbs which interact with warfarin when possible. If these herbal products are taken concurrently with warfarin, monitor INR and adjust warfarin dosage to attain clinical and anticoagulant endpoints.
    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: (Major) Ginkgo, Ginkgo biloba is reported to inhibit platelet aggregation and several case reports describe bleeding complications with Ginkgo biloba, with or without concomitant drug therapy. Since ginkgo produces clinically-significant antiplatelet effects, it should be used cautiously in patients drugs that inhibit platelet aggregation or pose a risk for bleeding, such as anticoagulants. Ginkgo, Ginkgo biloba is reported to inhibit platelet aggregation and several case reports describe bleeding complications with Ginkgo biloba, with or without concomitant drug therapy. Since ginkgo produces clinically-significant antiplatelet effects, it should be used cautiously in patients drugs that inhibit platelet aggregation or pose a risk for bleeding, such as anticoagulants (e.g., warfarin), aspirin, ASA or other platelet inhibitors, or thrombolytic agents. A patient who had been taking aspirin 325 mg/day PO for 3 years following coronary-artery bypass surgery, developed spontaneous bleeding into his eye after taking a standardized extract of Ginkgo biloba (Ginkoba commercial product) 40 mg PO twice daily for one week. The patient stopped taking the ginkgo but continued taking the aspirin with no recurrence of bleeding over a 3-month period. Other clinical data exist that describe spontaneous subdural hematomas associated with chronic ginkgo biloba ingestion.
    Grapefruit juice: (Moderate) Coadministration of edoxaban and grapefruit juice may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and grapefruit juice is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of grapefuit juice; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    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.
    Guarana: (Major) Guarana has been shown to possess minor antiplatelet activity and, therefore, concurrent use of guarana and anticoagulants or platelet inhibitors should be avoided.
    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) Avoid concurrent use of edoxaban with heparin 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.
    Hydrocodone; Ibuprofen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Hydroxyurea: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and edoxaban should be monitored closely for bleeding.
    Ibritumomab Tiuxetan: (Moderate) Due to the thrombocytopenic effects of the ibritumomab tiuxetan therapeutic regimen, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Ibuprofen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Ibuprofen; Oxycodone: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Ibuprofen; Pseudoephedrine: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    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.
    Ifosfamide: (Moderate) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Iloperidone: (Moderate) Coadministration of edoxaban and iloperidone may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and iloperidone is a mild P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of iloperidone; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Iloprost: (Moderate) When used concurrently with anticoagulants, inhaled iloprost may increase the risk of bleeding.
    Indomethacin: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Interferon Alfa-2a: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Interferon Alfa-2b: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Interferon Alfa-2b; Ribavirin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Interferon Alfacon-1: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    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.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Coadministration of edoxaban and rifampin should be avoided. Edoxaban is a P-glycoprotein (P-gp) substrate; rifampin is a strong inducer of P-gp. Coadminsitration decreases the serum concentration of edoxaban; reduced serum concentrations of edoxaban are expected to result in decreased efficacy of the anticoagulant.
    Isoniazid, INH; Rifampin: (Major) Coadministration of edoxaban and rifampin should be avoided. Edoxaban is a P-glycoprotein (P-gp) substrate; rifampin is a strong inducer of P-gp. Coadminsitration decreases the serum concentration of edoxaban; reduced serum concentrations of edoxaban are expected to result in decreased efficacy of the anticoagulant.
    Itraconazole: (Major) Reduce the dose of edoxaban to 30 mg/day PO in patients being treated for deep venous thrombosis (DVT) or pulmonary embolism and receiving concomitant therapy with oral itraconazole. No dosage adjustment is required in patients with atrial fibrillation. Edoxaban is a P-glycoprotein (P-gp) substrate and oral itraconazole is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of itraconazole; monitor for increased adverse effects of edoxaban.
    Ivacaftor: (Moderate) Coadministration of edoxaban and ivacaftor may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and ivacaftor is a mild P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of ivacaftor; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Kava Kava, Piper methysticum: (Moderate) Kava kava, Piper methysticum does appear to have some anti-thrombotic activity. Persons who are receiving anticoagulants should not take kava kava without first discussing use with their health care professional. Kava kava, Piper methysticum exhibits antithrombotic activity and also inhibits CYP isozymes important in warfarin clearance such as CYP2C9, 2C19, 1A2 and 3A4. Avoid concurrent use of herbs which interact with warfarin when possible. If these herbal products are taken concurrently with warfarin, monitor INR and adjust warfarin dosage to attain clinical and anticoagulant endpoints.
    Ketoconazole: (Major) Reduce the dose of edoxaban to 30 mg/day PO in patients being treated for deep venous thrombosis (DVT) or pulmonary embolism and receiving concomitant therapy with oral ketoconazole. No dosage adjustment is required in patients with atrial fibrillation. Edoxaban is a P-glycoprotein (P-gp) substrate and oral ketoconazole is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of ketoconazole; monitor for increased adverse effects of edoxaban.
    Ketoprofen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Ketorolac: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Lansoprazole: (Moderate) Coadministration of edoxaban and lansoprazole may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and lansoprazole is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of lansoprazole; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Lansoprazole; Naproxen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use. (Moderate) Coadministration of edoxaban and lansoprazole may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and lansoprazole is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of lansoprazole; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Lapatinib: (Moderate) Coadministration of edoxaban and lapatinib may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and lapatinib is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of lapatinib; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Lepirudin: (Major) Avoid concurrent use of edoxaban with thrombin inhibitors 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.
    Levomilnacipran: (Major) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) 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. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    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.
    Lopinavir; Ritonavir: (Moderate) Coadministration of edoxaban and ritonavir may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and ritonavir is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of ritonavir; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Lovastatin: (Moderate) Coadministration of edoxaban and lovastatin may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and lovastatin is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of lovastatin; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Lovastatin; Niacin: (Moderate) Coadministration of edoxaban and lovastatin may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and lovastatin is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of lovastatin; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Low Molecular Weight Heparins: (Major) Avoid concurrent use of edoxaban with low molecular weight heparins 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.
    Lumacaftor; Ivacaftor: (Moderate) Coadministration of edoxaban and ivacaftor may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and ivacaftor is a mild P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of ivacaftor; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Magnesium Salicylate: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and edoxaban should be monitored closely for bleeding.
    Meclofenamate Sodium: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Mefenamic Acid: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Mefloquine: (Moderate) Coadministration of edoxaban and mefloquine may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and mefloquine is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of mefloquine; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Meloxicam: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Methoxsalen: (Minor) Agents, such as anticoagulants, that decrease clotting could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    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.
    Mifepristone, RU-486: (Major) When mifepristone, RU-486 (Mifeprex) is used for the termination of pregnancy, concurrent use of anticoagulants is contraindicated due to the increased risk of serious bleeding. When mifepristone (Korlym) is used, concurrent use of some anticoagulants should be approached with caution. In addition, coadministration of edoxaban and mifepristone, RU-486 may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and mifepristone is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of mifepristone; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Milnacipran: (Major) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) 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. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Miltefosine: (Moderate) Caution is advised when administering miltefosine with anticoagulants, as use of these drugs together may increase risk for bleeding. Miltefosine, when administered for 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.
    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: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Naltrexone: (Moderate) Give the extended-release injectable suspension of naltrexone cautiously to patients taking anticoagulants. Steps should be taken to avoid the risk of bleeding and hematoma formation following intramuscular injection.
    Nandrolone Decanoate: (Moderate) Androgens can enhance the effects of anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain prothrombin time at the desired therapeutic level. When anabolic steroid or androgen therapy is started or stopped in patients on anticoagulant therapy, close monitoring is required. Additionally, nandrolone decanoate may generate a pharmacodynamic interaction with warfarin by independently affecting the activity of circulating coagulation proteins. Androgens reduce the amount or activity of circulating coagulant proteins thereby enhancing the anticoagulant effect of warfarin.
    Naproxen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Naproxen; Pseudoephedrine: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Naproxen; Sumatriptan: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Natural Antineoplastics: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Nelarabine: (Moderate) Due to the thrombocytopenic effects of nelarabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Nelfinavir: (Moderate) Coadministration of edoxaban and nelfinavir may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and nelfinavir is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of nelfinavir; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Niacin; Simvastatin: (Moderate) Coadministration of edoxaban and simvastatin may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and simvastatin is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of simvastatin; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Nicardipine: (Moderate) Coadministration of edoxaban and nicardipine may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and nicardipine is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of nicardipine; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Nifedipine: (Moderate) Coadministration of edoxaban and nifedipine may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and nifedipine is a mild P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of nifedipine; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Nilotinib: (Moderate) Coadministration of edoxaban and nilotinib may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and nilotinib is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of nilotinib; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    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.
    Nonsteroidal antiinflammatory drugs: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    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.
    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.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Coadministration of edoxaban and ritonavir may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and ritonavir is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of ritonavir; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Omeprazole: (Moderate) Coadministration of edoxaban and omeprazole may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and omeprazole is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of omeprazole; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Omeprazole; Sodium Bicarbonate: (Moderate) Coadministration of edoxaban and omeprazole may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and omeprazole is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of omeprazole; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Orlistat: (Moderate) Patients on chronic stable doses of anticoagulants like edoxaban should be monitored closely for changes in coagulation parameters when orlistat is prescribed. 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.
    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: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Paliperidone: (Moderate) Coadministration of edoxaban and paliperidone may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and paliperidone is a mild P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of paliperidone; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Pantoprazole: (Moderate) Coadministration of edoxaban and pantoprazole may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and pantoprazole is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of pantoprazole; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Pazopanib: (Moderate) Coadministration of edoxaban and pazopanib may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and pazopanib is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of pazopanib; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Pentosan: (Major) Avoid concurrent use of edoxaban with pentosan 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. Pentosan is a weak anticoagulant. Pentosan has one-fifteenth the anticoagulant activity of heparin.
    Phenobarbital: (Moderate) Coadministration of edoxaban and phenobarbital may result in decreased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and phenobarbital is a P-gp inducer. Decreased concentrations of edoxaban may occur during concomitant use of phenobarbital; monitor for decreased efficacy of edoxaban.
    Phentermine; Topiramate: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Photosensitizing agents: (Minor) Drugs that decrease clotting, such as anticoagulants, could decrease the efficacy of photodynamic therapy.
    Piperacillin: (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.
    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.
    Pirfenidone: (Moderate) Coadministration of edoxaban and pirfenidone may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and in vitro data indicate pirfenidone is a mild P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of pirfenidone; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Piroxicam: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Platelet Inhibitors: (Major) Coadministration of edoxaban and platelet inhibitors should be avoided due to an increased risk of bleeding during concurrent use. Occasionally, short-term coadministration may be necessary in patients transitioning to and from edoxaban. Long-term coadminstration is not recommended. Promptly evaluate any signs or symptoms of blood loss in patients on concomitant therapy.
    Porfimer: (Minor) Drugs that decrease clotting, such as anticoagulants, could decrease the efficacy of photodynamic therapy.
    Posaconazole: (Moderate) Coadministration of edoxaban and posaconazole may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and posaconazole may inhibit P-gp. Increased concentrations of edoxaban may occur during concomitant use of posaconazole; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    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: (Major) Coadministration of edoxaban and platelet inhibitors should be avoided due to an increased risk of bleeding during concurrent use. Occasionally, short-term coadministration may be necessary in patients transitioning to and from edoxaban. Long-term coadminstration is not recommended. Promptly evaluate any signs or symptoms of blood loss in patients on concomitant therapy.
    Primidone: (Moderate) Coadministration of edoxaban and primidone may result in decreased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and primidone is a P-gp inducer. Decreased concentrations of edoxaban may occur during concomitant use of primidone; monitor for decreased efficacy of edoxaban.
    Propafenone: (Moderate) Coadministration of edoxaban and propafenone may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and propafenone is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of propafenone; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Prothrombin Complex Concentrate, Human: (Major) The actions of factor X are likely to be counteracted by direct and indirect factor Xa inhibitors such as apixaban, edoxaban, rivaroxaban, and fondaparinux.
    Quinidine: (Major) Reduce the dose of edoxaban to 30 mg/day PO in patients being treated for deep venous thrombosis (DVT) or pulmonary embolism and receiving concomitant therapy with quinidine. No dosage adjustment is required in patients with atrial fibrillation. Edoxaban is a P-glycoprotein (P-gp) substrate and quinidine is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of quinidine; monitor for increased adverse effects of edoxaban. Similar interactions may occur with dextromethorphan; quinidine.
    Rabies Immune Globulin, human RIG: (Minor) The intramuscular rabies immune globulin, human RIG should be administered cautiously to persons receiving anticoagulants. If used concurrently, monitor patients closely for bleeding at the IM injection site. All steps to avoid hematoma formation are recommended.
    Ranolazine: (Moderate) Coadministration of edoxaban and ranolazine may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and in vitro data indicate ranolazine is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of ranolazine; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Regorafenib: (Moderate) Coadministration of edoxaban and regorafenib may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and regorafenib is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of regorafenib; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Reteplase, r-PA: (Major) Coadministration of edoxaban and thrombolytic agents should be avoided due to an increased risk of bleeding during concurrent use. Occasionally, short-term coadministration may be necessary in patients transitioning to and from edoxaban. Long-term coadminstration is not recommended. Promptly evaluate any signs or symptoms of blood loss in patients on concomitant therapy.
    Rifampin: (Major) Coadministration of edoxaban and rifampin should be avoided. Edoxaban is a P-glycoprotein (P-gp) substrate; rifampin is a strong inducer of P-gp. Coadminsitration decreases the serum concentration of edoxaban; reduced serum concentrations of edoxaban are expected to result in decreased efficacy of the anticoagulant.
    Ritonavir: (Moderate) Coadministration of edoxaban and ritonavir may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and ritonavir is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of ritonavir; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Rivaroxaban: (Major) Avoid concurrent use of edoxaban with rivaroxaban 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.
    Rofecoxib: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Salicylates: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and edoxaban should be monitored closely for bleeding.
    Salsalate: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and edoxaban should be monitored closely for bleeding.
    Saquinavir: (Moderate) Coadministration of edoxaban and saquinavir may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and saquinavir is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of saquinavir; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Selective norepinephrine reuptake inhibitors: (Major) Coadministration of edoxaban with other drugs that affect hemostasis, such as selective norepinephrine reuptake inhibitors (SNRIs), increases the risk of bleeding. If these drugs are administered together, instruct patients to monitor for signs and symptoms of bleeding, and to promptly report any bleeding events to their practitioner.
    Selective serotonin reuptake inhibitors: (Major) Selective serotonin reuptake inhibitors (SSRIs) can inhibit serotonin uptake by platelets, thus causing platelet dysfunction and increasing the risk for bleeding with edoxaban; however, the absolute risk is not known. If these drugs are administered together, instruct patients to monitor for signs and symptoms of bleeding, and to promptly report any bleeding events to their practitioner.
    Simeprevir: (Moderate) Coadministration of edoxaban and simeprevir may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and simeprevir is a mild P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of simeprevir; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Simvastatin: (Moderate) Coadministration of edoxaban and simvastatin may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and simvastatin is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of simvastatin; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Simvastatin; Sitagliptin: (Moderate) Coadministration of edoxaban and simvastatin may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and simvastatin is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of simvastatin; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Sodium Iodide: (Moderate) Anticoagulants may alter sodium iodide I-131 pharmacokinetics and dynamics for up to 1 week after administrations.
    Sorafenib: (Moderate) Coadministration of edoxaban and sorafenib may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and in vitro data indicate sorafenib is a mild P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of sorafenib; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    St. John's Wort, Hypericum perforatum: (Moderate) Coadministration of edoxaban and St. John's Wort, Hypericum perforatum may result in decreased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and St. John's Wort is a P-gp inducer. Decreased concentrations of edoxaban may occur during concomitant use of St. John's Wort; monitor for decreased efficacy of edoxaban.
    Streptokinase: (Major) Coadministration of edoxaban and thrombolytic agents should be avoided due to an increased risk of bleeding during concurrent use. Occasionally, short-term coadministration may be necessary in patients transitioning to and from edoxaban. Long-term coadminstration is not recommended. Promptly evaluate any signs or symptoms of blood loss in patients on concomitant therapy.
    Sulfinpyrazone: (Major) Sulfinpyrazone should be avoided when possible with concurrent anticoagulants, thrombin inhibitors, and thrombolytic agents due to potential for increased bleeding risk. Alternative uricosuric agents may be considered. Sulfinpyrazone is a platelet inhibitor and exhibits antithrombotic actions in addition to its uricosuric effects. Additive hematological effects are possible as a result of the platelet inhibitory effects of sulfinpyrazone; the sulfide metabolite of sulfinpyrazone appears responsible for this effect. Sulfinpyrazone is also known to markedly potentiate the effect of warfarin. Sulfinpyrazone may inhibit CYP2C9, leading to a decrease in the clearance of S-warfarin. If concurrent therapy is warranted, significant initial dosage reductions (e.g., 50%) of warfarin may be necessary, with further dosage adjusted based on INR values. The INR should be closely monitored during concurrent therapy with warfarin, particularly during the initiation or termination phases of sulfinpyrazone treatment.
    Sulindac: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Tamoxifen: (Moderate) Coadministration of edoxaban and tamoxifen may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and tamoxifen is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of tamoxifen; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Taxanes: (Moderate) Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Telaprevir: (Moderate) Coadministration of edoxaban and telaprevir may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and telaprevir is a mild P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of telaprevir; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Telithromycin: (Moderate) Coadministration of edoxaban and telithromycin may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and telithromycin is a mild P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of telithromycin; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Tenecteplase, TNK-tPA: (Major) Coadministration of edoxaban and thrombolytic agents should be avoided due to an increased risk of bleeding during concurrent use. Occasionally, short-term coadministration may be necessary in patients transitioning to and from edoxaban. Long-term coadminstration is not recommended. Promptly evaluate any signs or symptoms of blood loss in patients on concomitant therapy.
    Testosterone: (Moderate) Coadministration of edoxaban and testosterone may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and testosterone is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of testosterone; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Thrombin Inhibitors: (Major) Avoid concurrent use of edoxaban with thrombin inhibitors 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.
    Thrombolytic Agents: (Major) Coadministration of edoxaban and thrombolytic agents should be avoided due to an increased risk of bleeding during concurrent use. Occasionally, short-term coadministration may be necessary in patients transitioning to and from edoxaban. Long-term coadminstration is not recommended. Promptly evaluate any signs or symptoms of blood loss in patients on concomitant therapy.
    Ticagrelor: (Major) Coadministration of edoxaban and platelet inhibitors should be avoided due to an increased risk of bleeding during concurrent use. Occasionally, short-term coadministration may be necessary in patients transitioning to and from edoxaban. Long-term coadminstration is not recommended. Promptly evaluate any signs or symptoms of blood loss in patients on concomitant therapy.
    Ticarcillin: (Moderate) Some penicillins (e.g., ticarcillin) 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.
    Ticarcillin; Clavulanic Acid: (Moderate) Some penicillins (e.g., ticarcillin) 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.
    Ticlopidine: (Major) Coadministration of edoxaban and platelet inhibitors should be avoided due to an increased risk of bleeding during concurrent use. Occasionally, short-term coadministration may be necessary in patients transitioning to and from edoxaban. Long-term coadminstration is not recommended. Promptly evaluate any signs or symptoms of blood loss in patients on concomitant therapy.
    Tinzaparin: (Major) Avoid concurrent use of edoxaban with low molecular weight heparins 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.
    Tipranavir: (Moderate) Coadministration of edoxaban and tipranavir may result in decreased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and tipranavir is a mild P-gp inducer. Decreased concentrations of edoxaban may occur during concomitant use of tipranavir; monitor for decreased efficacy of edoxaban.
    Tirofiban: (Major) Coadministration of edoxaban and platelet inhibitors should be avoided due to an increased risk of bleeding during concurrent use. Occasionally, short-term coadministration may be necessary in patients transitioning to and from edoxaban. Long-term coadminstration is not recommended. Promptly evaluate any signs or symptoms of blood loss in patients on concomitant therapy.
    Tolmetin: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Tolvaptan: (Moderate) Coadministration of edoxaban and tolvaptan may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and tolvaptan is a mild P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of tolvaptan; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Topiramate: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Trandolapril; Verapamil: (Major) Reduce the dose of edoxaban to 30 mg/day PO in patients being treated for deep venous thrombosis (DVT) or pulmonary embolism and receiving concomitant therapy with verapamil. No dosage adjustment is required in patients with atrial fibrillation. Edoxaban is a P-glycoprotein (P-gp) substrate and verapamil is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of verapamil; monitor for increased adverse effects of edoxaban.
    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.
    Tretinoin, ATRA: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Ulipristal: (Moderate) Coadministration of edoxaban and ulipristal may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and in vitro data indicate ulipristal is a mild P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of ulipristal; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Urokinase: (Major) Coadministration of edoxaban and thrombolytic agents should be avoided due to an increased risk of bleeding during concurrent use. Occasionally, short-term coadministration may be necessary in patients transitioning to and from edoxaban. Long-term coadminstration is not recommended. Promptly evaluate any signs or symptoms of blood loss in patients on concomitant therapy.
    Valdecoxib: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Vemurafenib: (Moderate) Coadministration of edoxaban and vemurafenib may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and in vitro data indicate vemurafenib is a mild P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of vemurafenib; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
    Venlafaxine: (Major) Platelet aggregation may be impaired by venlafaxine 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. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. Monitor INR levels when venlafaxine is added to or discontinued from warfarin therapy. Patients should be instructed to monitor for signs and symptoms of bleeding while taking venlafaxine concurrently with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Verapamil: (Major) Reduce the dose of edoxaban to 30 mg/day PO in patients being treated for deep venous thrombosis (DVT) or pulmonary embolism and receiving concomitant therapy with verapamil. No dosage adjustment is required in patients with atrial fibrillation. Edoxaban is a P-glycoprotein (P-gp) substrate and verapamil is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of verapamil; monitor for increased adverse effects of edoxaban.
    Verteporfin: (Minor) Drugs that decrease clotting, such as anticoagulants, could decrease the efficacy of photodynamic therapy.
    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.
    Vorapaxar: (Major) Coadministration of edoxaban and platelet inhibitors should be avoided due to an increased risk of bleeding during concurrent use. Occasionally, short-term coadministration may be necessary in patients transitioning to and from edoxaban. Long-term coadminstration is not recommended. Promptly evaluate any signs or symptoms of blood loss in patients on concomitant therapy.
    Vorinostat: (Moderate) Concomitant use of vorinostat with anticoagulants may result in an additive risk of bleeding due to vorinostat-induced thrombocytopenia; monitor patients closely.
    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.
    Warfarin: (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.

    PREGNANCY AND LACTATION

    Pregnancy

    Available data are insufficient to determine whether there are drug-associated risks with edoxaban use in pregnancy. No adverse developmental effects were seen when edoxaban was administered to pregnant rats and rabbits during organogenesis at up to 16-times and 8-times, respectively, the human exposure when based on body surface area and AUC, respectively. Increased postimplantation loss and embryofetal and maternal toxicities in rats and rabbits, respectively, occurred at doses 49-times and more than 20-times, respectively, the human exposure. The use of anticoagulants, including edoxaban, may increase the risk of bleeding in the fetus and neonate. Monitor neonates for bleeding. Edoxaban use during labor or obstetric delivery in women who are receiving neuraxial anesthesia may result in epidural or spinal hematomas. Consider use of a shorter acting anticoagulant as delivery approaches.

    MECHANISM OF ACTION

    Edoxaban is a selective inhibitor of Factor Xa and does not require antithrombin III for antithrombotic activity. It inhibits free factor Xa and prothrombinase activity; inhibition of factor Xa decreases the generation of thrombin. Edoxaban has no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin.

    PHARMACOKINETICS

    Edoxaban is administered orally. In vitro, plasma protein binding of edoxaban is approximately 55%. The volume of distribution is 107 L at steady state. Unchanged edoxaban is the major drug-related component in human plasma; the predominant active metabolite M-4 is formed by hydrolysis and reaches less than 10% of the exposure of the parent compound in healthy subjects. Exposure to the other metabolites is less than 5% of exposure to edoxaban. Unchanged drug is excreted into urine. Renal excretion accounts for approximately 50% of total edoxaban clearance. Metabolism and biliary/intestinal excretion account for the remaining clearance. The terminal elimination half-life of edoxaban is 10—14 hours.
     
    There is no established way to reverse the anticoagulant effects of edoxaban and it cannot be monitored with standard laboratory testing. As a result of factor Xa inhibition, edoxaban prolongs prothrombin time (PT) and activated partial thromboplastin time (aPTT). However, the changes observed in PT, INR, and aPTT are small, subject to a high degree of variability and not useful in monitoring the anticoagulant effect of edoxaban. Protamine sulfate, vitamin K, and tranexamic acid are not expected to reverse the anticoagulant effects of edoxaban.
     
    Affected cytochrome P450 isoenzymes and drug transporters: P-gp
    Edoxaban is a substrate of the P-glycoprotein (P-gp) transporter (MDR1). According to in vitro data, edoxaban does not inhibit the major cytochrome P450 enzymes (CYP1A2, 2A6, 2B6, 2C8/9, 2C19, 2D6, 2E1, or 3A4) and does not induce CYP1A2, CYP3A4 or P-gp. In vitro data also indicate that edoxaban does not inhibit the following transporters at clinically relevant concentrations: P-gp, the organic anion transporters OAT1 or OAT3; the organic cation transporters OCT1 or OCT2; or the organic ion transporting polypeptides OATP1B1 or OATP1B3.

    Oral Route

    The absolute bioavailability of edoxaban is 62% and is not affected by food. Edoxaban is rapidly absorbed following oral adminsitration with peak plasma concentrations reached within 1—2 hours. Edoxaban displays approximately dose-proportional pharmacokinetics. No data are available regarding the bioavailability upon crushing and/or mixing of edoxaban tablets into food, liquids, or administration through feeding tubes.