Savaysa

Factor Xa Inhibitors

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.

Severe

GI bleeding / Delayed / 1.8-4.2
intracranial bleeding / Delayed / 0.1-0.5
spinal hematoma / Delayed / Incidence not known
angioedema / Rapid / Incidence not known
nephrotoxicity / Delayed / Incidence not known

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
interstitial lung disease / Delayed / 0.2-0.2
bleeding / Early / Incidence not known
thrombocytopenia / Delayed / Incidence not known

Mild

rash / Early / 3.6-4.2
epistaxis / Delayed / 4.7
urticaria / Rapid / Incidence not known
abdominal pain / Early / Incidence not known
headache / Early / Incidence not known
dizziness / Early / Incidence not known

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/minute. Dose reductions are required in patients with CrCl 15 to 50 mL/minute. According to the Beers Criteria, data are lacking for efficacy and safety of edoxaban in geriatric patients with a creatinine clearance (CrCl) less than 30 mL/minute. The Beers panel recommends dose reduction in geriatric patients with a CrCl of 15 to 50 mL/minute and that edoxaban be avoided if the CrCl is less than 15 mL/minute or more than 95 mL/minute.

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.

Savaysa

Rx

Oral anticoagulant
For risk reduction of stroke in atrial fibrillation and treatment of DVT and PE after initial injectable therapy
Dose reduction required in some patients treated for DVT or PE and a CrCl of 15 to 50 mL/min or a body weight of 60 kg or less or also receiving P-gp inhibitors

For stroke and systemic embolism prophylaxis in nonvalvular atrial fibrillation. Oral dosage Adults

60 mg PO once daily. For eligible persons, novel oral anticoagulants are preferred over warfarin therapy.

For the treatment of deep venous thrombosis (DVT) or pulmonary embolism (PE) after 5 to 10 days of initial therapy with a parenteral anticoagulant. Oral dosage Adults weighing more than 60 kg

60 mg PO once daily for at least 3 months. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Adults weighing 60 kg or less

30 mg PO once daily for at least 3 months. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

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

Deep vein thrombosis and pulmonary embolism:
CrCl 15 to 50 mL/minute: 30 mg PO once daily.
CrCl less than 15 mL/minute: Use not recommended.
 
Nonvalvular atrial fibrillation:
CrCl greater than 95 mL/minute: Use not recommended. Risk for ischemic stroke increases as renal function improves and edoxaban concentrations decrease.
CrCl 51 to 95 mL/minute: No dosage adjustment needed.
CrCl 15 to 50 mL/minute: 30 mg PO once daily.
CrCl less than 15 mL/minute: Use not recommended.

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.
Abrocitinib: (Major) Consider an edoxaban dosage reduction for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE) if concomitant use of abrocitinib is necessary. Concomitant use may increase edoxaban exposure; edoxaban is a P-gp substrate and abrocitinib is a P-gp inhibitor. An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with abrocitinib. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of abrocitinib. Increased concentrations of edoxaban may occur during concomitant use of abrocitinib; monitor for increased adverse effects of edoxaban.
Acetaminophen; Aspirin, ASA; Caffeine: (Major) Monitor for bleeding in patients who require chronic treatment with aspirin. Concomitant use of edoxaban with drugs that affect hemostasis, such as aspirin, may increase the risk of bleeding. The coadministration of aspirin (100 mg or 325 mg) and edoxaban increased bleeding time relative to that seen with either drug alone.
Acetaminophen; Aspirin: (Major) Monitor for bleeding in patients who require chronic treatment with aspirin. Concomitant use of edoxaban with drugs that affect hemostasis, such as aspirin, may increase the risk of bleeding. The coadministration of aspirin (100 mg or 325 mg) and edoxaban increased bleeding time relative to that seen with either drug alone.
Acetaminophen; Aspirin; Diphenhydramine: (Major) Monitor for bleeding in patients who require chronic treatment with aspirin. Concomitant use of edoxaban with drugs that affect hemostasis, such as aspirin, may increase the risk of bleeding. The coadministration of aspirin (100 mg or 325 mg) and edoxaban increased bleeding time relative to that seen with either drug alone.
Acetaminophen; 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.
Adagrasib: (Major) Consider an edoxaban dosage reduction for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE) if concomitant use of adagrasib is necessary. Concomitant use may increase edoxaban exposure; edoxaban is a P-gp substrate and adagrasib is a P-gp inhibitor. An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with adagrasib. Based on clinical experience in patients with non-valvular atrial fibrillation, no dose reduction is recommended for concomitant use of adagrasib. Increased concentrations of edoxaban may occur during concomitant use of adagrasib; monitor for increased adverse effects of edoxaban.
Ado-Trastuzumab emtansine: (Moderate) Use caution if coadministration of anticoagulants with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
Alteplase: (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.
Aminosalicylate sodium, Aminosalicylic acid: (Moderate) Patients taking large doses of salicylates and edoxaban should be monitored closely for bleeding. Large doses of salicylates (3 g to 4 g/day or more) can cause hypoprothrombinemia, an additional risk factor 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.
Amlodipine; 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.
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.
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.
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.
Apalutamide: (Moderate) Monitor for decreased efficacy of edoxaban if coadministration with apalutamide is necessary; decreased concentrations of edoxaban may occur with concomitant use. Edoxaban is a P-glycoprotein (P-gp) substrate and apalutamide is a weak P-gp inducer.
Apixaban: (Major) Avoid concomitant use of apixaban and edoxaban due to the increased risk for bleeding. Short-term overlaps in anticoagulation therapy may be necessary for patients transitioning from one anticoagulant to another. Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if the use of multiple anticoagulants is necessary.
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.
Aspirin, ASA: (Major) Monitor for bleeding in patients who require chronic treatment with aspirin. Concomitant use of edoxaban with drugs that affect hemostasis, such as aspirin, may increase the risk of bleeding. The coadministration of aspirin (100 mg or 325 mg) and edoxaban increased bleeding time relative to that seen with either drug alone.
Aspirin, ASA; Butalbital; Caffeine: (Major) Monitor for bleeding in patients who require chronic treatment with aspirin. Concomitant use of edoxaban with drugs that affect hemostasis, such as aspirin, may increase the risk of bleeding. The coadministration of aspirin (100 mg or 325 mg) and edoxaban increased bleeding time relative to that seen with either drug alone.
Aspirin, ASA; Caffeine: (Major) Monitor for bleeding in patients who require chronic treatment with aspirin. Concomitant use of edoxaban with drugs that affect hemostasis, such as aspirin, may increase the risk of bleeding. The coadministration of aspirin (100 mg or 325 mg) and edoxaban increased bleeding time relative to that seen with either drug alone.
Aspirin, ASA; Caffeine; Orphenadrine: (Major) Monitor for bleeding in patients who require chronic treatment with aspirin. Concomitant use of edoxaban with drugs that affect hemostasis, such as aspirin, may increase the risk of bleeding. The coadministration of aspirin (100 mg or 325 mg) and edoxaban increased bleeding time relative to that seen with either drug alone.
Aspirin, ASA; Carisoprodol; Codeine: (Major) Monitor for bleeding in patients who require chronic treatment with aspirin. Concomitant use of edoxaban with drugs that affect hemostasis, such as aspirin, may increase the risk of bleeding. The coadministration of aspirin (100 mg or 325 mg) and edoxaban increased bleeding time relative to that seen with either drug alone.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Major) Monitor for bleeding in patients who require chronic treatment with aspirin. Concomitant use of edoxaban with drugs that affect hemostasis, such as aspirin, may increase the risk of bleeding. The coadministration of aspirin (100 mg or 325 mg) and edoxaban increased bleeding time relative to that seen with either drug alone.
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) Monitor for bleeding in patients who require chronic treatment with aspirin. Concomitant use of edoxaban with drugs that affect hemostasis, such as aspirin, may increase the risk of bleeding. The coadministration of aspirin (100 mg or 325 mg) and edoxaban increased bleeding time relative to that seen with either drug alone.
Aspirin, ASA; Omeprazole: (Major) Monitor for bleeding in patients who require chronic treatment with aspirin. Concomitant use of edoxaban with drugs that affect hemostasis, such as aspirin, may increase the risk of bleeding. The coadministration of aspirin (100 mg or 325 mg) and edoxaban increased bleeding time relative to that seen with either drug alone.
Aspirin, ASA; Oxycodone: (Major) Monitor for bleeding in patients who require chronic treatment with aspirin. Concomitant use of edoxaban with drugs that affect hemostasis, such as aspirin, may increase the risk of bleeding. The coadministration of aspirin (100 mg or 325 mg) and edoxaban increased bleeding time relative to that seen with either drug alone.
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.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Patients taking large doses of salicylates and edoxaban should be monitored closely for bleeding. Large doses of salicylates (3 g to 4 g/day or more) can cause hypoprothrombinemia, an additional risk factor 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.
Bismuth Subsalicylate: (Moderate) Patients taking large doses of salicylates and edoxaban should be monitored closely for bleeding. Large doses of salicylates (3 g to 4 g/day or more) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Patients taking large doses of salicylates and edoxaban should be monitored closely for bleeding. Large doses of salicylates (3 g to 4 g/day or more) can cause hypoprothrombinemia, an additional risk factor 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.
Brigatinib: (Moderate) Monitor for an increase in edoxaban-related adverse reactions if coadministration with brigatinib is necessary. Edoxaban is a substrate of P-glycoprotein (P-gp). Brigatinib inhibits P-gp in vitro and may have the potential to increase concentrations of P-gp substrates.
Bupivacaine; 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.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Monitor for bleeding in patients who require chronic treatment with aspirin. Concomitant use of edoxaban with drugs that affect hemostasis, such as aspirin, may increase the risk of bleeding. The coadministration of aspirin (100 mg or 325 mg) and edoxaban increased bleeding time relative to that seen with either drug alone.
Cannabidiol: (Major) Consider an edoxaban dosage reduction for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE) if concomitant use of cannabidiol is necessary. Concomitant use may increase edoxaban exposure; edoxaban is a P-gp substrate and cannabidiol is a P-gp inhibitor. An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with cannabidiol. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of cannabidiol. Increased concentrations of edoxaban may occur during concomitant use of cannabidiol; monitor for increased adverse effects of edoxaban.
Caplacizumab: (Major) Avoid concomitant use of caplacizumab and anticoagulants when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Capmatinib: (Major) If coadministered with capmatinib, a P-gp inhibitor, dosage reduction of edoxaban, a P-gp substrate, may be necessary for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE). An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with capmatinib. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of capmatinib. Increased concentrations of edoxaban may occur during concomitant use of capmatinib; monitor for increased adverse effects of edoxaban.
Carbamazepine: (Major) Avoid the concomitant administration of edoxaban and carbamazepine. Concomitant administration of edoxaban and carbamazepine results in decreased plasma concentrations of edoxaban that may be insufficient to achieve the intended therapeutic effect.
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.
Celecoxib; Tramadol: (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.
Chloroquine: (Moderate) Use caution if chloroquine is coadministered with edoxaban due to the potential for increased edoxaban exposure which may increase the risk of bleeding. Edoxaban is a P-gp substrate; limited data suggests that chloroquine is a P-gp inhibitor.
Chlorpheniramine; 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.
Choline Salicylate; Magnesium Salicylate: (Moderate) Patients taking large doses of salicylates and edoxaban should be monitored closely for bleeding. Large doses of salicylates (3 g to 4 g/day or more) can cause hypoprothrombinemia, an additional risk factor for 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.
Citalopram: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like edoxaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
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.
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.
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.
Daridorexant: (Major) Consider an edoxaban dosage reduction for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE) if concomitant use of daridorexant is necessary. Concomitant use may increase edoxaban exposure; edoxaban is a P-gp substrate and daridorexant is a P-gp inhibitor. An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with daridorexant. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of daridorexant. Increased concentrations of edoxaban may occur during concomitant use of daridorexant; monitor for increased adverse effects of edoxaban.
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.
Darunavir; Cobicistat; 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.
Dasatinib: (Moderate) Monitor for evidence of bleeding if coadministration of dasatinib and anticoagulants is necessary. Dasatinib can cause serious and fatal bleeding. Concomitant anticoagulants may increase the risk of hemorrhage.
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: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like anticoagulants is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue systemic antithrombotic agents (not including use for routine maintenance or reopening of central venous catheters) prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Deoxycholic Acid: (Moderate) Use deoxycholic acid with caution in patients receiving anticoagulants. Excessive bruising or bleeding may occur in and around the treatment area.
Desvenlafaxine: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like edoxaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Dextran: (Moderate) Because of the potential effects of certain dextran formulations on bleeding time, use with caution in patients on anticoagulants concurrently.
Dextromethorphan; 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.
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.
Duloxetine: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like edoxaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Elacestrant: (Major) Consider an edoxaban dosage reduction for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE) if concomitant use of elacestrant is necessary. Concomitant use may increase edoxaban exposure; edoxaban is a P-gp substrate and elacestrant is a P-gp inhibitor. An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with elacestrant. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of elacestrant. Increased concentrations of edoxaban may occur during concomitant use of elacestrant; monitor for increased adverse effects of edoxaban.
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.
Elvitegravir; Cobicistat; 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.
Elvitegravir; Cobicistat; 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.
Enasidenib: (Major) Consider an edoxaban dosage reduction for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE) if concomitant use of enasidenib is necessary. Concomitant use may increase edoxaban exposure; edoxaban is a P-gp substrate and enasidenib is a P-gp inhibitor. An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with enasidenib. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of enasidenib. Increased concentrations of edoxaban may occur during concomitant use of enasidenib; monitor for increased adverse effects of edoxaban.
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.
Escitalopram: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like edoxaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
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.
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.
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.
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.
Fluoxetine: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like edoxaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
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.
Fluvoxamine: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like edoxaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
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.
Fosphenytoin: (Moderate) Monitor for decreased efficacy of edoxaban if coadministration with fosphenytoin is necessary; decreased concentrations of edoxaban may occur with concomitant use. Edoxaban is a P-glycoprotein (P-gp) substrate and fosphenytoin is a P-gp inducer.
Fostamatinib: (Moderate) Monitor for edoxaban toxicities that may require edoxaban dose reduction if given concurrently with fostamatinib. Concomitant use of fostamatinib with a P-gp substrate may increase the concentration of the P-gp substrate. Fostamatinib is a P-gp inhibitor; edoxaban is a substrate for P-gp. Coadministration of fostamatinib with another P-gp substrate increased the substrate AUC by 37% and Cmax by 70%.
Futibatinib: (Major) Consider an edoxaban dosage reduction for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE) if concomitant use of futibatinib is necessary. Concomitant use may increase edoxaban exposure; edoxaban is a P-gp substrate and futibatinib is a P-gp inhibitor. An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with futibatinib. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of futibatinib. Increased concentrations of edoxaban may occur during concomitant use of futibatinib; monitor for increased adverse effects of edoxaban.
Garlic, Allium sativum: (Moderate) Garlic produces clinically significant antiplatelet effects so additive risk of bleeding may occur if anticoagulants are given in combination. Avoid concurrent use of herbs which interact with anticoagulants when possible. If garlic dietary supplements are taken, monitor the INR or other appropriate parameters to attain clinical and anticoagulant endpoints. In regard to warfarin, published data are limited to a random case report; however, the product labeling for warfarin includes garlic as having potential for interaction due to additive pharmacologic activity. A case of spontaneous spinal epidural hematoma, attributed to dysfunctional platelets from excessive garlic use in a patient not receiving concomitant anticoagulation, has been reported.
Gilteritinib: (Major) Consider an edoxaban dosage reduction for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE) if concomitant use of gilteritinib is necessary. Concomitant use may increase edoxaban exposure; edoxaban is a P-gp substrate and gilteritinib is a P-gp inhibitor. An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with gilteritinib. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of gilteritinib. Increased concentrations of edoxaban may occur during concomitant use of gilteritinib; monitor for increased adverse effects of edoxaban.
Ginger, Zingiber officinale: (Moderate) Additive bleeding may occur if anticoagulants are given in combination with ginger, zingiber officinale. Ginger inhibits thromboxane synthetase (platelet aggregation inducer) and is a prostacyclin agonist. Patients taking ginger and an anticoagulant should be monitored closely for bleeding.
Ginkgo, Ginkgo biloba: (Moderate) Monitor for signs or symptoms of bleeding with coadministration of ginkgo biloba and Direct Oral Anticoagulants (DOACs) as an increased bleeding risk may occur. Although data are mixed, ginkgo biloba is reported to inhibit platelet aggregation and several case reports describe bleeding complications with ginkgo biloba, with or without concomitant drug therapy.
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.
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.
Hydroxychloroquine: (Moderate) Use caution if hydroxychloroquine is coadministered with edoxaban due to the potential for increased edoxaban exposure which may increase the risk of bleeding. Edoxaban is a P-gp substrate; limited data suggests that hydroxychloroquine is a P-gp inhibitor.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Patients taking large doses of salicylates and edoxaban should be monitored closely for bleeding. Large doses of salicylates (3 g to 4 g/day or more) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Ibritumomab Tiuxetan: (Major) During and after therapy, avoid the concomitant use of Yttrium (Y)-90 ibrutumomab tiuxetan with drugs that interfere with coagulation such as anticoagulants; the risk of bleeding may be increased. If coadministration with anticoagulants is necessary, monitor platelet counts more frequently for evidence of thrombocytopenia.
Ibrutinib: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as edoxaban may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
Ibuprofen: (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; Famotidine: (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.
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.
Inotersen: (Moderate) Use caution with concomitant use of inotersen and anticoagulants due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of anticoagulants in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
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.
Istradefylline: (Major) If coadministered with istradefylline, a weak P-gp inhibitor, dosage reduction of edoxaban, a P-gp substrate, may be necessary for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE). An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with istradefylline. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of istradefylline. Increased concentrations of edoxaban may occur during concomitant use of istradefylline; monitor for increased adverse effects of edoxaban.
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.
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; Amoxicillin; 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.
Lapatinib: (Moderate) If coadministered with lapatinib, a P-gp inhibitor, dosage reduction of edoxaban, a P-gp substrate, may be necessary for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE). An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with lapatinib. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of lapatinib. Increased concentrations of edoxaban may occur during concomitant use of lapatinib; monitor for increased adverse effects of edoxaban.
Lasmiditan: (Major) Consider an edoxaban dosage reduction for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE) if concomitant use of lasmiditan is necessary. Concomitant use may increase edoxaban exposure; edoxaban is a P-gp substrate and lasmiditan is a P-gp inhibitor. An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with lasmiditan. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for con

comitant use of lasmiditan. Increased concentrations of edoxaban may occur during concomitant use of lasmiditan; monitor for increased adverse effects of edoxaban.
Lenacapavir: (Major) Consider an edoxaban dosage reduction for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE) if concomitant use of lenacapavir is necessary. Concomitant use may increase edoxaban exposure; edoxaban is a P-gp substrate and lenacapavir is a P-gp inhibitor. An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with lenacapavir. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of lenacapavir. Increased concentrations of edoxaban may occur during concomitant use of lenacapavir; monitor for increased adverse effects of edoxaban.
Levoketoconazole: (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.
Levomilnacipran: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like edoxaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Lomustine, CCNU: (Moderate) Due to the bone marrow suppressive and thrombocytopenic effects of lomustine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
Lonafarnib: (Major) If coadministered with lonafarnib, a P-gp inhibitor, dosage reduction of edoxaban, a P-gp substrate, may be necessary for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE). An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with lonafarnib. Based on clinical experience in patients with non-valvular atrial fibrillation, no dose reduction is recommended for concomitant use of lonafarnib. Increased concentrations of edoxaban may occur during concomitant use of lonafarnib; monitor for increased adverse effects of edoxaban.
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.
Lorlatinib: (Moderate) Monitor for decreased efficacy of edoxaban if coadministration with lorlatinib is necessary; decreased concentrations of edoxaban may occur with concomitant use. Edoxaban is a P-glycoprotein (P-gp) substrate and lorlatinib is a P-gp inducer.
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.
Magnesium Salicylate: (Moderate) Patients taking large doses of salicylates and edoxaban should be monitored closely for bleeding. Large doses of salicylates (3 g to 4 g/day or more) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Maribavir: (Major) Consider an edoxaban dosage reduction for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE) if concomitant use of maribavir is necessary. Concomitant use may increase edoxaban exposure; edoxaban is a P-gp substrate and maribavir is a P-gp inhibitor. An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with maribavir. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of maribavir. Increased concentrations of edoxaban may occur during concomitant use of maribavir; monitor for increased adverse effects of edoxaban.
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.
Meropenem: (Moderate) Monitor for decreased efficacy of edoxaban if coadministration with meropenem is necessary; decreased concentrations of edoxaban may occur with concomitant use. Edoxaban is a P-gp substrate and meropenem is a P-gp inducer.
Meropenem; Vaborbactam: (Moderate) Monitor for decreased efficacy of edoxaban if coadministration with meropenem is necessary; decreased concentrations of edoxaban may occur with concomitant use. Edoxaban is a P-gp substrate and meropenem is a P-gp inducer.
Methotrexate: (Major) Avoid concomitant use of methotrexate and direct oral anticoagulants due to the risk of severe methotrexate-related adverse reactions. If concomitant use is unavoidable, closely monitor for adverse reactions. Methotrexate is approximately 50% protein bound; direct oral anticoagulants are highly protein-bound. Coadministration may displace methotrexate from its protein binding sites, increasing methotrexate plasma concentrations.
Methoxsalen: (Minor) Agents, such as anticoagulants, that decrease clotting could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
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: (Contraindicated) When mifepristone is used for the termination of pregnancy, the concurrent use of anticoagulants is contraindicated due to the risk of serious bleeding.
Milnacipran: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like edoxaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
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.
Mitapivat: (Major) Consider an edoxaban dosage reduction for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE) if concomitant use of mitapivat is necessary. Concomitant use may increase edoxaban exposure; edoxaban is a P-gp substrate and mitapivat is a P-gp inhibitor. An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with mitapivat. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of mitapivat. Increased concentrations of edoxaban may occur during concomitant use of mitapivat; monitor for increased adverse effects of edoxaban.
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.
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; Esomeprazole: (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.
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.
Neratinib: (Major) If coadministered with neratinib, a P-gp inhibitor, dosage reduction of edoxaban, a P-gp substrate, may be necessary for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE). An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with neratinib. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of neratinib. Increased concentrations of edoxaban may occur during concomitant use of neratinib; monitor for increased adverse effects of edoxaban.
Nintedanib: (Moderate) Nintedanib is a VEGFR inhibitor and may increase the risk of bleeding. Monitor patients who are taking anticoagulants closely and adjust anticoagulation therapy as necessary. Use nintedanib in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.
Nirmatrelvir; Ritonavir: (Moderate) 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.
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.
Olanzapine; Fluoxetine: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like edoxaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
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.
Omidubicel: (Moderate) Because of the potential effects of certain dextran formulations on bleeding time, use with caution in patients on anticoagulants concurrently.
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.
Osimertinib: (Moderate) Monitor for an increase in edoxaban-related adverse reactions if coadministration with osimertinib is necessary. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism. Edoxaban is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use.
Oxaliplatin: (Major) Increase the frequency of monitoring in patients who are receiving concomitant therapy with oxaliplatin and edoxaban. Prolonged PT/INR occasionally associated with hemorrhage have been reported in patients who received oxaliplatin in combination with fluorouracil/leucovorin while on anticoagulants.
Oxandrolone: (Moderate) An increased effect of anticoagulants may occur with oxandrolone; the anticoagulant dosage may need adjustment downward with oxandrolone initiation or adjustment upward with oxandrolone discontinuation to maintain the desired clinical effect. Oxandrolone suppresses clotting factors II, V, VII, and X, which results in an increased prothrombin time. An increase in plasminogen-activator activity, and serum concentrations of plasminogen, protein C, and antithrombin III have occurred with several 17-alpha-alkylated androgens. For example, concurrent use of oxandrolone and warfarin may result in unexpectedly large increases in the INR or prothrombin time (PT). A multidose study of oxandrolone (5 or 10 mg PO twice daily) in 15 healthy individuals concurrently treated with warfarin resulted in significant increases in warfarin half-life and AUC; a 5.5-fold decrease in the mean warfarin dosage from 6.13 mg/day to 1.13 mg/day (approximately 80 to 85% dose reduction) was necessary to maintain a target INR of 1.5. According to the manufacturer, if oxandrolone therapy is initiated in a patient already receiving warfarin, the dose of warfarin may need to be decreased significantly to reduce the potential for excessive INR elevations and associated risk of serious bleeding events. The patient should be closely monitored with frequent evaluation of the INR and clinical parameter, and the dosage of warfarin should be adjusted as necessary until a stable target INR is achieved. Careful monitoring of the INR and necessary adjustment of the warfarin dosage are also recommended when the androgen therapy is changed or discontinued.
Oxaprozin: (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.
Pacritinib: (Major) Consider an edoxaban dosage reduction for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE) if concomitant use of pacritinib is necessary. Concomitant use may increase edoxaban exposure; edoxaban is a P-gp substrate and pacritinib is a P-gp inhibitor. An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with pacritinib. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of pacritinib. Increased concentrations of edoxaban may occur during concomitant use of pacritinib; monitor for increased adverse effects of edoxaban.
Paroxetine: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like edoxaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
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.
Phenobarbital; Hyoscyamine; Atropine; 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.
Phenytoin: (Moderate) Monitor for decreased efficacy of edoxaban if coadministration with phenytoin is necessary; decreased concentrations of edoxaban may occur with concomitant use. Edoxaban is a P-glycoprotein (P-gp) substrate and phenytoin is a P-gp inducer.
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.
Pirtobrutinib: (Major) Consider an edoxaban dosage reduction for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE) if concomitant use of pirtobrutinib is necessary. Concomitant use may increase edoxaban exposure; edoxaban is a P-gp substrate and pirtobrutinib is a P-gp inhibitor. An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with pirtobrutinib. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of pirtobrutinib. Increased concentrations of edoxaban may occur during concomitant use of pirtobrutinib; monitor for increased adverse effects of edoxaban.
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.
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.
Pretomanid: (Major) Consider an edoxaban dosage reduction for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE) if concomitant use of pretomanid is necessary. Concomitant use may increase edoxaban exposure; edoxaban is a P-gp substrate and pretomanid is a P-gp inhibitor. An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with pretomanid. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of pretomanid. Increased concentrations of edoxaban may occur during concomitant use of pretomanid; monitor for increased adverse effects of edoxaban.
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.
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.
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.
Salsalate: (Moderate) Patients taking large doses of salicylates and edoxaban should be monitored closely for bleeding. Large doses of salicylates (3 g to 4 g/day or more) can cause hypoprothrombinemia, an additional risk factor 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: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like edoxaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Selpercatinib: (Major) Consider an edoxaban dosage reduction for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE) if concomitant use of selpercatinib is necessary. Concomitant use may increase edoxaban exposure; edoxaban is a P-gp substrate and selpercatinib is a P-gp inhibitor. An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with selpercatinib. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of selpercatinib. Increased concentrations of edoxaban may occur during concomitant use of selpercatinib; monitor for increased adverse effects of edoxaban.
Serotonin norepinephrine reuptake inhibitors: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like edoxaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Sertraline: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like edoxaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Sodium Iodide: (Moderate) Anticoagulants may alter sodium iodide I-131 pharmacokinetics and dynamics for up to 1 week after administrations.
Sodium Phenylbutyrate; Taurursodiol: (Major) Consider an edoxaban dosage reduction for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE) if concomitant use of taurursodiol is necessary. Concomitant use may increase edoxaban exposure; edoxaban is a P-gp substrate and taurursodiol is a P-gp inhibitor. An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with taurursodiol. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of taurursodiol. Increased concentrations of edoxaban may occur during concomitant use of taurursodiol; monitor for increased adverse effects of edoxaban.
Sorafenib: (Major) If coadministered with sorafenib, a P-gp inhibitor, dosage reduction of edoxaban, a P-gp substrate, may be necessary for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE). An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with sorafenib. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of sorafenib. Increased concentrations of edoxaban may occur during concomitant use of sorafenib; monitor for increased adverse effects of edoxaban.
Sotorasib: (Major) Consider an edoxaban dosage reduction for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE) if concomitant use of sotorasib is necessary. Concomitant use may increase edoxaban exposure; edoxaban is a P-gp substrate and sotorasib is a P-gp inhibitor. An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with sotorasib. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of sotorasib. Increased concentrations of edoxaban may occur during concomitant use of sotorasib; monitor for increased adverse effects of edoxaban.
Sparsentan: (Major) Consider an edoxaban dosage reduction for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE) if concomitant use of sparsentan is necessary. Concomitant use may increase edoxaban exposure; edoxaban is a P-gp substrate and sparsentan is a P-gp inhibitor. An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with sparsentan. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of sparsentan. Increased concentrations of edoxaban may occur during concomitant use of sparsentan; monitor for increased adverse effects of edoxaban.
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.
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.
Sumatriptan; 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.
Temsirolimus: (Moderate) Monitor for an increase in edoxaban-related adverse reactions if coadministration with temsirolimus is necessary. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism. Edoxaban is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of edoxaban.
Tenecteplase: (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.
Tepotinib: (Major) Consider an edoxaban dosage reduction for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE) if concomitant use of tepotinib is necessary. Concomitant use may increase edoxaban exposure; edoxaban is a P-gp substrate and tepotinib is a P-gp inhibitor. An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with tepotinib. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of tepotinib. Increased concentrations of edoxaban may occur during concomitant use of tepotinib; monitor for increased adverse effects of edoxaban.
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.
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.
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.
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.
Tucatinib: (Major) If coadministered with tucatinib, a P-gp inhibitor, dosage reduction of edoxaban, a P-gp substrate, may be necessary for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE). An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with tucatinib. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of tucatinib. Increased concentrations of edoxaban may occur during concomitant use of tucatinib; monitor for increased adverse effects of edoxaban.
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: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like edoxaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
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: (Moderate) Use caution if coadministration of verteporfin with anticoagulants is necessary due to the risk of decreased verteporfin efficacy. Verteporfin is a light-activated drug. Once activated, local damage to neovascular endothelium results in a release of procoagulant and vasoactive factors resulting in platelet aggregation, fibrin clot formation, and vasoconstriction. Concomitant use of drugs that decrease clotting could decrease the efficacy of verteporfin therapy.
Vilazodone: (Moderate) Patients should be instructed to monitor for signs and symptoms of bleeding while taking vilazodone concurrently with anticoagulants and to promptly report any bleeding events to the practitioner. Serotonergic agents may increase the risk of bleeding when combined with anticoagulants via inhibition of serotonin uptake by platelets; however, the absolute risk is not known. In addition, both vilazodone and warfarin are highly protein bound, which may result in displacement of warfarin from protein binding sites and an increased anticoagulant effect. It would be prudent for clinicians to monitor the INR and clinical status of the patient closely if vilazodone is added to or removed from the regimen of a patient stabilized on warfarin.
Viloxazine: (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.
Voclosporin: (Major) Consider an edoxaban dosage reduction for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE) if concomitant use of voclosporin is necessary. Concomitant use may increase edoxaban exposure; edoxaban is a P-gp substrate and voclosporin is a P-gp inhibitor. An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with voclosporin. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of voclosporin. Increased concentrations of edoxaban may occur during concomitant use of voclosporin; monitor for increased adverse effects of edoxaban.
Vonoprazan; Amoxicillin; 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.
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.
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.

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

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.

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.

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 to 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. After oral administration, peak pharmacodynamic effects occur within 1 to 2 hours, which correspond to peak edoxaban concentrations. 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 after oral administration with peak plasma concentrations reached within 1 to 2 hours. Edoxaban displays approximately dose-proportional pharmacokinetics. Administration of a crushed 60 mg tablet, either mixed in applesauce or suspended in water and administered via a nasogastric tube, showed similar exposure compared to administration of an intact tablet.
 
The effects of 4-factor prothrombin complex concentrate (PCC) on the pharmacodynamics of edoxaban were studied in healthy subjects undergoing a punch biopsy. After administration of a single dose of edoxaban, endogenous thrombin potential (ETP) returned to pre-edoxaban baseline concentrations in 0.5 hours after a 15 minute infusion of PCC 50 International Units/kg, compared to more than 24 hours with placebo. Mean ETP concentrations continued to increase and exceed pre-edoxaban baseline, reaching maximum elevations (approximately 40% over pre-edoxaban concentrations) at 22 hours after initiating the PCC dose. The clinical relevance of this ETP increase is unknown.

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.