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  • CLASSES

    Factor Xa Inhibitors

    BOXED WARNING

    Abrupt discontinuation

    Avoid the abrupt discontinuation of apixaban in the absence of adequate alternative anticoagulation. Discontinuing apixaban puts patients at an increased risk of thrombotic events. An increased rate of stroke was seen in atrial fibrillation trials when patients were transitioned from apixaban to warfarin. If apixaban 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

    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 24 hours after the last administration of apixaban, and do not administer the next apixaban dose earlier than 5 hours after the catheter removal. Delay apixaban administration for 48 hours if traumatic epidural or spinal puncture occurs. If epidural anesthesia, lumbar puncture, or spinal anesthesia is employed, monitor patients frequently for signs and symptoms of neurological impairment (e.g., numbness or weakness of legs, bowel or bladder dysfunction). Instruct patients to immediately report if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment.

    DEA CLASS

    Rx

    DESCRIPTION

    Oral and selective factor Xa inhibitor anticoagulant
    Used to prevent stroke and other systemic embolism in patients with nonvalvular atrial fibrillation, to prevent DVT in patients undergoing hip or knee replacement surgery, for the treatment of DVT and PE, and for the reduction in risk of recurrence of DVT and PE
    Black box warning against abruption discontinuation in atrial fibrillation and for risk of spinal/epidural hematoma when neuraxial anesthesia or spinal puncture is employed

    COMMON BRAND NAMES

    Eliquis

    HOW SUPPLIED

    Eliquis Oral Tab: 2.5mg, 5mg

    DOSAGE & INDICATIONS

    For the treatment of deep venous thrombosis (DVT) or pulmonary embolism (PE).
    NOTE: Initiation of apixaban is not recommended acutely as an alternative to unfractionated heparin in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.
    Oral dosage
    Adults

    10 mg PO twice daily for 7 days, followed by 5 mg PO twice daily for at least 6 months.

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

    For most patients, the dose is 5 mg PO twice daily. In patients with any 2 of the following characteristics: age >= 80 years; body weight <= 60 kg; or serum creatinine >= 1.5 mg/dL, reduce the dose to 2.5 mg PO twice daily. Also decrease the dose to 2.5 mg PO twice daily if patients are taking a drug that is a strong inhibitor of both CYP3A4 and P-glycoprotein.

    For deep venous thrombosis (DVT) prophylaxis and pulmonary embolism prophylaxis.
    For reduction in the risk of recurrent DVT and/or PE after completion of treatment for acute deep vein thrombosis (DVT) or pulmonary embolism (PE).
    Oral dosage
    Adults

    2.5 mg PO twice daily after at least 6 months of treatment for DVT or PE.

    For deep venous thrombosis (DVT) prophylaxis and pulmonary embolism prophylaxis in patients undergoing knee or hip replacement surgery.
    Oral dosage
    Adults

    2.5 mg PO twice daily for 12 days after knee replacement surgery or for 35 days after hip replacement surgery. Administer the initial dose 12—24 hours after surgery.

    MAXIMUM DOSAGE

    Adults

    10 mg/day PO for most patients; 20 mg/day PO for initial treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE).

    Geriatric

    10 mg/day PO for most patients; 20 mg/day PO for initial treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE).

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Mild impairment: No dosage adjustments are needed.
    Moderate impairment: There is limited experience with this population; dosing recommendations are not available.
    Severe impairment: Not recommended.

    Renal Impairment

    NOTE: Dosage adjustment is required in patients with nonvalvular atrial fibrillation. No dosage adjustment is required when apixaban is used for treatment or prevention of venous thromboembolism.
     
    Serum creatinine 1.5 mg/dL or more: 2.5 mg PO twice daily if the patient is 80 years or older and/or weighs 60 kg or less. This dose is recommended in any patient that meets at least 2 of 3 criteria (serum creatinine 1.5 mg/dL or more, age 80 years or older, weight 60 kg or less).
     
    Hemodialysis
    In patients with nonvalvular atrial fibrillation and end-stage renal disease maintained on intermittent hemodialysis, the recommended dose is 5 mg PO twice daily. Reduce the dose to 2.5 mg PO twice daily if patient is 80 years or older or weighs 60 kg or less.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    May be taken without regard to food.
    For patients unable to swallow whole tablets, apixaban tablets may be crushed and suspended in water, 5% Dextrose Injection, or apple juice, or mixed with applesauce for prompt administration; crushed tablets are stable as these mixtures for up to 4 hours. Alternatively, tablets may be crushed and suspended in 60 mL of water or 5% Dextrose Injection and promptly delivered through a nasogastric tube.
    If a dose is missed, it should be taken as soon as possible on the same day. Twice daily dosing should be resumed. Do not double the dose to make up for a missed dose.

    STORAGE

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

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Apixaban is contraindicated for use by patients with severe hypersensitivity to the drug.

    Bleeding

    Apixaban is contraindicated in any patient with active pathological bleeding, as apixaban use increases the risk of bleeding and can cause serious and potentially fatal bleeding. The concomitant use of other drugs that affect hemostasis (e.g., aspirin and other antiplatelet drugs, other anticoagulants, heparin, thrombolytic agents, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and nonsteroidal anti-inflammatory drugs) increases the risk of bleeding. Patients should be educated on the signs and symptoms of bleeding and instructed to report them immediately or go to an emergency room. Discontinue apixaban in patients with active pathological bleeding. There is no specific antidote or established way to reverse the effects of apixaban, which can persist for at least 24 hours after the last dose. Activated oral charcoal reduces absorption and lowers the plasma concentration of apixaban and may be useful in apixaban overdose or accidental ingestion. Although not evaluated in clinical trials, the use of procoagulant reversal agents (e.g., prothrombin complex concentrate [PCC], activated prothrombin complex concentrate, or recombinant factor VIIa) may be considered. Monitoring for the anticoagulation effect of apixaban using a clotting test (e.g., PT, INR, aPTT) or anti-factor Xa activity is not useful or recommended when PCCs are used. The effects of 4-factor PCCs on steady state apixaban pharmacodynamics have been studied in healthy subjects. Endogenous thrombin potential (ETP) returned to pre-apixaban baseline concentrations 4 hours after the initiation of a 30-minute PCC infusion compared to 45 hours after a placebo infusion. Mean ETP concentrations continued to increase and exceeded baseline concentrations, reaching a maximum (34% to 51% increase) 21 hours after PCC initiation. Concentrations remained elevated (21% to 27%) 69 hours after PCC initiation (end of study). The clinical relevance of this increase in ETP is unknown. Hemodialysis does not appear to have a significant impact on the exposure to apixaban. Protamine sulfate and vitamin K are not expected to affect the anticoagulant effect of apixaban, and there is no experience with antifibrinolytic agents (e.g., tranexamic acid, aminocaproic acid). In addition, there is no experience and no scientific rationale for the use of systemic hemostatics (i.e., desmopressin and aprotinin).

    Abrupt discontinuation

    Avoid the abrupt discontinuation of apixaban in the absence of adequate alternative anticoagulation. Discontinuing apixaban puts patients at an increased risk of thrombotic events. An increased rate of stroke was seen in atrial fibrillation trials when patients were transitioned from apixaban to warfarin. If apixaban must be discontinued for reasons other than pathological bleeding or completion of a course of therapy, consider administering another anticoagulant.

    Prosthetic heart valves

    The use of apixaban in patients with prosthetic heart valves has not been studied; use in this population is not recommended.

    Surgery

    The anticoagulant effect of apixaban persists for about 24 hours after the last dose. Apixaban should be discontinued 48 hours before elective surgery or invasive procedures that carry a moderate or high risk of unacceptable or clinically significant bleeding. Discontinue apixaban 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding or where bleeding would be considered noncritical in location and easily controlled. In general, it is not necessary to bridge anticoagulation during the 24—48 hours after stopping apixaban. Restart apixaban as soon as adequate homeostasis is achieved after the surgery or other procedure.

    Hepatic disease

    Apixaban has not been studied and use is not recommended in patients with severe hepatic disease. Additionally, dosing recommendations in patients with moderate hepatic impairment are not available. Patients with moderate hepatic disease may have coagulation abnormalities; a clear understanding of the impact of this degree of hepatic function impairment on the coagulation cascade and its relationship to efficacy and bleeding is not available.

    Dialysis, geriatric, renal failure, renal impairment

    Use apixaban cautiously in patients with renal impairment and/or renal failure. A dose reduction is recommended in any patient with nonvalvular atrial fibrillation, including patients with dialysis-dependent end-stage renal disease, who meets at least 2 of the 3 following criteria: serum creatinine >= 1.5 mg/dL, weight of <= 60 kg, and/or geriatric patient >= 80 years. Clinical efficacy and safety studies did not enroll patients with ESRD on dialysis. According to the Beers Criteria, apixaban should be avoided in geriatric patients with a creatinine clearance less than 25 mL/minute due to an increased risk of bleeding. The creatinine clearance threshold for which the Beers expert panel recommends avoiding use of apixaban is based on clinical trial exclusion criteria and may not be the same as that in the product labeling.

    Labor, obstetric delivery, pregnancy

    Apixaban is classified as FDA pregnancy category B. Treatment is likely to increase the risk of hemorrhage during pregnancy. Animal studies showed no increase in the risk of fetal malformations or toxicity; in rats, increased maternal bleeding was observed in doses corresponding to >= 1.3x the human exposure of unbound drug. Use during pregnancy only if the potential benefit outweighs the potential risk to the mother and fetus. The safety and efficacy of apixaban during labor and delivery have not been studied; however, labor and obstetric delivery are considered risk factors for bleeding. Consider the increased risk of bleeding and stroke before using apixaban in this setting.

    Breast-feeding

    It is not known if apixaban or its metabolites are excreted in human milk. The molecular weight, partial metabolism, moderate plasma protein binding, and long effective half-life suggest that the drug will be excreted into human milk. Women should be instructed to discontinue breast-feeding or to discontinue apixaban, taking into account the importance of the drug to the mother. If pharmacotherapy is necessary in the nursing mother, the American Academy of Pediatrics (AAP) considers warfarin to be usually compatible with breast-feeding. Low-molecular weight heparins and heparin have relatively high molecular weights ; therefore, these drugs are not expected to be excreted into human milk to a clinically significant degree. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Epidural anesthesia, lumbar puncture, spinal anesthesia

    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 24 hours after the last administration of apixaban, and do not administer the next apixaban dose earlier than 5 hours after the catheter removal. Delay apixaban administration for 48 hours if traumatic epidural or spinal puncture occurs. 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.

    Intramuscular injections

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

    ADVERSE REACTIONS

    Severe

    GI bleeding / Delayed / 0-1.0
    stroke / Early / 0-1.0
    hematemesis / Delayed / 0-1.0
    anaphylactoid reactions / Rapid / 0-1.0
    intracranial bleeding / Delayed / 0.3-0.3
    ocular hemorrhage / Delayed / 0-0.2

    Moderate

    anemia / Delayed / 2.6-2.6
    hematuria / Delayed / 0-2.1
    bleeding / Early / 0.6-2.1
    hematoma / Early / 0.9-2.0
    hemoptysis / Delayed / 0-1.2
    vaginal bleeding / Delayed / 1.1-1.1
    melena / Delayed / 0-1.0
    thrombocytopenia / Delayed / 0-1.0
    hypotension / Rapid / 0-1.0
    hyperbilirubinemia / Delayed / 0-1.0
    elevated hepatic enzymes / Delayed / 0.6-0.8

    Mild

    epistaxis / Delayed / 0-3.6
    menorrhagia / Delayed / 1.4-1.4
    rash (unspecified) / Early / 0-1.0
    syncope / Early / 0-1.0

    DRUG INTERACTIONS

    Abciximab: (Major) The concomitant use of apixaban and platelet inhibitors (e.g, aspirin) may increase the risk of bleeding. In the ARISTOTLE trial (comparative trial of apixaban and warfarin in patients with nonvalvular atrial fibrillation), concomitant use of aspirin increased the bleeding risk of apixaban from 1.8%/year to 3.4%/year. If given concomitantly, patients should be educated about the signs and symptoms of bleeding and be instructed to report them immediately or go to an emergency room.
    Acetaminophen; Aspirin, ASA; Caffeine: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and apixaban should be monitored closely for bleeding.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and apixaban should be monitored closely for bleeding.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and apixaban should be monitored closely for bleeding.
    Ado-Trastuzumab emtansine: (Major) Use caution if coadministration of anticoagulants such as antithrombin III, apixaban, argatroban, bivalirudin, dabigatran, dalteparin, danaparoid, desirudin, enoxaparin, fondaparinux, heparin, lepirudin, rivaroxaban, and warfarin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anticoagulant therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Alteplase, tPA: (Severe) Due to the increased bleeding risk, avoid concurrent use of apixaban with thrombolytic agents.
    Altretamine: (Moderate) Due to the thrombocytopenic effects of altretamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Aminosalicylate sodium, Aminosalicylic acid: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and apixaban should be monitored closely for bleeding.
    Amiodarone: (Major) Use apixaban and amiodarone together with caution, especially in patients with significant renal dysfunction, as risk of bleeding may be increased. Amiodarone is a moderate CYP3A4 and P-glycoprotein (P-gp) inhibitor. Apixaban is a substrate of CYP3A4 and P-gp. One cohort study found an increased risk of major bleeding when amiodarone and a non-vitamin K oral anticoagulant were used together. The combination was associated with an adjusted incidence rate difference for major bleeding of 13.94 events per 1,000 person-years (99% CI, 9.76 to 18.13).
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Reduce the apixaban dose to 2.5 mg twice daily when coadministered with drugs that are both strong inhibitors of CYP3A4 and P-gp, such as clarithromycin. Concomitant administration of clarithromycin and apixaban results in increased exposure to apixaban and an increase in the risk of bleeding. If patients are already receiving the reduced dose of 2.5 mg twice daily, avoid concomitant administration of apixaban and clarithromycin.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Reduce the apixaban dose to 2.5 mg twice daily when coadministered with drugs that are both strong inhibitors of CYP3A4 and P-gp, such as clarithromycin. Concomitant administration of clarithromycin and apixaban results in increased exposure to apixaban and an increase in the risk of bleeding. If patients are already receiving the reduced dose of 2.5 mg twice daily, avoid concomitant administration of apixaban and clarithromycin.
    Anagrelide: (Major) The concomitant use of apixaban and platelet inhibitors (e.g, aspirin) may increase the risk of bleeding. In the ARISTOTLE trial (comparative trial of apixaban and warfarin in patients with nonvalvular atrial fibrillation), concomitant use of aspirin increased the bleeding risk of apixaban from 1.8%/year to 3.4%/year. If given concomitantly, patients should be educated about the signs and symptoms of bleeding and be instructed to report them immediately or go to an emergency room.
    Anthracyclines: (Moderate) Due to the thrombocytopenic effects of anthracyclines, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. In addition, rivaroxaban is a mild P-glycoprotein (P-gp) inhibitor and doxorubicin is a major substrate of P-gp. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of P-gp, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of rivaroxaban and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Antithrombin III: (Major) Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if apixaban and other anticoagulants are used concomitantly. If switching from apixaban to another anticoagulant, discontinue apixaban and start the other anticoagulant at the usual time of the next dose of apixaban. If switching from another anticoagulant to apixaban, discontinue the other anticoagulant and start apixaban at the usual time of the next dose of the other anticoagulant. Coadministration of apixaban and other anticoagulants may increase the risk of bleeding.
    Antithymocyte Globulin: (Moderate) Drugs that can cause thrombocytopenia, such as antithymocyte globulin, may lead to an increased risk of bleeding when given concurrently with anticoagulants.
    Ardeparin: (Major) Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if apixaban and other anticoagulants are used concomitantly. If switching from apixaban to another anticoagulant, discontinue apixaban and start the other anticoagulant at the usual time of the next dose of apixaban. If switching from another anticoagulant to apixaban, discontinue the other anticoagulant and start apixaban at the usual time of the next dose of the other anticoagulant. Coadministration of apixaban and other anticoagulants may increase the risk of bleeding.
    Arsenic Trioxide: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Aspirin, ASA: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and apixaban should be monitored closely for bleeding.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and apixaban should be monitored closely for bleeding.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and apixaban should be monitored closely for bleeding.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and apixaban should be monitored closely for bleeding.
    Aspirin, ASA; Carisoprodol: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and apixaban should be monitored closely for bleeding.
    Aspirin, ASA; Carisoprodol; Codeine: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and apixaban should be monitored closely for bleeding.
    Aspirin, ASA; Dipyridamole: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and apixaban should be monitored closely for bleeding. (Major) The concomitant use of apixaban and platelet inhibitors (e.g, aspirin) may increase the risk of bleeding. In the ARISTOTLE trial (comparative trial of apixaban and warfarin in patients with nonvalvular atrial fibrillation), concomitant use of aspirin increased the bleeding risk of apixaban from 1.8%/year to 3.4%/year. If given concomitantly, patients should be educated about the signs and symptoms of bleeding and be instructed to report them immediately or go to an emergency room.
    Aspirin, ASA; Omeprazole: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and apixaban should be monitored closely for bleeding.
    Aspirin, ASA; Oxycodone: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and apixaban should be monitored closely for bleeding.
    Aspirin, ASA; Pravastatin: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and apixaban should be monitored closely for bleeding.
    Atazanavir: (Major) Apixaban is a substrate of CYP3A4 and CYP2C8; atazanavir is a CYP3A4 substrate/inhibitor and a minor inhibitor of CYP2C8. Coadministration of these drugs may increase apixaban plasma concentrations and risk of adverse events such as bleeding. Avoid concurrent administration if possible; if concurrent administration is required, monitor for signs of bleeding.
    Atazanavir; Cobicistat: (Major) Apixaban is a substrate of CYP3A4 and CYP2C8; atazanavir is a CYP3A4 substrate/inhibitor and a minor inhibitor of CYP2C8. Coadministration of these drugs may increase apixaban plasma concentrations and risk of adverse events such as bleeding. Avoid concurrent administration if possible; if concurrent administration is required, monitor for signs of bleeding. (Major) Reduce the apixaban dose to 2.5 mg twice daily when coadministered with drugs that are both strong inhibitors of CYP3A4 and P-gp, such as cobicistat containing medications. Concomitant administration results in increased exposure to apixaban and an increase in the risk of bleeding. If patients are already receiving 2.5 mg twice daily, avoid concomitant administration.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and apixaban should be monitored closely for bleeding.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid the concomitant administration of apixaban and drugs that are both strong inducers of CYP3A4 and P-gp, such as phenobarbital. Concomitant administration of apixaban and phenobarbital results in decreased exposure to apixaban and an increase in the risk of stroke.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid the concomitant administration of apixaban and drugs that are both strong inducers of CYP3A4 and P-gp, such as phenobarbital. Concomitant administration of apixaban and phenobarbital results in decreased exposure to apixaban and an increase in the risk of stroke.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and apixaban should be monitored closely for bleeding.
    Betrixaban: (Major) Avoid concurrent use of betrixaban with apixaban due to the increased bleeding risk. Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if betrixaban and other anticoagulants are used concomitantly. If switching from apixaban to another anticoagulant, discontinue apixaban and start the other anticoagulant at the usual time of the next dose of apixaban. If switching from another anticoagulant to apixaban, discontinue the other anticoagulant and start apixaban at the usual time of the next dose of the other anticoagulant. Coadministration of betrixaban and other anticoagulants may increase the risk of bleeding.
    Bevacizumab: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Bismuth Subsalicylate: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and apixaban should be monitored closely for bleeding.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and apixaban should be monitored closely for bleeding.
    Bupropion; Naltrexone: (Moderate) Give the extended-release injectable suspension of naltrexone cautiously to patients taking anticoagulants. Steps should be taken to avoid the risk of bleeding and hematoma formation following intramuscular injection.
    Cabozantinib: (Moderate) Monitor for an increase in apixaban-related adverse events if concomitant use with cabozantinib is necessary, as plasma concentrations of apixaban may be increased. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and apixaban is a substrate of P-gp; the clinical relevance of this finding is unknown.
    Carbamazepine: (Major) Avoid the concomitant administration of apixaban and drugs that are both strong inducers of CYP3A4 and P-gp, such as carbamazepine. Concomitant administration of apixaban and carbamazepine results in decreased exposure to apixaban and an increase in the risk of stroke.
    Carbenicillin: (Moderate) Some penicillins (e.g., carbenicillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Carvedilol: (Major) Concomitant use of carvedilol and apixaban may result in increased apixaban concentrations. Carvedilol is a P-glycoprotein (P-gp) inhibitor and apixaban is a P-gp substrate. Increased exposure to apixaban may result in increased risk of bleeding. Monitor for evidence of bleeding during concurrent use.
    Celecoxib: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Chlorambucil: (Moderate) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Choline Salicylate; Magnesium Salicylate: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and apixaban should be monitored closely for bleeding.
    Chondroitin; Glucosamine: (Moderate) Increased effects from concomitant anticoagulant drugs such as increased bruising or blood in the stool have been reported in patients taking methylsulfonylmethane, MSM. Although these effects have not been confirmed in published medical literature or during clinical studies, clinicians should consider using methylsulfonylmethane, MSM with caution in patients who are taking anticoagulants such as warfarin until data confirming the safety of MSM in patients taking these drugs are available. During one of the available, published clinical trials in patients with osteoarthritis, those patients with bleeding disorders or using anticoagulants or antiplatelets were excluded from enrollment. Patients who choose to consume methylsulfonylmethane, MSM while receiving warfarin should be observed for increased bleeding.
    Cilostazol: (Major) The concomitant use of apixaban and platelet inhibitors (e.g, aspirin) may increase the risk of bleeding. In the ARISTOTLE trial (comparative trial of apixaban and warfarin in patients with nonvalvular atrial fibrillation), concomitant use of aspirin increased the bleeding risk of apixaban from 1.8%/year to 3.4%/year. If given concomitantly, patients should be educated about the signs and symptoms of bleeding and be instructed to report them immediately or go to an emergency room.
    Citalopram: (Major) The concomitant use of selective serotonin reuptake inhibitors (SSRIs) and apixaban can increase the risk of bleeding. If given concomitantly, patients should be educated about the signs and symptoms of bleeding and be instructed to report them immediately or go to an emergency room.
    Clarithromycin: (Major) Reduce the apixaban dose to 2.5 mg twice daily when coadministered with drugs that are both strong inhibitors of CYP3A4 and P-gp, such as clarithromycin. Concomitant administration of clarithromycin and apixaban results in increased exposure to apixaban and an increase in the risk of bleeding. If patients are already receiving the reduced dose of 2.5 mg twice daily, avoid concomitant administration of apixaban and clarithromycin.
    Clofarabine: (Moderate) Due to the thrombocytopenic effects of clofarabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Clopidogrel: (Major) The concomitant use of apixaban and platelet inhibitors (e.g, aspirin) may increase the risk of bleeding. In the ARISTOTLE trial (comparative trial of apixaban and warfarin in patients with nonvalvular atrial fibrillation), concomitant use of aspirin increased the bleeding risk of apixaban from 1.8%/year to 3.4%/year. If given concomitantly, patients should be educated about the signs and symptoms of bleeding and be instructed to report them immediately or go to an emergency room.
    Cobicistat: (Major) Reduce the apixaban dose to 2.5 mg twice daily when coadministered with drugs that are both strong inhibitors of CYP3A4 and P-gp, such as cobicistat containing medications. Concomitant administration results in increased exposure to apixaban and an increase in the risk of bleeding. If patients are already receiving 2.5 mg twice daily, avoid concomitant administration.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Reduce the apixaban dose to 2.5 mg twice daily when coadministered with drugs that are both strong inhibitors of CYP3A4 and P-gp, such as cobicistat containing medications. Concomitant administration results in increased exposure to apixaban and an increase in the risk of bleeding. If patients are already receiving 2.5 mg twice daily, avoid concomitant administration.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Reduce the apixaban dose to 2.5 mg twice daily when coadministered with drugs that are both strong inhibitors of CYP3A4 and P-gp, such as cobicistat containing medications. Concomitant administration results in increased exposure to apixaban and an increase in the risk of bleeding. If patients are already receiving 2.5 mg twice daily, avoid concomitant administration.
    Cod Liver Oil: (Major) Cod liver oil should be used only with caution and with frequent monitoring in patients on concurrent anticoagulants. In a limited number of patients, the hypoprothrombinemic response to warfarin was increased following large doses of vitamin A. Additionally, omega-3 fatty acids contained in cod liver oil may inhibit platelet aggregation. Theoretically, the risk of bleeding may be increased, but some studies that combined omega-3 fatty acids and anticoagulant agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3 to 6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant cod liver oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly. (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Collagenase: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Conivaptan: (Major) Concomitant administration of conivaptan, a strong CYP3A4 inhibitor and P-glycoprotein (P-gp) inhibitor, and apixaban, a CYP3A/P-gp substrate, results in increased exposure to apixaban and an increase in the risk of bleeding. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided and subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. The manufacturer of apixaban recommends reducing the dose of apixaban to 2.5 mg twice daily when coadministered with a dual inhibitor of CYP3A4 and P-gp. If patients are already receiving 2.5 mg twice daily, avoid concomitant administration of apixaban and conivaptan.
    Crizotinib: (Moderate) Use apixaban and crizotinib together with caution in patients with significant renal dysfunction as risk of bleeding may be increased. Crizotinib is a moderate CYP3A4 and P-glycoprotein (P-gp) inhibitor. Apixaban is a substrate of CYP3A4 and P-gp. In a pharmacokinetic study, apixaban Cmax and AUC increased by 31% and 40%, respectively, when given with another moderate CYP3A4 and P-gp inhibitor. Although serum concentrations of non-vitamin K oral anticoagulants have been increased in the presence of moderate inhibitors, one cohort study found that the risk of bleeding was not increased with moderate inhibitors.
    Cyclosporine: (Moderate) Use apixaban and cyclosporine together with caution in patients with significant renal dysfunction as risk of bleeding may be increased. Cyclosporine is a moderate CYP3A4 and P-glycoprotein (P-gp) inhibitor. Apixaban is a substrate of CYP3A4 and P-gp. In a pharmacokinetic study, apixaban Cmax and AUC increased by 31% and 40%, respectively, when given with another moderate CYP3A4 and P-gp inhibitor. Although serum concentrations of non-vitamin K oral anticoagulants have been increased in the presence of moderate inhibitors, one cohort study found that the risk of bleeding was not increased.
    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) Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if apixaban and other anticoagulants are used concomitantly. If switching from apixaban to another anticoagulant, discontinue apixaban and start the other anticoagulant at the usual time of the next dose of apixaban. If switching from another anticoagulant to apixaban, discontinue the other anticoagulant and start apixaban at the usual time of the next dose of the other anticoagulant. Coadministration of apixaban and other anticoagulants may increase the risk of bleeding.
    Dalteparin: (Major) Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if apixaban and other anticoagulants are used concomitantly. If switching from apixaban to another anticoagulant, discontinue apixaban and start the other anticoagulant at the usual time of the next dose of apixaban. If switching from another anticoagulant to apixaban, discontinue the other anticoagulant and start apixaban at the usual time of the next dose of the other anticoagulant. Coadministration of apixaban and other anticoagulants may increase the risk of bleeding.
    Darunavir: (Major) Reduce the apixaban dose to 2.5 mg twice daily when coadministered with drugs that are both strong inhibitors of CYP3A4 and P-gp, such as darunavir coadministered with ritonavir. Concomitant administration of darunavir/ritonavir and apixaban results in increased exposure to apixaban which increases the risk of bleeding. If patients are already receiving 2.5 mg twice daily, avoid concomitant administration of apixaban and darunavir/ritonavir. The manufacturer of darunavir does not recommend concomitant use with apixaban.
    Darunavir; Cobicistat: (Major) Reduce the apixaban dose to 2.5 mg twice daily when coadministered with drugs that are both strong inhibitors of CYP3A4 and P-gp, such as cobicistat containing medications. Concomitant administration results in increased exposure to apixaban and an increase in the risk of bleeding. If patients are already receiving 2.5 mg twice daily, avoid concomitant administration. (Major) Reduce the apixaban dose to 2.5 mg twice daily when coadministered with drugs that are both strong inhibitors of CYP3A4 and P-gp, such as darunavir coadministered with ritonavir. Concomitant administration of darunavir/ritonavir and apixaban results in increased exposure to apixaban which increases the risk of bleeding. If patients are already receiving 2.5 mg twice daily, avoid concomitant administration of apixaban and darunavir/ritonavir. The manufacturer of darunavir does not recommend concomitant use with apixaban.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Concurrent administration of apixaban with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir requires a dosage adjustment for apixaban. For patients receiving more than 2.5 mg PO twice daily of apixaban, reduce the apixaban dosage by 50%. For patients receiving apixaban 2.5 mg PO twice daily, avoid coadministration with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir. Apixaban is a substrate of both CYP3A4 and P-glycoprotein (P-gp); ritonavir inhibits both CYP3A4 and P-gp and paritaprevir inhibits P-gp. Coadministration of these agents increases apixaban plasma concentrations and risk of adverse events such as bleeding. (Major) Reduce the apixaban dose to 2.5 mg twice daily when coadministered with drugs that are both strong inhibitors of CYP3A4 and P-gp, such as ritonavir. Concomitant administration of ritonavir and apixaban results in increased exposure to apixaban and an increase in the risk of bleeding. If patients are already receiving the reduced dose of 2.5 mg twice daily, avoid concomitant administration of apixaban and ritonavir.
    Dasatinib: (Moderate) Due to the thrombocytopenic and possible platelet inhibiting effects of dasatinib, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. In addition, dasatinib is an inhibitor of CYP3A4, and rivaroxaban is a substrate of CYP3A4. Coadministration may result in increases in rivaroxaban exposure and may increase bleeding risk. Caution should be exercised if patients are required to take anticoagulants concomitantly with dasatinib.
    Decitabine: (Moderate) Due to the thrombocytopenic effects of antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Defibrotide: (Severe) Coadministration of defibrotide with antithrombotic agents like anticoagulants is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue systemic antithrombotic agents (not including use for routine maintenance or reopening of central venous catheters) prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
    Denileukin Diftitox: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Desvenlafaxine: (Major) Platelet aggregation may be impaired by desvenlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving anticoagulants. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Dextran: (Moderate) Because of the potential effects of certain dextran formulations on bleeding time, use with caution in patients on anticoagulants concurrently.
    Diclofenac: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Diclofenac; Misoprostol: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Diflunisal: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Diltiazem: (Moderate) Use apixaban and diltiazem together with caution in patients with significant renal dysfunction as risk of bleeding may be increased. Diltiazem is a moderate CYP3A4 and P-glycoprotein (P-gp) inhibitor. Apixaban is a substrate of CYP3A4 and P-gp. In a pharmacokinetic study, apixaban Cmax and AUC increased by 31% and 40%, respectively, when given with diltiazem. Although serum concentrations of non-vitamin K oral anticoagulants have been increased in the presence of moderate inhibitors, one cohort study found that the risk of bleeding was not increased.
    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) The concomitant use of apixaban and platelet inhibitors (e.g, aspirin) may increase the risk of bleeding. In the ARISTOTLE trial (comparative trial of apixaban and warfarin in patients with nonvalvular atrial fibrillation), concomitant use of aspirin increased the bleeding risk of apixaban from 1.8%/year to 3.4%/year. If given concomitantly, patients should be educated about the signs and symptoms of bleeding and be instructed to report them immediately or go to an emergency room.
    Dronedarone: (Moderate) Use apixaban and dronedarone together with caution in patients with significant renal dysfunction as risk of bleeding may be increased. Dronedarone is a moderate CYP3A4 and P-glycoprotein (P-gp) inhibitor. Apixaban is a substrate of CYP3A4 and P-gp. In a pharmacokinetic study, apixaban Cmax and AUC increased by 31% and 40%, respectively, when given with another moderate CYP3A4 and P-gp inhibitor. Although serum concentrations of non-vitamin K oral anticoagulants have been increased in the presence of moderate inhibitors, one cohort study found that the risk of bleeding was not increased.
    Drotrecogin Alfa: (Major) Treatment with drotrecogin alfa should be carefully considered in patients who are receiving or have received any anticoagulants. There is an additive risk of beeding.
    Duloxetine: (Major) Platelet aggregation may be impaired by duloxetine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving anticoagulants. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Edoxaban: (Major) Avoid concurrent use of edoxaban with apixaban due to the increased bleeding risk. Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if edoxaban and other anticoagulants are used concomitantly. If switching from apixaban to another anticoagulant, discontinue apixaban and start the other anticoagulant at the usual time of the next dose of apixaban. If switching from another anticoagulant to apixaban, discontinue the other anticoagulant and start apixaban at the usual time of the next dose of the other anticoagulant. Coadministration of edoxaban and other anticoagulants may increase the risk of bleeding. Long-term concomitant treatment with edoxaban and other anticoagulants is not recommended; short-term use may be necessary for patients transitioning to or from edoxaban.
    Eliglustat: (Moderate) Coadministration of apixaban and eliglustat may increase exposure to apixaban and increase the risk of bleeding; monitor patients closely. Apixaban is a P-glycoprotein (P-gp) substrate; eliglustat is a P-gp inhibitor.
    Eltrombopag: (Moderate) Use caution when discontinuing eltrombopag in patients receiving anticoagulants (e.g., warfarin, enoxaparin, dabigatran, rivaroxaban). The risk of bleeding and recurrent thrombocytopenia is increased in patients receiving these drugs when eltrombopag is discontinued.
    Enoxaparin: (Major) Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if apixaban and other anticoagulants are used concomitantly. If switching from apixaban to another anticoagulant, discontinue apixaban and start the other anticoagulant at the usual time of the next dose of apixaban. If switching from another anticoagulant to apixaban, discontinue the other anticoagulant and start apixaban at the usual time of the next dose of the other anticoagulant. Coadministration of apixaban and other anticoagulants may increase the risk of bleeding.
    Epoprostenol: (Moderate) When used concurrently with anticoagulants, epoprostenol may increase the risk of bleeding.
    Eptifibatide: (Major) The concomitant use of apixaban and platelet inhibitors (e.g, aspirin) may increase the risk of bleeding. In the ARISTOTLE trial (comparative trial of apixaban and warfarin in patients with nonvalvular atrial fibrillation), concomitant use of aspirin increased the bleeding risk of apixaban from 1.8%/year to 3.4%/year. If given concomitantly, patients should be educated about the signs and symptoms of bleeding and be instructed to report them immediately or go to an emergency room.
    Erythromycin: (Moderate) Use apixaban and erythromycin together with caution in patients with significant renal dysfunction as risk of bleeding may be increased. Erythromycin is a moderate CYP3A4 and P-glycoprotein (P-gp) inhibitor. Apixaban is a substrate of CYP3A4 and P-gp. In a pharmacokinetic study, apixaban Cmax and AUC increased by 31% and 40%, respectively, when given with another moderate CYP3A4 and P-gp inhibitor. Although serum concentrations of non-vitamin K oral anticoagulants have been increased in the presence of moderate inhibitors, one cohort study found that the risk of bleeding was not increased.
    Erythromycin; Sulfisoxazole: (Moderate) Use apixaban and erythromycin together with caution in patients with significant renal dysfunction as risk of bleeding may be increased. Erythromycin is a moderate CYP3A4 and P-glycoprotein (P-gp) inhibitor. Apixaban is a substrate of CYP3A4 and P-gp. In a pharmacokinetic study, apixaban Cmax and AUC increased by 31% and 40%, respectively, when given with another moderate CYP3A4 and P-gp inhibitor. Although serum concentrations of non-vitamin K oral anticoagulants have been increased in the presence of moderate inhibitors, one cohort study found that the risk of bleeding was not increased.
    Escitalopram: (Major) The concomitant use of selective serotonin reuptake inhibitors (SSRIs) and apixaban can increase the risk of bleeding. If given concomitantly, patients should be educated about the signs and symptoms of bleeding and be instructed to report them immediately or go to an emergency room.
    Esomeprazole; Naproxen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Esterified Estrogens; Methyltestosterone: (Moderate) Methyltestosterone can increase the effects of anticoagulants through reduction of procoagulant factor. Patients receiving oral anticoagulant therapy should be closely monitored, especially when methyltestosterone treatment is initiated or discontinued.
    Estramustine: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Etodolac: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Factor X: (Severe) The actions of factor X are likely to be counteracted by direct and indirect factor Xa inhibitors such as apixaban, edoxaban, rivaroxaban, and fondaparinux.
    Famotidine; Ibuprofen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Fenoprofen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Floxuridine: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Fluorouracil, 5-FU: (Major) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Fluoxetine: (Major) The concomitant use of selective serotonin reuptake inhibitors (SSRIs) and apixaban can increase the risk of bleeding. If given concomitantly, patients should be educated about the signs and symptoms of bleeding and be instructed to report them immediately or go to an emergency room.
    Fluoxetine; Olanzapine: (Major) The concomitant use of selective serotonin reuptake inhibitors (SSRIs) and apixaban can increase the risk of bleeding. If given concomitantly, patients should be educated about the signs and symptoms of bleeding and be instructed to report them immediately or go to an emergency room.
    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: (Major) The concomitant use of selective serotonin reuptake inhibitors (SSRIs) and apixaban can increase the risk of bleeding. If given concomitantly, patients should be educated about the signs and symptoms of bleeding and be instructed to report them immediately or go to an emergency room.
    Folate analogs: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Fondaparinux: (Major) Discontinue apixaban before starting fondaparinux, unless these agents are essential. If coadministration is necessary, monitor patients closely and promptly evaluate any signs or symptoms of bleeding. If switching from apixaban to another anticoagulant, discontinue apixaban and start the other anticoagulant at the usual time of the next dose of apixaban. If switching from another anticoagulant to apixaban, discontinue the other anticoagulant and start apixaban at the usual time of the next dose of the other anticoagulant. Coadministration of apixaban and other anticoagulants may increase the risk of bleeding.
    Fosamprenavir: (Major) Avoid the concomitant administration of apixaban and drugs that are both strong inducers of CYP3A4 and P-gp, such as fosamprenavir. Concomitant administration of apixaban and fosamprenavir results in decreased exposure to apixaban and an increase in the risk of stroke.
    Fosphenytoin: (Major) Avoid the concomitant administration of apixaban and drugs that are both strong inducers of CYP3A4 and P-gp, such as phenytoin or fosphenytoin. Concomitant administration of apixaban with either phenytoin or fosphenytoin results in decreased exposure to apixaban and an increase in the risk of stroke.
    Fulvestrant: (Moderate) Because fulvestrant is given intramuscularly, it should not be used or given with caution in patients receiving anticoagulants. Fulvestrant IM injections may cause bleeding, bruising, or hematomas in these patients.
    Garlic, Allium sativum: (Moderate) Garlic produces clinically significant antiplatelet effects so additive bleeding may occur if anticoagulants are given in combination with garlic, allium sativum. In regard to warfarin, no substantial clinical data are available to support or deny a potential for interaction; the data are limited to a random case report. A case of spontaneous spinal epidural hematoma, attributed to dysfunctional platelets from excessive garlic use in a patient not receiving concomitant anticoagulation, has been reported. Avoid concurrent use of herbs which interact with warfarin when possible. If these herbal products are taken concurrently with warfarin, monitor INR and adjust warfarin dosage to attain clinical and anticoagulant endpoints.
    Gemfibrozil: (Moderate) Use apixaban and gemfibrozil together with caution. CYP2C8 plays a minor role in the metabolism of apixaban, and gemfibrozil is a strong CYP2C8 inhibitor. Coadministration may result in an increase in apixaban exposure. A dose reduction of apixaban may be required if used concomitantly with gemfibrozil.
    Ginger, Zingiber officinale: (Moderate) Additive bleeding may occur if anticoagulants are given in combination with ginger, zingiber officinale. Ginger inhibits thromboxane synthetase (platelet aggregation inducer) and is a prostacyclin agonist. Patients taking ginger and an anticoagulant should be monitored closely for bleeding.
    Ginkgo, Ginkgo biloba: (Major) Ginkgo, Ginkgo biloba is reported to inhibit platelet aggregation and several case reports describe bleeding complications with Ginkgo biloba, with or without concomitant drug therapy. Since ginkgo produces clinically-significant antiplatelet effects, it should be used cautiously in patients drugs that inhibit platelet aggregation or pose a risk for bleeding, such as anticoagulants. Ginkgo, Ginkgo biloba is reported to inhibit platelet aggregation and several case reports describe bleeding complications with Ginkgo biloba, with or without concomitant drug therapy. Since ginkgo produces clinically-significant antiplatelet effects, it should be used cautiously in patients drugs that inhibit platelet aggregation or pose a risk for bleeding, such as anticoagulants (e.g., warfarin), aspirin, ASA or other platelet inhibitors, or thrombolytic agents. A patient who had been taking aspirin 325 mg/day PO for 3 years following coronary-artery bypass surgery, developed spontaneous bleeding into his eye after taking a standardized extract of Ginkgo biloba (Ginkoba commercial product) 40 mg PO twice daily for one week. The patient stopped taking the ginkgo but continued taking the aspirin with no recurrence of bleeding over a 3-month period. Other clinical data exist that describe spontaneous subdural hematomas associated with chronic ginkgo biloba ingestion.
    Grapefruit juice: (Major) Reduce the apixaban dose to 2.5 mg twice daily when coadministered with grapefruit juice which is a P-gp inhibitor and strong CYP3A4 inhibitor. Concomitant use of grapefruit juice and apixaban may result in increased exposure to apixaban and an increase in the risk of bleeding. If patients are already receiving 2.5 mg twice daily, avoid concomitant administration of apixaban and grapefruit juice.
    Green Tea: (Moderate) Green tea has demonstrated antiplatelet and fibrinolytic actions in animals. It is possible that the use of green tea may increase the risk of bleeding if co-administered with anticoagulants (e.g., enoxaparin, heparin, warfarin, and others) thrombolytic agents, or platelet inhibitors (e.g., aspirin, clopidogrel, cilostazol and others). Caution and careful monitoring of clinical and/or laboratory parameters are warranted if green tea is coadministered with any of these agents. Exogenous administration or occult sources of vitamin K may decrease or reverse the activity of warfarin; stability of the diet can be an important factor in maintaining anticoagulation goals. Occult sources of vitamin K include green tea and green tea dietary supplements. Published data are limited in regard to this interaction. A patient with previous INRs of 3.2. and 3.79 on a dose of 7.5mg daily of warfarin (goal INR 2.5 to 3.5) had an INR of 1.37. One month later, the patient's INR was 1.14. The patient admitted that he had started consuming 0.51 gallon of green tea daily approximately one week prior to the INR of 1.37. The patient denied noncompliance and other changes in diet, medications, or health. The patient discontinued green tea and one week later his INR was 2.55. While the amount of vitamin K in a single cup of brewed green tea may not be high (0.03 mcg/100 g), the actual amount may vary from cup to cup depending on the amount of tea leaves used, the length of time the tea bags are allowed to brew, and the volume of tea consumed. Additionally, if a patient drinks multiple cups of tea per day, the amount of vitamin K could reach significance. It is recommended that patients on warfarin maintain a stable intake of green tea.
    Guarana: (Major) Guarana has been shown to possess minor antiplatelet activity and, therefore, concurrent use of guarana and anticoagulants or platelet inhibitors should be avoided.
    Hemin: (Major) Because hemin has exhibited transient, mild anticoagulant effects during clinical studies, concurrent use of anticoagulants should be avoided. The extent and duration of the hypocoagulable state induced by hemin has not been established.
    Heparin: (Major) Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if apixaban and other anticoagulants are used concomitantly. If switching from apixaban to another anticoagulant, discontinue apixaban and start the other anticoagulant at the usual time of the next dose of apixaban. If switching from another anticoagulant to apixaban, discontinue the other anticoagulant and start apixaban at the usual time of the next dose of the other anticoagulant. Coadministration of apixaban and other anticoagulants may increase the risk of bleeding.
    Hydrocodone; Ibuprofen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Hydroxyurea: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and apixaban should be monitored closely for bleeding.
    Ibritumomab Tiuxetan: (Moderate) Due to the thrombocytopenic effects of the ibritumomab tiuxetan therapeutic regimen, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Ibuprofen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Ibuprofen; Oxycodone: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Ibuprofen; Pseudoephedrine: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Icosapent ethyl: (Moderate) Icosapent ethyl is an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA). Because omega-3 fatty acids inhibit platelet aggregation, caution is advised when icosapent ethyl is used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 36 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant icosapent ethyl therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with apixaban, a CYP3A substrate, as apixaban toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Ifosfamide: (Moderate) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Iloprost: (Moderate) When used concurrently with anticoagulants, inhaled iloprost may increase the risk of bleeding.
    Indomethacin: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Interferon Alfa-2a: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Interferon Alfa-2b: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Interferon Alfa-2b; Ribavirin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Interferon Alfacon-1: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Intravenous Lipid Emulsions: (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Isavuconazonium: (Moderate) Use apixaban and isavuconazonium together with caution in patients with significant renal dysfunction as risk of bleeding may be increased. Isavuconazonium is a moderate CYP3A4 and mild P-glycoprotein (P-gp) inhibitor. Apixaban is a substrate of CYP3A4 and P-gp. In a pharmacokinetic study, apixaban Cmax and AUC increased by 31% and 40%, respectively, when given with another moderate CYP3A4 and P-gp inhibitor. Although serum concentrations of non-vitamin K oral anticoagulants have been increased in the presence of moderate inhibitors, one cohort study found that the risk of bleeding was not increased.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid the concomitant administration of apixaban and drugs that are both strong inducers of CYP3A4 and P-gp, such as rifampin. Concomitant administration of apixaban and rifampin results in decreased exposure to apixaban and an increase in the risk of stroke.
    Isoniazid, INH; Rifampin: (Major) Avoid the concomitant administration of apixaban and drugs that are both strong inducers of CYP3A4 and P-gp, such as rifampin. Concomitant administration of apixaban and rifampin results in decreased exposure to apixaban and an increase in the risk of stroke.
    Itraconazole: (Major) Use of apixaban is not recommended during and for 2 weeks after discontinuation of itraconazole. If itraconazole therapy is necessary in a patient receiving apixaban 5 mg or 10 mg twice daily, reduce the apixaban dose by 50%. Avoid coadminsitration in patients already receiving apixaban 2.5 mg twice daily. Apixaban is a CYP3A4 and P-glycoprotein substrate; itraconazole is a strong CYP3A4 and P-gp inhibitor. Concomitant administration of itraconazole and apixaban results in increased exposure to apixaban and an increase in the risk of bleeding.
    Kava Kava, Piper methysticum: (Moderate) Kava kava, Piper methysticum does appear to have some anti-thrombotic activity. Persons who are receiving anticoagulants should not take kava kava without first discussing use with their health care professional. Kava kava, Piper methysticum exhibits antithrombotic activity and also inhibits CYP isozymes important in warfarin clearance such as CYP2C9, 2C19, 1A2 and 3A4. Avoid concurrent use of herbs which interact with warfarin when possible. If these herbal products are taken concurrently with warfarin, monitor INR and adjust warfarin dosage to attain clinical and anticoagulant endpoints.
    Ketoconazole: (Major) Reduce the apixaban dose to 2.5 mg twice daily when coadministered with drugs that are both strong inhibitors of CYP3A4 and P-gp, such as ketoconazole. Concomitant administration of ketoconazole and apixaban results in increased exposure to apixaban and an increase in the risk of bleeding. If patients are already receiving the reduced dose of 2.5 mg twice daily, avoid concomitant administration of apixaban and ketoconazole.
    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; 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.
    Levomilnacipran: (Major) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving anticoagulants. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Lomustine, CCNU: (Moderate) Due to the bone marrow suppressive and thrombocytopenic effects of lomustine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Lopinavir; Ritonavir: (Major) Reduce the apixaban dose to 2.5 mg twice daily when coadministered with drugs that are both strong inhibitors of CYP3A4 and P-gp, such as ritonavir. Concomitant administration of ritonavir and apixaban results in increased exposure to apixaban and an increase in the risk of bleeding. If patients are already receiving the reduced dose of 2.5 mg twice daily, avoid concomitant administration of apixaban and ritonavir.
    Low Molecular Weight Heparins: (Major) Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if apixaban and other anticoagulants are used concomitantly. If switching from apixaban to another anticoagulant, discontinue apixaban and start the other anticoagulant at the usual time of the next dose of apixaban. If switching from another anticoagulant to apixaban, discontinue the other anticoagulant and start apixaban at the usual time of the next dose of the other anticoagulant. Coadministration of apixaban and other anticoagulants may increase the risk of bleeding.
    Magnesium Salicylate: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and apixaban should be monitored closely for bleeding.
    Meclofenamate Sodium: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Mefenamic Acid: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Meloxicam: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Methoxsalen: (Minor) Agents, such as anticoagulants, that decrease clotting could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    Methylsulfonylmethane, MSM: (Moderate) Increased effects from concomitant anticoagulant drugs such as increased bruising or blood in the stool have been reported in patients taking methylsulfonylmethane, MSM. Although these effects have not been confirmed in published medical literature or during clinical studies, clinicians should consider using methylsulfonylmethane, MSM with caution in patients who are taking anticoagulants such as warfarin until data confirming the safety of MSM in patients taking these drugs are available. During one of the available, published clinical trials in patients with osteoarthritis, those patients with bleeding disorders or using anticoagulants or antiplatelets were excluded from enrollment. Patients who choose to consume methylsulfonylmethane, MSM while receiving warfarin should be observed for increased bleeding.
    Methyltestosterone: (Moderate) Methyltestosterone can increase the effects of anticoagulants through reduction of procoagulant factor. Patients receiving oral anticoagulant therapy should be closely monitored, especially when methyltestosterone treatment is initiated or discontinued.
    Mifepristone, RU-486: (Major) When mifepristone is used for the termination of pregnancy, concurrent use of anticoagulants is contraindicated due to the increased risk of serious bleeding. When mifepristone is used for the treatment of Cushing's disease or other hormonal conditions, use apixaban with extreme caution as risk of bleeding may be increased. Mifepristone is a moderate CYP3A4 and P-glycoprotein (P-gp) inhibitor. Apixaban is a substrate of CYP3A4 and P-gp. When possible, anticoagulants metabolized through different pathways are advised with concomitant mifepristone.
    Milnacipran: (Major) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving anticoagulants. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Miltefosine: (Moderate) Caution is advised when administering miltefosine with anticoagulants, as use of these drugs together may increase risk for bleeding. Miltefosine, when administered for the treatment of visceral leishmaniasis, has been associated with thrombocytopenia; monitor platelet counts in patients receiving treatment for this indication. In addition, monitor closely for increased bleeding if use in combination with an anticoagulant.
    Mycophenolate: (Moderate) Mycophenolate may causes thrombocytopenia and increase the risk for bleeding. Agents which may lead to an increased incidence of bleeding in patients with thrombocytopenia include anticoagulants.
    Nabumetone: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Naltrexone: (Moderate) Give the extended-release injectable suspension of naltrexone cautiously to patients taking anticoagulants. Steps should be taken to avoid the risk of bleeding and hematoma formation following intramuscular injection.
    Nandrolone Decanoate: (Moderate) Androgens can enhance the effects of anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain prothrombin time at the desired therapeutic level. When anabolic steroid or androgen therapy is started or stopped in patients on anticoagulant therapy, close monitoring is required. Additionally, nandrolone decanoate may generate a pharmacodynamic interaction with warfarin by independently affecting the activity of circulating coagulation proteins. Androgens reduce the amount or activity of circulating coagulant proteins thereby enhancing the anticoagulant effect of warfarin.
    Naproxen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Naproxen; Pseudoephedrine: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Naproxen; Sumatriptan: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Natural Antineoplastics: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Nelarabine: (Moderate) Due to the thrombocytopenic effects of nelarabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Nelfinavir: (Major) Reduce the apixaban dose to 2.5 mg twice daily when coadministered with drugs that are both strong inhibitors of CYP3A4 and P-gp, such as nelfinavir. Concomitant administration of nelfinavir and apixaban may result in increased exposure to apixaban and an increase in the risk of bleeding. If patients are already receiving 2.5 mg twice daily, avoid concomitant administration of apixaban and nelfinavir.
    Netupitant; Palonosetron: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as apixaban. The plasma concentrations of apixaban can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days. Monitor for evidence of increased anticoagulant effect.
    Nicardipine: (Moderate) Use apixaban and nicardipine together with caution in patients with significant renal dysfunction as risk of bleeding may be increased. Nicardipine is a moderate CYP3A4 and potent P-glycoprotein (P-gp) inhibitor in vitro. Apixaban is a substrate of CYP3A4 and P-gp. In a pharmacokinetic study, apixaban Cmax and AUC increased by 31% and 40%, respectively, when given with another moderate CYP3A4 and P-gp inhibitor. Although serum concentrations of non-vitamin K oral anticoagulants have been increased in the presence of moderate inhibitors, one cohort study found that the risk of bleeding was not increased.
    Nilotinib: (Moderate) Use apixaban and nilotinib together with caution, especially in patients with significant renal dysfunction, as risk of bleeding may be increased. Nilotinib is a moderate CYP3A4 and P-glycoprotein (P-gp) inhibitor. Apixaban is a substrate of CYP3A4 and P-gp. In a pharmacokinetic study, apixaban Cmax and AUC increased by 31% and 40%, respectively, when given with another moderate CYP3A4 and P-gp inhibitor. Although serum concentrations of non-vitamin K oral anticoagulants have been increased in the presence of moderate inhibitors, one cohort study found that the risk of bleeding was not increased.
    Nintedanib: (Moderate) Nintedanib is a VEGFR inhibitor and may increase the risk of bleeding. Monitor patients who are taking anticoagulants closely and adjust anticoagulation therapy as necessary.
    Nonsteroidal antiinflammatory drugs: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Obinutuzumab: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Omacetaxine: (Major) Avoid the concomitant use of omacetaxine and anticoagulants when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Concurrent administration of apixaban with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir requires a dosage adjustment for apixaban. For patients receiving more than 2.5 mg PO twice daily of apixaban, reduce the apixaban dosage by 50%. For patients receiving apixaban 2.5 mg PO twice daily, avoid coadministration with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir. Apixaban is a substrate of both CYP3A4 and P-glycoprotein (P-gp); ritonavir inhibits both CYP3A4 and P-gp and paritaprevir inhibits P-gp. Coadministration of these agents increases apixaban plasma concentrations and risk of adverse events such as bleeding. (Major) Reduce the apixaban dose to 2.5 mg twice daily when coadministered with drugs that are both strong inhibitors of CYP3A4 and P-gp, such as ritonavir. Concomitant administration of ritonavir and apixaban results in increased exposure to apixaban and an increase in the risk of bleeding. If patients are already receiving the reduced dose of 2.5 mg twice daily, avoid concomitant administration of apixaban and ritonavir.
    Oritavancin: (Moderate) Coadministration of oritavancin and apixaban may result in increases or decreases in apixaban exposure and may increase side effects or decrease efficacy of apixaban. Apixaban is primarily metabolized by CYP3A4, but is also metabolized by CYP2C19 and CYP2C9. Oritavancin weakly induces CYP3A4, while weakly inhibiting CYP2C19 and CYP2C9. If these drugs are administered concurrently, monitor the patient for signs of toxicity or lack of efficacy.
    Orlistat: (Moderate) Patients on chronic stable doses of anticoagulants, like apixaban, should be monitored closely for changes in coagulation parameters when orlistat is prescribed. Reports of decreased prothrombin, increased INR, and unbalanced anticoagulant treatment resulting in change of hemostatic parameters have been reported in patients treated concomitantly with orlistat and anticoagulants.
    Oxandrolone: (Moderate) An increased effect of anticoagulants may occur with oxandrolone; the anticoagulant dosage may need adjustment downward with oxandrolone initiation or adjustment upward with oxandrolone discontinuation to maintain the desired clinical effect. Oxandrolone suppresses clotting factors II, V, VII, and X, which results in an increased prothrombin time. An increase in plasminogen-activator activity, and serum concentrations of plasminogen, protein C, and antithrombin III have occurred with several 17-alpha-alkylated androgens. For example, concurrent use of oxandrolone and warfarin may result in unexpectedly large increases in the INR or prothrombin time (PT). A multidose study of oxandrolone (5 or 10 mg PO twice daily) in 15 healthy individuals concurrently treated with warfarin resulted in significant increases in warfarin half-life and AUC; a 5.5-fold decrease in the mean warfarin dosage from 6.13 mg/day to 1.13 mg/day (approximately 80 to 85% dose reduction) was necessary to maintain a target INR of 1.5. According to the manufacturer, if oxandrolone therapy is initiated in a patient already receiving warfarin, the dose of warfarin may need to be decreased significantly to reduce the potential for excessive INR elevations and associated risk of serious bleeding events. The patient should be closely monitored with frequent evaluation of the INR and clinical parameter, and the dosage of warfarin should be adjusted as necessary until a stable target INR is achieved. Careful monitoring of the INR and necessary adjustment of the warfarin dosage are also recommended when the androgen therapy is changed or discontinued.
    Oxaprozin: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Paroxetine: (Major) The concomitant use of selective serotonin reuptake inhibitors (SSRIs) and apixaban can increase the risk of bleeding. If given concomitantly, patients should be educated about the signs and symptoms of bleeding and be instructed to report them immediately or go to an emergency room.
    Pentosan: (Major) Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if apixaban and other anticoagulants are used concomitantly. Discontinue apixaban in patients with active bleeding. Coadministration of apixaban and other anticoagulants may increase the risk of bleeding. Pentosan is a weak anticoagulant. Pentosan has one-fifteenth the anticoagulant activity of heparin.
    Phenobarbital: (Major) Avoid the concomitant administration of apixaban and drugs that are both strong inducers of CYP3A4 and P-gp, such as phenobarbital. Concomitant administration of apixaban and phenobarbital results in decreased exposure to apixaban and an increase in the risk of stroke.
    Phentermine; Topiramate: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Phenytoin: (Major) Avoid the concomitant administration of apixaban and drugs that are both strong inducers of CYP3A4 and P-gp, such as phenytoin. Concomitant administration of apixaban and phenytoin results in decreased exposure to apixaban and an increase in the risk of stroke.
    Photosensitizing agents: (Minor) Drugs that decrease clotting, such as anticoagulants, could decrease the efficacy of photodynamic therapy.
    Piperacillin: (Moderate) Some penicillins (e.g., piperacillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Piperacillin; Tazobactam: (Moderate) Some penicillins (e.g., piperacillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Piroxicam: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Platelet Inhibitors: (Major) The concomitant use of apixaban and platelet inhibitors (e.g, aspirin) may increase the risk of bleeding. In the ARISTOTLE trial (comparative trial of apixaban and warfarin in patients with nonvalvular atrial fibrillation), concomitant use of aspirin increased the bleeding risk of apixaban from 1.8%/year to 3.4%/year. If given concomitantly, patients should be educated about the signs and symptoms of bleeding and be instructed to report them immediately or go to an emergency room.
    Porfimer: (Minor) Drugs that decrease clotting, such as anticoagulants, could decrease the efficacy of photodynamic therapy.
    Posaconazole: (Major) Reduce the apixaban dose to 2.5 mg twice daily when coadministered with drugs that are both strong inhibitors of CYP3A4 and P-gp, such as posaconazole. Concomitant administration of posaconazole and apixaban results in increased exposure to apixaban and an increase in the risk of bleeding. If patients are already receiving 2.5 mg twice daily, avoid concomitant administration of apixaban and posaconazole.
    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) The concomitant use of apixaban and platelet inhibitors (e.g, aspirin) may increase the risk of bleeding. In the ARISTOTLE trial (comparative trial of apixaban and warfarin in patients with nonvalvular atrial fibrillation), concomitant use of aspirin increased the bleeding risk of apixaban from 1.8%/year to 3.4%/year. If given concomitantly, patients should be educated about the signs and symptoms of bleeding and be instructed to report them immediately or go to an emergency room.
    Primidone: (Major) Avoid the concomitant administration of apixaban and drugs that are both strong inducers of CYP3A4 and P-gp, such as primidone. Phenobarbital is a strong inducer of both CYP3A4 and P-gp. Because primidone is metabolized to phenobarbital, drug interactions occurring with phenobarbital must be considered when primidone is administered. Concomitant administration of apixaban and primidone results in decreased exposure to apixaban and an increase in the risk of stroke.
    Prothrombin Complex Concentrate, Human: (Severe) The actions of factor X are likely to be counteracted by direct and indirect factor Xa inhibitors such as apixaban, edoxaban, rivaroxaban, and fondaparinux.
    Rabies Immune Globulin, human RIG: (Minor) The intramuscular rabies immune globulin, human RIG should be administered cautiously to persons receiving anticoagulants. If used concurrently, monitor patients closely for bleeding at the IM injection site. All steps to avoid hematoma formation are recommended.
    Reteplase, r-PA: (Severe) Due to the increased bleeding risk, avoid concurrent use of apixaban with thrombolytic agents.
    Rifampin: (Major) Avoid the concomitant administration of apixaban and drugs that are both strong inducers of CYP3A4 and P-gp, such as rifampin. Concomitant administration of apixaban and rifampin results in decreased exposure to apixaban and an increase in the risk of stroke.
    Ritonavir: (Major) Reduce the apixaban dose to 2.5 mg twice daily when coadministered with drugs that are both strong inhibitors of CYP3A4 and P-gp, such as ritonavir. Concomitant administration of ritonavir and apixaban results in increased exposure to apixaban and an increase in the risk of bleeding. If patients are already receiving the reduced dose of 2.5 mg twice daily, avoid concomitant administration of apixaban and ritonavir.
    Rivaroxaban: (Major) Avoid concurrent use of rivaroxaban with apixaban due to the increased bleeding risk. Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if rivaroxaban and other anticoagulants are used concomitantly. If switching from apixaban to another anticoagulant, discontinue apixaban and start the other anticoagulant at the usual time of the next dose of apixaban. If switching from another anticoagulant to apixaban, discontinue the other anticoagulant and start apixaban at the usual time of the next dose of the other anticoagulant. Coadministration of rivaroxaban and other anticoagulants may increase the risk of bleeding.
    Rofecoxib: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Salicylates: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and apixaban should be monitored closely for bleeding.
    Salsalate: (Major) Large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Patients taking large doses of salicylates and apixaban should be monitored closely for bleeding.
    Sapropterin: (Moderate) Caution is advised with the concomitant use of sapropterin and apixaban as coadministration may result in increased systemic exposure of apixaban. Apixaban is a substrate for the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); in vitro data show that sapropterin may inhibit these transporters. If these drugs are used together, closely monitor for increased side effects of apixaban, such as bleeding.
    Saquinavir: (Major) Reduce the apixaban dose to 2.5 mg twice daily when coadministered with drugs that are both strong inhibitors of CYP3A4 and P-gp, such as saquinavir coadministered with ritonavir. Concomitant administration of saquinavir plus ritonavir and apixaban results in increased exposure to apixaban which increases the risk of bleeding. If patients are already receiving 2.5 mg twice daily, avoid concomitant administration of apixaban and saquinavir plus ritonavir.
    Selective serotonin reuptake inhibitors: (Major) The concomitant use of selective serotonin reuptake inhibitors (SSRIs) and apixaban can increase the risk of bleeding. If given concomitantly, patients should be educated about the signs and symptoms of bleeding and be instructed to report them immediately or go to an emergency room.
    Sertraline: (Major) The concomitant use of selective serotonin reuptake inhibitors (SSRIs) and apixaban can increase the risk of bleeding. If given concomitantly, patients should be educated about the signs and symptoms of bleeding and be instructed to report them immediately or go to an emergency room.
    Sodium Iodide: (Moderate) Anticoagulants may alter sodium iodide I-131 pharmacokinetics and dynamics for up to 1 week after administrations.
    St. John's Wort, Hypericum perforatum: (Major) Avoid the concomitant administration of apixaban and herbal medications that are both strong inducers of CYP3A4 and P-gp, such as St. John's Wort, Hypericum perforatum. Concomitant administration of apixaban and St. John's wort results in decreased exposure to apixaban and an increase in the risk of stroke.
    Streptokinase: (Severe) Due to the increased bleeding risk, avoid concurrent use of apixaban with thrombolytic agents.
    Sulfinpyrazone: (Major) Sulfinpyrazone should be avoided when possible with concurrent anticoagulants, thrombin inhibitors, and thrombolytic agents due to potential for increased bleeding risk. Alternative uricosuric agents may be considered. Sulfinpyrazone is a platelet inhibitor and exhibits antithrombotic actions in addition to its uricosuric effects. Additive hematological effects are possible as a result of the platelet inhibitory effects of sulfinpyrazone; the sulfide metabolite of sulfinpyrazone appears responsible for this effect. Sulfinpyrazone is also known to markedly potentiate the effect of warfarin. Sulfinpyrazone may inhibit CYP2C9, leading to a decrease in the clearance of S-warfarin. If concurrent therapy is warranted, significant initial dosage reductions (e.g., 50%) of warfarin may be necessary, with further dosage adjusted based on INR values. The INR should be closely monitored during concurrent therapy with warfarin, particularly during the initiation or termination phases of sulfinpyrazone treatment.
    Sulindac: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Taxanes: (Moderate) Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Telavancin: (Moderate) Telavancin has no effect on coagulation or platelet aggregation; however, caution is advised when administering telavancin concurrently with anticoagulants as telavancin may interfere with laboratory tests used in monitoring these medications. The coagulation tests affected by telavancin include prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (aPTT), activated clotting time, and coagulation based factor Xa tests. When measured shortly after completion of a telavancin infusion, the results of these tests are increased; however, the effects of telavancin on these tests dissipate over time as plasma concentrations of telavancin decrease. Therefore, when administering telavancin in conjunction with anticoagulants ensure that blood samples for these coagulation tests are collected as close as possible to the patient's next telavancin dose.
    Temsirolimus: (Moderate) Use caution if coadministration of temsirolimus with apixaban is necessary, and monitor for an increase in apixaban-related adverse reactions including bleeding. If also taking a CYP3A4 inhibitor, this risk is greater and an apixaban dosage adjustment may be necessary. Temsirolimus is a P-glycoprotein (P-gp) inhibitor in vitro, and apixaban is a P-gp and CYP3A4 substrate. Concomitant use may cause increased exposure to apixaban.
    Tenecteplase, TNK-tPA: (Severe) Due to the increased bleeding risk, avoid concurrent use of apixaban with thrombolytic agents.
    Thrombin Inhibitors: (Major) Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if apixaban and other anticoagulants are used concomitantly. If switching from apixaban to another anticoagulant, discontinue apixaban and start the other anticoagulant at the usual time of the next dose of apixaban. If switching from another anticoagulant to apixaban, discontinue the other anticoagulant and start apixaban at the usual time of the next dose of the other anticoagulant. Coadministration of apixaban and other anticoagulants may increase the risk of bleeding.
    Thrombolytic Agents: (Severe) Due to the increased bleeding risk, avoid concurrent use of apixaban with thrombolytic agents.
    Ticagrelor: (Major) The concomitant use of apixaban and platelet inhibitors (e.g, aspirin) may increase the risk of bleeding. In the ARISTOTLE trial (comparative trial of apixaban and warfarin in patients with nonvalvular atrial fibrillation), concomitant use of aspirin increased the bleeding risk of apixaban from 1.8%/year to 3.4%/year. If given concomitantly, patients should be educated about the signs and symptoms of bleeding and be instructed to report them immediately or go to an emergency room.
    Ticarcillin: (Moderate) Some penicillins (e.g., ticarcillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Ticarcillin; Clavulanic Acid: (Moderate) Some penicillins (e.g., ticarcillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Ticlopidine: (Major) The concomitant use of apixaban and platelet inhibitors (e.g, aspirin) may increase the risk of bleeding. In the ARISTOTLE trial (comparative trial of apixaban and warfarin in patients with nonvalvular atrial fibrillation), concomitant use of aspirin increased the bleeding risk of apixaban from 1.8%/year to 3.4%/year. If given concomitantly, patients should be educated about the signs and symptoms of bleeding and be instructed to report them immediately or go to an emergency room.
    Tinzaparin: (Major) Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if apixaban and other anticoagulants are used concomitantly. If switching from apixaban to another anticoagulant, discontinue apixaban and start the other anticoagulant at the usual time of the next dose of apixaban. If switching from another anticoagulant to apixaban, discontinue the other anticoagulant and start apixaban at the usual time of the next dose of the other anticoagulant. Coadministration of apixaban and other anticoagulants may increase the risk of bleeding.
    Tirofiban: (Major) The concomitant use of apixaban and platelet inhibitors (e.g, aspirin) may increase the risk of bleeding. In the ARISTOTLE trial (comparative trial of apixaban and warfarin in patients with nonvalvular atrial fibrillation), concomitant use of aspirin increased the bleeding risk of apixaban from 1.8%/year to 3.4%/year. If given concomitantly, patients should be educated about the signs and symptoms of bleeding and be instructed to report them immediately or go to an emergency room.
    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.
    Topiramate: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Trandolapril; Verapamil: (Moderate) Use apixaban and verapamil together with caution in patients with significant renal dysfunction as risk of bleeding may be increased. Verapamil is a moderate CYP3A4 and P-glycoprotein (P-gp) inhibitor. Apixaban is a substrate of CYP3A4 and P-gp. In a pharmacokinetic study, apixaban Cmax and AUC increased by 31% and 40%, respectively, when given with another moderate CYP3A4 and P-gp inhibitor. Although serum concentrations of non-vitamin K oral anticoagulants have been increased in the presence of moderate inhibitors, one cohort study found that the risk of bleeding was not increased.
    Trazodone: (Moderate) Patients should be instructed to monitor for signs and symptoms of bleeding while taking trazodone concurrently with anticoagulants and to promptly report any bleeding events to the practitioner. Serotonergic agents may increase the risk of bleeding when combined with anticoagulants via inhibition of serotonin uptake by platelets; however, the absolute risk is not known. It would be prudent for clinicians to monitor the INR and patient's clinical status closely if trazodone is added to or removed from the regimen of a patient stabilized on anticoagulant therapy.
    Treprostinil: (Moderate) When used concurrently with anticoagulants, treprostinil may increase the risk of bleeding.
    Tretinoin, ATRA: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Urokinase: (Severe) Due to the increased bleeding risk, avoid concurrent use of apixaban with thrombolytic agents.
    Valdecoxib: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Venlafaxine: (Major) Platelet aggregation may be impaired by venlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving anticoagulants. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. Monitor INR levels when venlafaxine is added to or discontinued from warfarin therapy. Patients should be instructed to monitor for signs and symptoms of bleeding while taking venlafaxine concurrently with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Verapamil: (Moderate) Use apixaban and verapamil together with caution in patients with significant renal dysfunction as risk of bleeding may be increased. Verapamil is a moderate CYP3A4 and P-glycoprotein (P-gp) inhibitor. Apixaban is a substrate of CYP3A4 and P-gp. In a pharmacokinetic study, apixaban Cmax and AUC increased by 31% and 40%, respectively, when given with another moderate CYP3A4 and P-gp inhibitor. Although serum concentrations of non-vitamin K oral anticoagulants have been increased in the presence of moderate inhibitors, one cohort study found that the risk of bleeding was not increased.
    Verteporfin: (Minor) Drugs that decrease clotting, such as anticoagulants, could decrease the efficacy of photodynamic therapy.
    Vilazodone: (Moderate) Patients should be instructed to monitor for signs and symptoms of bleeding while taking vilazodone concurrently with anticoagulants and to promptly report any bleeding events to the practitioner. Serotonergic agents may increase the risk of bleeding when combined with anticoagulants via inhibition of serotonin uptake by platelets; however, the absolute risk is not known. In addition, both vilazodone and warfarin are highly protein bound, which may result in displacement of warfarin from protein binding sites and an increased anticoagulant effect. It would be prudent for clinicians to monitor the INR and clinical status of the patient closely if vilazodone is added to or removed from the regimen of a patient stabilized on warfarin.
    Vorapaxar: (Major) The concomitant use of apixaban and platelet inhibitors (e.g, aspirin) may increase the risk of bleeding. In the ARISTOTLE trial (comparative trial of apixaban and warfarin in patients with nonvalvular atrial fibrillation), concomitant use of aspirin increased the bleeding risk of apixaban from 1.8%/year to 3.4%/year. If given concomitantly, patients should be educated about the signs and symptoms of bleeding and be instructed to report them immediately or go to an emergency room.
    Vorinostat: (Moderate) Concomitant use of vorinostat with anticoagulants may result in an additive risk of bleeding due to vorinostat-induced thrombocytopenia; monitor patients closely.
    Vortioxetine: (Moderate) Platelet aggregation may be impaired by vortioxetine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving anticoagulants. Bleeding events related to drugs that inhibit serotonin reuptake have ranged from ecchymosis to life-threatening hemorrhages. Patients should be instructed to monitor for signs and symptoms of bleeding while taking vortioxetine concurrently with anticoagulants and to promptly report any bleeding events to the practitioner. Co-administration of vortioxetine and warfarin has not been shown to significantly affect the pharmacokinetics of either agent.
    Warfarin: (Major) Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if apixaban and other anticoagulants are used concomitantly. If switching from apixaban to warfarin, discontinue apixaban and start warfarin and a parenteral anticoagulant at the usual time of the next dose of apixaban; because apixaban affects INR, initial INR measurements may not be useful in transition. If switching from another anticoagulant to apixaban, discontinue the other anticoagulant and start apixaban at the usual time of the next dose of the other anticoagulant. Coadministration of apixaban and other anticoagulants may increase the risk of bleeding.
    Zonisamide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and apixaban is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.

    PREGNANCY AND LACTATION

    Pregnancy

    It is not known if apixaban or its metabolites are excreted in human milk. The molecular weight, partial metabolism, moderate plasma protein binding, and long effective half-life suggest that the drug will be excreted into human milk. Women should be instructed to discontinue breast-feeding or to discontinue apixaban, taking into account the importance of the drug to the mother. If pharmacotherapy is necessary in the nursing mother, the American Academy of Pediatrics (AAP) considers warfarin to be usually compatible with breast-feeding. Low-molecular weight heparins and heparin have relatively high molecular weights ; therefore, these drugs are not expected to be excreted into human milk to a clinically significant degree. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Apixaban is a selective inhibitor of Factor Xa and does not require antithrombin III for antithrombotic activity. It inhibits Factor Xa that is both free and bound to clots and also inhibits prothrombinase activity. By inhibiting Factor Xa, apixaban decreases thrombin generation and the development of a thrombus. Although apixaban has no direct effect on platelet aggregation, it indirectly inhibits platelet aggregation induced by thrombin.

    PHARMACOKINETICS

    Apixaban is administered orally and is 87% bound to plasma proteins. The volume of distribution is approximately 21 L. Apixaban is metabolized mainly by CYP3A4 with CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP2J2 having minor roles in metabolism. Unchanged apixaban is the major drug-related component in human plasma; there are no active circulating metabolites. Approximately 25% of an orally administered dose is recovered in the urine and feces as metabolites. Renal excretion accounts for about 27% of total apixaban clearance. Biliary and direct intestinal excretion contribute to fecal elimination. The apparent half-life of apixaban is approximately 12 hours.
     
    Affected cytochrome P450 isoenzymes and transporters: CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2J2, CYP3A4, P-gp, BCRP
    Apixaban is a substrate for CYP3A4 and minor substrate for CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP2J2. Apixaban is a substrate for the P-glycoprotein (P-gp) transport protein and the breast cancer resistance protein (BCRP).
     
    During clinical trials of apixaban, a concentration-dependent increase in anti-factor Xa activity was observed in the dose range tested and was similar in healthy subjects and patients with atrial fibrillation. Due to the inhibition of factor Xa, apixaban administration at therapeutic doses results in prolonged clotting tests such as prothrombin time (PT), international normalized ration (INR), and activated partial thromboplastin time (aPTT). However, these prolonged clotting times are small and subject to a high degree or variability and are not useful in monitoring the anticoagulation effect of apixaban.

    Oral Route

    The absolute bioavailability of apixaban is about 50% for doses up to 10 mg. Food has no effect on absorption. Maximum plasma concentrations (Cmax) are seen within 3 to 4 hours of oral administration. At doses of 25 mg or more, apixaban displays dissolution-limited absorption with decreased bioavailability. Apixaban exposure is similar after oral administration of 2 crushed 5 mg tablets suspended in 30 mL of water and 2 intact 5 mg tablets. Cmax and AUC are 20% and 16% lower, respectively, after administration of 2 crushed 5 mg tablets mixed with 30 grams of applesauce compared to 2 intact 5 mg tablets. Apixaban exposure is similar after administration of a crushed 5 mg tablet suspended in 60 mL of 5% Dextrose Injection and delivered via nasogastric tube to that seen in clinical trials involving healthy volunteers receiving a single 5 mg oral tablet. Apixaban absorption was studied in a small (n = 12), open-label, 4-treatment crossover trial in which subjects received a single dose of apixaban 2.5 mg solution or crushed apixaban 2.5 mg tablet administered orally and delivered to the distal small bowel or ascending colon via an Enterion capsule that was monitored using scintigraphic imaging. Compared to oral administration, the Cmax and AUC of apixaban solution were both 60% lower when released in the distal small bowel and 90% and 84% lower, respectively, with release in the ascending colon. Relative bioavailability of the crushed tablet released in the ascending colon was about 60% lower than that of the solution released in the colon and 95% lower than the solution after oral administration. Apixaban absorption appears to occur primarily in the small intestine and decrease progressively in the distal gastrointestinal tract.