Version January 2024
Premature discontinuation of any oral anticoagulant, including apixaban, increases the risk of thrombotic events. If anticoagulation with apixaban is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.
Epidural or spinal hematomas may occur in patients treated with apixaban who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. 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 traumatic or repeated epidural or spinal punctures; a history of spinal deformity or spinal surgery; optimal timing between the administration of apixaban and neuraxial procedures is not known.
Monitor patients frequently for signs and symptoms of neurologic impairment. If neurologic compromise is noted, urgent treatment is necessary.
Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated.
The adult dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editor: Edith A Nutescu, PharmD, MS, FCCP.
Atrial fibrillation, nonvalvular (to prevent stroke and systemic embolism): Oral: 5 mg twice daily unless patient has any 2 of the following: Age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL (133 micromole/L), then reduce dose to 2.5 mg twice daily.
Post-percutaneous coronary intervention with stent placement and nonvalvular atrial fibrillation: Oral: 5 mg twice daily unless patient has any 2 of the following: Age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL (133 micromole/L), then reduce dose to 2.5 mg twice daily; administer with an appropriate antithrombotic regimen including clopidogrel (preferred P2Y12 inhibitor in this situation) with or without aspirin, depending on risks for thrombosis and bleeding, and time since percutaneous coronary intervention (PCI) (Ref). It is recommended to discontinue aspirin 1 to 4 weeks after PCI and continue apixaban and clopidogrel (Ref).
Heparin-induced thrombocytopenia (off-label use): Note: For treatment of acute heparin-induced thrombocytopenia, either as initial therapy in selected hemodynamically stable patients or after initial therapy with a parenteral non-heparin anticoagulant (Ref).
Heparin-induced thrombocytopenia with or without thrombosis: Oral: 10 mg twice daily for 7 days or until platelet count recovery, whichever is longer, followed by 5 mg twice daily. Note: If initially treated with a parenteral non-heparin anticoagulant, can transition to 5 mg twice daily after platelet count recovery. However, if the parenteral non-heparin anticoagulant is administered for <7 days, transition to 10 mg twice daily; then after a total of 7 days with non-heparin anticoagulation, reduce to 5 mg twice daily (Ref). For patients without thrombosis, may consider starting 5 mg twice daily regardless of whether parenteral anticoagulation was used initially (Ref).
Duration: Not well established:
Heparin-induced thrombocytopenia without thrombosis: Typically, 4 weeks to 3 months (Ref). Alternatively, may discontinue anticoagulation after platelet count recovery, potentially resulting in a shorter duration (Ref).
Heparin-induced thrombocytopenia with thrombosis: Typically, 3 to 6 months (Ref).
Left ventricular thrombus, treatment or prophylaxis (off-label use):
Treatment:
Post myocardial infarction:
Note: When an antiplatelet agent is used in combination with an anticoagulant, selection and duration of antiplatelet therapy for myocardial infarction (MI) may vary; consider risks of bleeding and thrombotic events when choosing antithrombotic therapy combinations (Ref).
Oral: 5 mg twice daily for ~3 months in patients with acute MI or ≥3 to 6 months in patients with distant MI (Ref). Duration may vary based on follow-up imaging (eg, assessment of thrombus resolution and left ventricular [LV] function) and shared decision making; indefinite therapy may be considered if LV function does not improve (eg, reduced systolic function, persistent apical akinesis or dyskinesis) or in patients with other ongoing thrombotic risk factors (Ref).
Nonischemic dilated cardiomyopathy: Oral: 5 mg twice daily for ≥3 to 6 months; duration may vary based on follow-up imaging (eg, assessment of thrombus resolution and LV function) and shared decision making; indefinite therapy may be considered even after thrombus resolution if LV function does not improve (eg, reduced systolic function, persistent apical akinesis or dyskinesis) or in patients with other ongoing thrombotic risk factors (Ref).
Prophylaxis for high-risk patients post myocardial infarction:
Note: May be used for high-risk patients (eg, ejection fraction <40% and/or anteroapical wall motion abnormality) to prevent LV thrombus. When an antiplatelet agent is used in combination with an anticoagulant, selection and duration of antiplatelet therapy for MI may vary; consider risks of bleeding and thrombotic events when choosing antithrombotic therapy combinations (Ref).
Oral: 5 mg twice daily for 1 to 3 months; duration may vary based on follow-up imaging (eg, assessment of LV function) and shared decision making (Ref).
Venous thromboembolism:
Deep vein thrombosis and/or pulmonary embolism treatment:
Note: May be used in patients with active cancer (eg, metastatic disease or receiving chemotherapy) (Ref).
Oral: 10 mg twice daily for 7 days followed by 5 mg twice daily.
Duration of therapeutic anticoagulation (first episode, general recommendations): Optimal duration of therapy is unknown and is dependent on many factors, such as whether provoking events were present, patient risk factors for recurrence and bleeding, and individual preferences:
Provoked venous thromboembolism: 3 months (provided provoking risk factor is no longer present) (Ref).
Unprovoked venous thromboembolism or provoked venous thromboembolism with a persistent risk factor: ≥3 months depending on risk of venous thromboembolism (VTE) recurrence and bleeding (Ref).
Note: All patients receiving indefinite therapeutic anticoagulation with no specified stop date should be reassessed at periodic intervals.
Indefinite anticoagulation (reduced-intensity dosing for prophylaxis against venous thromboembolism recurrence): Note: For patients at elevated risk of recurrent VTE following at least 6 months of therapeutic anticoagulation. This reduced-intensity regimen is not recommended if indefinite full anticoagulation is indicated (Ref): Oral: 2.5 mg twice daily (Ref).
Venous thromboembolism prophylaxis:
Total hip arthroplasty or total knee arthroplasty: Oral: 2.5 mg twice daily beginning 12 to 24 hours postoperatively.
Duration: Optimal duration of prophylaxis is unknown but it is usually given for a minimum of 10 to 14 days and can be extended for up to 35 days (Ref); some experts suggest a duration in the lower end of the range (10 to 14 days) for total knee arthroplasty or higher end of range (~30 days) for THA (Ref).
Transitioning between anticoagulants: Note: This provides general guidance on transitioning between anticoagulants; also refer to local protocol for additional detail.
Transitioning from another anticoagulant to apixaban:
Transitioning from low-molecular-weight heparin or fondaparinux (therapeutic dose) to apixaban: Initiate apixaban at the time of the next scheduled dose of the parenteral anticoagulant.
Transitioning from unfractionated heparin continuous infusion to apixaban: Start apixaban when the parenteral anticoagulant infusion is stopped (consult local protocol if the aPTT is above the target range) (Ref).
Transitioning from warfarin to apixaban: Discontinue warfarin and initiate apixaban as soon as the INR falls to <2 (US labeling).
Transitioning from apixaban to another anticoagulant:
Transitioning from apixaban to unfractionated heparin continuous infusion, low-molecular-weight heparin, or fondaparinux: Start the parenteral anticoagulant when the next dose of apixaban was scheduled to be given.
Transitioning from apixaban to warfarin: Apixaban can elevate the INR, complicating interpretation if overlapped with warfarin. To minimize interference, check INR near the end of apixaban dosing interval. Some experts suggest overlapping apixaban with warfarin for ≥2 days until INR is therapeutic. An alternative is to stop apixaban, start warfarin the same day, and bridge with a parenteral anticoagulant until the desired INR is reached (Ref).
Transitioning between direct oral anticoagulants: Start the new direct oral anticoagulant (DOAC) when the next dose of the previous DOAC was scheduled to be given (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Note: Clinical trials for the below indications excluded patients either with serum creatinine >2.5 mg/dL or CrCl <25 mL/minute (Ref) or with CrCl <30 mL/minute (Ref). Therefore, there is no clinical trial data on safety or efficacy in patients with advanced chronic kidney disease (CKD). Retrospective studies suggest similar efficacy and no increased bleeding risk with use of apixaban when compared to warfarin in patients with advanced CKD (CrCl <25 mL/minute) (Ref) and dialysis patients (Ref). However, until more robust data become available, some experts avoid use of apixaban for all indications in patients with a severe reduction in kidney function (CrCl <25 mL/minute, including dialysis) since safety and efficacy remain untested and cannot be assured (Ref).
Atrial fibrillation, nonvalvular
Serum creatinine <1.5 mg/dL (133 micromole/L): No dosage adjustment necessary unless ≥80 years of age and body weight ≤60 kg, then reduce dose to 2.5 mg twice daily.
Serum creatinine ≥1.5 mg/dL (133 micromole/L) and either ≥80 years of age or body weight ≤60 kg: 2.5 mg twice daily.
Severe or end-stage kidney disease (ESKD) not requiring dialysis: Apixaban or warfarin is considered appropriate (Ref). Some experts recommend apixaban 2.5 mg twice daily for CrCl 15 to 29 mL/minute (Ref).
Hemodialysis, intermittent (thrice weekly): Not dialyzable to minimally dialyzable (AUC decreased by 14% over 4 hours) (Ref). According to the manufacturer, no dosage adjustment necessary unless either ≥80 years of age or body weight ≤60 kg, then reduce to 2.5 mg twice daily. The manufacturer recommendations are derived from a single-dose pharmacokinetic and pharmacodynamic (anti-Factor Xa activity) evaluation in 8 patients (Ref). A multiple-dose pharmacokinetic study demonstrated drug accumulation in ESKD patients requiring hemodialysis, with a dose of 2.5 mg twice daily producing exposures similar to those produced by a 5 mg twice-daily dose in patients with normal kidney function (Ref). Despite this finding, a retrospective, propensity-matched cohort study of patients with ESKD requiring hemodialysis found that apixaban 5 mg twice daily resulted in fewer thromboembolic events and fewer major bleeding events, while apixaban 2.5 mg twice daily only resulted in fewer major bleeding events compared to warfarin (Ref).
Note: Use with caution due to limited available data. Some experts avoid anticoagulation in patients with ESKD and atrial fibrillation unless risk of thromboembolism is very high (Ref). In patients with ESKD and atrial fibrillation requiring dialysis, in whom a decision is made to anticoagulate, apixaban or warfarin is considered appropriate (Ref).
Left ventricular thrombus, treatment or prophylaxis (off-label use):
Note: Specific data in patients with kidney impairment are lacking; several small studies utilized dose adjustment that is consistent with nonvalvular atrial fibrillation as follows (Ref):
Serum creatinine <1.5 mg/dL (133 micromole/L): No dosage adjustment necessary unless ≥80 years of age and body weight ≤60 kg, then reduce dose to 2.5 mg twice daily.
Serum creatinine ≥1.5 mg/dL (133 micromole/L) and either ≥80 years of age or body weight ≤60 kg: 2.5 mg twice daily.
Venous thromboembolism:
Deep vein thrombosis and/or pulmonary embolism treatment: No dosage adjustment is recommended by the manufacturer for any degree of reduced kidney function.
Hemodialysis, intermittent (thrice weekly): Not dialyzable to minimally dialyzable (AUC decreased by 14% over 4 hours) (Ref). According to the manufacturer, no dosage adjustment necessary.
Indefinite anticoagulation (reduced-intensity dosing for prophylaxis against venous thromboembolism recurrence): Note: For patients at elevated risk of recurrent venous thromboembolism following at least 6 months of therapeutic anticoagulation. This reduced-intensity regimen is not recommended if indefinite full anticoagulation is indicated (Ref): No dosage adjustment is recommended by the manufacturer for any degree of reduced kidney function.
Hemodialysis, intermittent (thrice weekly): Not dialyzable to minimally dialyzable (AUC decreased by 14% over 4 hours) (Ref). According to the manufacturer, no dosage adjustment necessary.
Venous thromboembolism prophylaxis:
Total hip arthroplasty or total knee arthroplasty: No dosage adjustment is recommended by the manufacturer for any degree of reduced kidney function.
Hemodialysis, intermittent (thrice weekly): Not dialyzable to minimally dialyzable (AUC decreased by 14% over 4 hours) (Ref). According to the manufacturer, no dosage adjustment necessary.
Mild impairment (Child-Pugh class A): No dosage adjustment required.
Moderate impairment (Child-Pugh class B): There are no dosage adjustments provided in manufacturer's labeling; use with caution (limited clinical experience in these patients).
Severe impairment (Child-Pugh class C): Use is not recommended.
The recommendations for dosing in obese patients are based upon the best available evidence and clinical expertise. Senior Editorial Team: Jeffrey F. Barletta, PharmD, FCCM; Manjunath P. Pai, PharmD, FCP; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC.
Class 1, 2, or 3 obesity (BMI ≥3 0 kg/m2): No dosage adjustment necessary (Ref). Refer to adult dosing for indication-specific doses.
Rationale for recommendations:
There are limited data in patients with obesity demonstrating changes in apixaban drug concentrations or anti-factor Xa activity (Ref). A pharmacokinetic study in patients with obesity (>120 kg) suggests ~30% decrease in Cmax and ~20% decrease in AUC; however, the decrease in exposure is unlikely to require a change in dosing (Ref). In patients with nonvalvular atrial fibrillation, a subanalysis of a randomized, controlled trial enrolling patients receiving apixaban showed less major bleeding in patients >120 kg compared with lower-weight patients (Ref). In patients with venous thromboembolism, retrospective data suggest that no dosage adjustment is necessary in patients with a BMI >40 kg/m2 or who weigh >100 to 300 kg; when compared to warfarin, there were similar recurrent thrombotic events and bleeding (Ref).
The International Society on Thrombosis and Haemostasis suggests not to regularly monitor peak and trough drug-specific concentrations due to insufficient data to impact clinical decisions (Ref).
Refer to adult dosing.
Atrial fibrillation, nonvalvular (to prevent stroke and systemic embolism): If patient is ≥80 years of age and either weighs ≤60 kg or has a serum creatinine ≥1.5 mg/dL (133 micromole/L), then reduce dose to 2.5 mg twice daily.
Left ventricular thrombus, treatment or prophylaxis (off-label use): Note: Specific data are lacking; several small studies utilized dose adjustment that is consistent with nonvalvular atrial fibrillation as follows: If patient is ≥80 years of age and either weighs ≤60 kg or has a serum creatinine ≥1.5 mg/dL (133 micromole/L), then reduce dose to 2.5 mg twice daily (Ref).
Apixaban may increase the risk of bleeding (hemorrhage), including severe and potentially fatal major bleeding as defined by the International Society on Thrombosis and Hemostasis (Ref).
Onset: Variable; for anticoagulants in general, risk may be highest within 3 months of initiation (Ref).
Risk factors:
General (any anticoagulant):
• History of GI bleeding (Ref)
• History of prior bleeding event (Ref)
• Hemostatic abnormalities (Ref)
• Kidney or hepatic impairment (Ref)
• Coadministration of drugs that affect hemostasis or interact to increase exposure (Ref)
• Alcohol use (Ref)
• Older patients (Ref)
• Nonwhite race (Ref)
• History of stroke (Ref)
• Hypertension (Ref)
• Diabetes (Ref)
• Malignancy (Ref)
• Excessive fall risk (Ref)
Spinal hematoma or epidural intracranial hemorrhage may occur in patients treated with apixaban who are receiving neuraxial anesthesia or undergoing spinal puncture; may result in long-term or permanent paralysis. Spontaneous spinal or epidural hematomas (SEH) have also been reported (Ref).
Mechanism: SEH due to neuraxial anesthesia or spinal puncture is related to trauma in the presence of impaired hemostasis with apixaban. Spontaneous SEH may be due to sudden increases in thoracic and/or abdominal pressure (Ref).
Onset: Spontaneous SEH: Variable; case reports have occurred from 10 days to 3 years after apixaban initiation (Ref).
Risk factors:
• Use of indwelling epidural catheters
• Concomitant administration of other drugs that affect hemostasis (eg, aspirin, nonsteroidal anti-inflammatory drugs, platelet inhibitors, other anticoagulants)
• History of traumatic or repeated epidural or spinal punctures
• History of spinal deformity or surgery
• If optimal timing between administration of apixaban and neuraxial procedures is unknown
• Older patients (Ref)
• Females (Ref)
• Hemostatic abnormalities (Ref)
• Epidural rather than spinal anesthesia (Ref)
• Challenging neuraxial procedures (Ref)
• Risk factors for spontaneous SEH: Stretch exercises, Valsalva maneuvers, defecation, hypertension, structural extradural anomalies, and rupture of fragile epidural veins by an adjacent herniated disk (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%: Hematologic & oncologic: Hemorrhage (≤15%; major hemorrhage: ≤2%; clinically relevant nonmajor hemorrhage: 4%)
1% to 10%:
Endocrine & metabolic: Heavy menstrual bleeding (1%)
Gastrointestinal: Gingival hemorrhage (≤1%), nausea (3%)
Genitourinary: Hematuria (≤2%)
Hematologic & oncologic: Anemia (3%), bruise (1% to 2%), hematoma (1% to 2%), rectal hemorrhage (≤1%)
Respiratory: Epistaxis (≤4%), hemoptysis (≤1%)
<1%:
Cardiovascular: Perioperative blood loss, syncope
Dermatologic: Dermal hemorrhage, skin rash, wound secretion
Endocrine & metabolic: Increased gamma-glutamyl transferase
Gastrointestinal: Gastrointestinal hemorrhage, hematemesis, hematochezia, hemorrhoidal bleeding, melena
Genitourinary: Abnormal uterine bleeding, genital bleeding
Hematologic & oncologic: Hemophthalmos, periorbital hematoma, petechia, postoperative hematoma (incision site), postprocedural hemorrhage, puncture site bleeding, thrombocytopenia, wound hemorrhage
Hepatic: Increased serum alkaline phosphatase, increased serum bilirubin, increased serum transaminases
Hypersensitivity: Allergic angioedema, anaphylaxis
Local: Hematoma at injection site, incision site hemorrhage
Nervous system: Intracranial hemorrhage
Neuromuscular & skeletal: Muscle hemorrhage
Ophthalmic: Conjunctival hemorrhage, retinal hemorrhage
Postmarketing:
Cardiovascular: Thrombosis (with premature discontinuation) (Garcia 2014; Granger 2015)
Hematologic & oncologic: Spinal hematoma (rare: <1%) (El Alayli 2020; Ardebol 2019)
Nervous system: Epidural intracranial hemorrhage (rare: <1%) (El Alayli 2020; Ardebol 2019)
Ophthalmic: Periorbital edema (Ahmad 2018)
US labeling: Severe hypersensitivity reaction (ie, anaphylaxis) to apixaban or any component of the formulation; active pathological bleeding
Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to apixaban or any component of the formulation; lesions or conditions at increased risk of clinically significant bleeding (eg, cerebral infarct [ischemic or hemorrhagic], active peptic ulcer disease with recent bleeding; patients with spontaneous or acquired impairment of hemostasis); hepatic disease associated with coagulopathy and clinically relevant bleeding risk; concomitant systemic treatment with agents that are strong inhibitors of both CYP3A4 and P-glycoprotein (P-gp); concomitant treatment with any other anticoagulant including unfractionated heparin (except at doses used to maintain patency of central venous or arterial catheter), low molecular weight heparins, heparin derivatives (eg, fondaparinux), and oral anticoagulants including warfarin, dabigatran, rivaroxaban except when transitioning to or from apixaban therapy
Disease-related concerns:
• Antiphospholipid syndrome: Use not recommended for patients with triple-positive antiphospholipid syndrome (APS). Patients with APS (especially if triple positive for all 3 antiphospholipid antibodies [lupus anticoagulant, anticardiolipin, and anti-beta 2-glycoprotein I]) may have increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.
• Atrial fibrillation (nonvalvular): When used to prevent stroke in patients with nonvalvular atrial fibrillation, an increased risk of stroke was observed upon transition from apixaban to warfarin in clinical trials. In patients with nonvalvular atrial fibrillation who had an acute ischemic stroke while receiving a direct oral anticoagulant (DOAC) (eg, apixaban), guidelines generally support withholding oral anticoagulation until 1 to 2 weeks after the ischemic stroke (time frame may vary with shorter times for transient ischemic attack or small, nondisabling stroke and longer times for moderate to severe stroke) (AHA/ASA [Kernan 2014]).
• GI/bariatric surgery: Altered absorption: Evaluate the risk versus benefit of possible decreased drug absorption. Impact may be greater for malabsorptive procedures that alter normal intestinal anatomy versus restrictive gastric procedures. Primary site of absorption and interaction with CYP3A4 or P-glycoprotein (P-gp) must be considered. Expression of CYP3A4 is found throughout the entire small intestine but is most prevalent in the duodenum and proximal jejunum. Expression of P-gp is highest in the distal small bowel and colon (Hakeam 2017). More than half of an apixaban dose is absorbed in the distal small bowel or ascending colon. Therefore, distal small bowel and colectomy surgeries could possibly reduce the bioavailability of apixaban. Procedures that preserve the majority of the jejunum (traditional Roux-en-Y gastric bypass) are unlikely to significantly affect apixaban bioavailability (Hakeam 2017). Peak apixaban concentrations and total AUC are reduced by 60% when released in the distal small intestine and further reduced to 90% and 84%, respectively, when released in the ascending colon (Frost 2013). The available data are conflicting for absorption alterations, derived from small populations, and underrepresent individual direct oral anticoagulants and distinct surgeries (Kröll 2017; Kröll 2018; Lee 2013; Rottenstreich 2018).
• Hepatic impairment: Use with caution in moderate impairment (Child-Pugh class B) as there is limited clinical experience in these patients; dosing recommendations cannot be provided. Use in severe hepatic impairment (Child-Pugh class C) is not recommended.
• Kidney impairment: Systemic exposure increases with worsening kidney function. Clinical trials for venous thromboembolism (treatment or prophylaxis) and nonvalvular atrial fibrillation (to prevent stroke and systemic embolism) excluded patients either with serum creatinine >2.5 mg/dL or CrCl <25 mL/minute (Agnelli 2013a; Agnelli 2013b; Connolly 2011; Granger 2011) or with CrCl <30 mL/minute (ADVANCE-1 [Lassen 2009]; ADVANCE-2 [Lassen 2010b]; ADVANCE-3 [Lassen 2010a]). Therefore, there are no clinical trial data on safety or efficacy in patients with advanced chronic kidney disease (CKD). Use with caution in patients with kidney impairment, worsening kidney function, and with interventions such as hemodialysis; dosage adjustment may be required.
• Valvular disease: Avoid use in patients with surgically implanted mechanical heart valve, transcatheter aortic valve replacement with no other indication for anticoagulation, moderate to severe mitral stenosis, or significant rheumatic heart disease. However, may be used in patients with atrial fibrillation and native aortic valve disease, tricuspid valve disease, mitral regurgitation, or surgical bioprosthetic mitral valve replacement when anticoagulation is required (ACC/AHA [Otto 2021]; AHA/ACC/HRS [January 2014]; AHA/ACC/HRS [January 2019]; Gaasch 2020).
Special populations:
• Older adult: Systemic exposure is increased ~32% in patients >65 years of age; however, dose reductions are not required. Dosage reduction is recommended for patients with nonvalvular atrial fibrillation who are ≥80 years of age and either weigh ≤60 kg or with a serum creatinine ≥1.5 mg/dL (133 micromole/L).
Other warnings/precautions:
• Elective surgery/procedure: When temporary interruption is necessary before surgery or a procedure, the timing of discontinuation depends on kidney function and risk for bleeding complications. In patients with CrCl ≥30 mL/minute, discontinue therapy approximately 24 to 48 hours before surgery, depending on risk for bleeding. In patients with CrCl <30 mL/minute, may consider discontinuing therapy ~48 to 72 hours before surgery, depending on risk for bleeding. Consider discontinuing for a longer period of time in patients undergoing major surgery, spinal puncture, or insertion of a spinal or epidural catheter or port. After discontinuation, bridging with low molecular weight heparin or heparin perioperatively is not necessary and may increase risk of bleeding. When there is adequate hemostasis after surgery, may reinstitute therapy after ≥24 hours depending on risk for bleeding. Specific considerations can be found in expert scientific statements and consensus pathways (ACC [Doherty 2017]; ACCP [Douketis 2022b]; AHA [Raval 2017]).
• Body weight: Systemic exposure may be increased by 20% to 30% in patients <50 kg and decreased by 20% to 30% in patients >120 kg; dosage reduction is recommended for patients with nonvalvular atrial fibrillation weighing ≤60 kg and either ≥80 years of age or with a serum creatinine ≥1.5 mg/dL (133 micromole/L).
• Spinal or epidural hematoma: Neuraxial intervention is best performed when the anticoagulant effect of apixaban is low. Guidelines recommend discontinuation of apixaban 72 hours prior to neuraxial intervention; if <72 hours, consider checking anti-factor Xa level (Horlocker 2018). For unanticipated neuraxial intervention, guidelines recommend waiting at least 26 to 30 hours following the last apixaban dose when using prophylactic dosing (eg, 2.5 mg twice daily) before neuraxial puncture and/or catheter manipulation/withdrawal (Gogarten 2010; Horlocker 2018). When higher doses are used (eg, 5 mg twice daily) or in patients with SCr ≥1.5 mg/dL, age ≥80 years, or body weight ≤60 kg, waiting 40 to 75 hours following the last apixaban dose is recommended (Gogarten 2010; Horlocker 2018). Avoid apixaban administration for at least 6 hours following neuraxial puncture or neuraxial catheter withdrawal (Horlocker 2018); if traumatic puncture occurs, avoid apixaban administration for at least 48 hours.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Eliquis: 2.5 mg, 5 mg
Tablet Therapy Pack, Oral:
Eliquis DVT/PE Starter Pack: 5 mg (74 ea)
No
Tablet Therapy Pack (Eliquis DVT/PE Starter Pack Oral)
5 mg (per each): $11.22
Tablets (Eliquis Oral)
2.5 mg (per each): $11.22
5 mg (per each): $11.22
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Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Eliquis: 2.5 mg, 5 mg
Generic: 2.5 mg, 5 mg
Oral: Administer without regard to meals. After hip/knee replacement, initial dose should be administered 12 to 24 hours postoperatively. If patient unable to swallow whole tablets, may crush 5 mg or 2.5 mg tablets and suspend in 60 mL of water, D5W, or apple juice or mix with applesauce; administer immediately. For delivery through a nasogastric tube, crushed tablets may be suspended in 60 mL of water or D5W followed by immediate delivery. Crushed tablets are stable in water, D5W, apple juice, and applesauce for up to 4 hours.
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/202155s032lbl.pdf#page=38, must be dispensed with this medication.
Atrial fibrillation, nonvalvular: To reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF)
Deep vein thrombosis: Treatment of deep vein thrombosis (DVT); to reduce the risk of recurrent DVT following initial therapy
Postoperative venous thromboprophylaxis following hip or knee replacement surgery: Prophylaxis of DVT, which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery
Pulmonary embolism: Treatment of PE; to reduce the risk of recurrent PE following initial therapy
Heparin-induced thrombocytopenia (treatment); Left ventricular thrombus, treatment or prophylaxis
Apixaban may be confused with axitinib
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
The Joint Commission (TJC) requires healthcare organizations that provide anticoagulant therapy to have approved protocols and evidence-based practice guidelines in place to reduce the risk of anticoagulant-associated patient harm. Patients receiving anticoagulants should receive individualized care through a defined process that includes medication selection, dosing (including adjustments for age, kidney function, or liver function), drug-drug interactions, drug-food interactions, other applicable risk factors, monitoring, patient and family education, proper administration, reversal of anticoagulation, management of bleeding events, and perioperative management. This does not apply to routine short-term use of anticoagulants for prevention of venous thromboembolism during procedures or hospitalizations (NPSG.03.05.01).
Substrate of BCRP/ABCG2, CYP1A2 (minor), CYP2C19 (minor), CYP2C8 (minor), CYP2C9 (minor), CYP3A4 (major), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Acalabrutinib: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the adverse/toxic effect of Apixaban. Specifically, the risk for bleeding may be increased. Management: Carefully consider risks and benefits of this combination and monitor closely. Risk C: Monitor therapy
Alemtuzumab: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Anacaulase: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Anagrelide: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Anticoagulants: Apixaban may enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of apixaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Risk X: Avoid combination
Antiplatelet Agents (P2Y12 Inhibitors): May enhance the adverse/toxic effect of Apixaban. Specifically, the risk for bleeding may be increased. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Risk D: Consider therapy modification
Aspirin: May enhance the adverse/toxic effect of Apixaban. Specifically, the risk for bleeding may be increased. Management: Carefully consider risks and benefits of this combination and monitor closely. Risk D: Consider therapy modification
Bromperidol: May enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapy
Caplacizumab: May enhance the anticoagulant effect of Anticoagulants. Management: Avoid coadministration of caplacizumab with antiplatelets if possible. If coadministration is required, monitor closely for signs and symptoms of bleeding. Interrupt use of caplacizumab if clinically significant bleeding occurs. Risk D: Consider therapy modification
Clarithromycin: May increase the serum concentration of Apixaban. Risk C: Monitor therapy
Collagenase (Systemic): Anticoagulants may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Apixaban. Management: Avoid concurrent use of apixaban with strong CYP3A4 inducers whenever possible. Use of a strong CYP3A4 inducer with apixaban should be strictly avoided in any patient who is using an agent (either the CYP3A4 inducer or a third drug) that induces P-gp. Risk D: Consider therapy modification
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Apixaban. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Apixaban. Risk C: Monitor therapy
Dabigatran Etexilate: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of dabigatran etexilate with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Risk X: Avoid combination
Dasatinib: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Deferasirox: Anticoagulants may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Risk C: Monitor therapy
Defibrotide: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination
Deoxycholic Acid: Anticoagulants may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Risk C: Monitor therapy
Edoxaban: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of edoxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Management: Some limited combined use may be indicated during periods of transition from one anticoagulant to another. See the full edoxaban drug monograph for specific recommendations on switching anticoagulant treatment. Risk X: Avoid combination
Factor X (Human): Anticoagulants (Inhibitors of Factor Xa) may diminish the therapeutic effect of Factor X (Human). Risk C: Monitor therapy
Fusidic Acid (Systemic): May increase the serum concentration of Apixaban. Management: Consider alternatives to this combination when possible. Apixaban dose adjustments may be required when used with systemic fusidic acid. Patients using this combination should be monitored extra closely. Risk D: Consider therapy modification
Hemin: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination
Herbal Products with Anticoagulant/Antiplatelet Effects (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Anticoagulants. Bleeding may occur. Risk C: Monitor therapy
Ibritumomab Tiuxetan: Anticoagulants may enhance the adverse/toxic effect of Ibritumomab Tiuxetan. Both agents may contribute to an increased risk of bleeding. Risk C: Monitor therapy
Ibrutinib: May enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapy
Icosapent Ethyl: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Inducers of CYP3A4 (Moderate) and P-glycoprotein: May decrease the serum concentration of Apixaban. Risk C: Monitor therapy
Inducers of CYP3A4 (Strong) and P-glycoprotein: May decrease the serum concentration of Apixaban. Risk X: Avoid combination
Inhibitors of CYP3A4 (Moderate) and P-glycoprotein: May increase the serum concentration of Apixaban. Risk C: Monitor therapy
Inhibitors of CYP3A4 (Strong) and P-glycoprotein: May increase the serum concentration of Apixaban. Management: US labeling recommends a 50% apixaban dose reduction in patients who would otherwise receive 5 or 10 mg twice daily, and avoiding in patients who would otherwise receive 2.5 mg twice daily. Canadian labeling lists any combined use as contraindicated. Risk D: Consider therapy modification
Inotersen: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Kanamycin: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Lecanemab: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the risk of hemorrhage may be increased. Risk C: Monitor therapy
LevETIRAcetam: May diminish the therapeutic effect of Apixaban. Risk C: Monitor therapy
Limaprost: May enhance the adverse/toxic effect of Anticoagulants. The risk for bleeding may be increased. Risk C: Monitor therapy
Lipid Emulsion (Fish Oil Based): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Mesoglycan: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
MiFEPRIStone: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the risk of bleeding may be increased. Risk X: Avoid combination
Naproxen: May enhance the adverse/toxic effect of Apixaban. Specifically, the risk for bleeding may be increased. Naproxen may increase the serum concentration of Apixaban. Management: A comprehensive risk to benefit assessment should be done for all patients before any concurrent use of apixaban and naproxen. If combined, monitor patients extra closely for signs and symptoms of bleeding. Risk D: Consider therapy modification
Nintedanib: Anticoagulants may enhance the adverse/toxic effect of Nintedanib. Specifically, the risk for bleeding may be increased. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents (Nonselective): May enhance the adverse/toxic effect of Apixaban. Specifically, the risk of bleeding may be increased. Management: A comprehensive risk to benefit assessment should be done for all patients before any concurrent use of apixaban and nonsteroidal anti-inflammatory drugs (NSAIDs). If combined, monitor patients extra closely for signs and symptoms of bleeding. Risk D: Consider therapy modification
Nonsteroidal Anti-Inflammatory Agents (Ophthalmic): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents (Topical): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Obinutuzumab: Anticoagulants may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Risk C: Monitor therapy
Omacetaxine: Anticoagulants may enhance the adverse/toxic effect of Omacetaxine. Specifically, the risk for bleeding-related events may be increased. Management: Avoid concurrent use of anticoagulants with omacetaxine in patients with a platelet count of less than 50,000/uL. Risk X: Avoid combination
Omega-3 Fatty Acids: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Oritavancin: May diminish the therapeutic effect of Anticoagulants. Specifically, oritavancin may artificially increase the results of laboratory tests commonly used to monitor anticoagulant effectiveness, which could lead to incorrect decisions to decrease anticoagulant doses. Risk C: Monitor therapy
Pentosan Polysulfate Sodium: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Pirtobrutinib: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the antiplatelet effects of these agents may lead to an increased risk of bleeding with the combination. Risk C: Monitor therapy
Protein C Concentrate (Human): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Rivaroxaban: Anticoagulants may enhance the anticoagulant effect of Rivaroxaban. Refer to separate drug interaction content and to full drug monograph content regarding use of rivaroxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Risk X: Avoid combination
Salicylates: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
St John's Wort: May decrease the serum concentration of Apixaban. Risk X: Avoid combination
Sugammadex: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Sulodexide: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Telavancin: May diminish the therapeutic effect of Anticoagulants. Specifically, telavancin may artificially increase the results of laboratory tests commonly used to monitor anticoagulant effectiveness, which could lead to incorrect decisions to decrease anticoagulant doses. Risk C: Monitor therapy
Thrombolytic Agents: May enhance the anticoagulant effect of Anticoagulants. Management: Monitor for signs and symptoms of bleeding if these agents are combined. For the treatment of acute ischemic stroke, avoidance with anticoagulants is often recommended, see full Lexicomp or drug interaction monograph for details. Risk C: Monitor therapy
Tibolone: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Tipranavir: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Urokinase: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination
Valproate Products: May diminish the therapeutic effect of Apixaban. Risk C: Monitor therapy
Vitamin E (Systemic): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Anticoagulants may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Vorapaxar: May enhance the adverse/toxic effect of Anticoagulants. More specifically, this combination is expected to increase the risk of bleeding. Risk X: Avoid combination
Zanubrutinib: May enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapy
Grapefruit juice may increase levels/effects of apixaban. Management: Advise patients who consume grapefruit juice during therapy to use caution; monitor for increased effects (eg, bleeding).
Information related to the use of direct acting oral anticoagulants in pregnancy is limited; until safety data are available, adequate contraception is recommended during therapy for patients who may become pregnant. Patients planning to become pregnant should be switched to alternative anticoagulants prior to conception (Cohen 2016). The risk of clinically significant uterine bleeding is increased in patients on oral anticoagulants; surgical interventions may be required.
Based on placenta perfusion studies, apixaban is expected to cross the placenta (Bapat 2016).
Information specific to the use of apixaban in pregnancy is limited (Beyer-Westendorf 2016; Beyer-Westendorf 2020; Lameijer 2018; Sessa 2019). Use of direct acting oral anticoagulants increases the risk of bleeding in all patients. When used in pregnancy, there is also the potential for fetal bleeding or subclinical placental bleeding which may increase the risk of miscarriage, preterm delivery, fetal compromise, or stillbirth (Cohen 2016).
Data are insufficient to evaluate the safety of direct acting oral anticoagulants during pregnancy and use in pregnant patients is not recommended (ACOG 2018; ESC [Regitz-Zagrosek 2018]). Agents other than apixaban are preferred for the treatment of AF, PE, or VTE in pregnant patients (Howard 2018; Kearon 2016; Lip 2018; ESC [Regitz-Zagrosek 2018]). Patients should be switched to an alternative anticoagulant if pregnancy occurs during therapy. Fetal monitoring that includes evaluations for fetal bleeding and assessments for risk of preterm delivery are recommended if the direct acting oral anticoagulant is continued (Cohen 2016).
It is not known if apixaban is present in breast milk.
Until safety data are available, direct acting oral anticoagulants are not recommended for use in patients who are breastfeeding; use of an alternative anticoagulant is preferred (ACOG 2018; Cohen 2016).
CBC, aPTT, PT, serum creatinine, and liver function tests prior to initiation, when clinically indicated, and at least annually (AHA/ACC/HRS [January 2014]; Leung 2019)
Routine coagulation testing is not required or necessary for direct oral anticoagulants (DOACs). There are currently no FDA-approved assays or calibration reagents available.
In clinical situations when assessment of the anticoagulant effect is useful (eg, acute care, periprocedural settings, absorption), evaluating a recent creatinine clearance and time since the last dose was ingested is usually sufficient for guiding clinical decisions. No commonly used coagulation tests can definitively exclude the presence of clinically relevant serum concentrations. A prolonged PT suggests clinically relevant serum concentrations are present, but normal PT and aPTT values cannot rule out the presence of apixaban.
If available, the preferred test to rule out clinically significant serum concentrations and quantify anticoagulant effect is anti-factor Xa activity calibrated specifically for apixaban (undetectable anti-factor Xa activity likely excludes clinically relevant drug concentrations). An anti-factor Xa assay calibrated for low molecular weight heparin can rule out clinically relevant drug concentrations, but is not useful for quantification (ACC [Tomaselli 2020]; AHA [Raval 2017]; Leung 2019).
When converting from apixaban to a vitamin K antagonist (VKA), it has been recommended to perform INR testing just prior to each dose of apixaban beginning on day 3 of concurrent therapy with the VKA (Eliquis Canadian product monograph).
In patients receiving apixaban therapy during neuraxial anesthesia (epidural or spinal anesthesia) or spinal/epidural puncture, monitor frequently for signs and symptoms of neurologic impairment (eg, numbness/weakness of legs, bowel/bladder dysfunction).
The International Council for Standardization in Haematology (ICSH) provides examples of apixaban drug levels for the 5 mg twice-daily dose, with an expected median peak of ~132 to 171 ng/mL (5th to 95th percentile of 59 to 321 ng/mL) and an expected median trough of ~63 to 103 ng/mL (5th to 95th percentile, 22 to 230 ng/mL) (Gosselin 2018). These values are intended to be used as guides to provide evidence of drug absorption, not as therapeutic targets (Leung 2019).
Inhibits platelet activation and fibrin clot formation via direct, selective and reversible inhibition of free and clot-bound factor Xa (FXa). FXa, as part of the prothrombinase complex consisting also of factor Va, calcium ions, and phospholipid, catalyzes the conversion of prothrombin to thrombin. Thrombin both activates platelets and catalyzes the conversion of fibrinogen to fibrin.
Onset: 3 to 4 hours
Distribution: Vss: ~21 L
Protein binding: ~87%
Metabolism: Hepatic predominantly via CYP3A4/5 and to a lesser extent via CYP1A2, 2C8, 2C9, 2C19, and 2J2 to inactive metabolites; O-demethylation and hydroxylation are the major sites of transformation; substrate of P-glycoprotein (P-gp) and breast cancer resistant protein (BCRP)
Bioavailability: ~50%
Half-life elimination: ~12 hours (8 to 15 hours) (AHA [Raval 2017])
Time to peak: 3 to 4 hours
Excretion: Urine (~27% as parent drug); feces (biliary and direct intestinal excretion)
Altered kidney function: In subjects with ESRD, the AUC of apixaban was 17% greater compared to those with normal kidney function.
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