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Apixaban: Drug information

Apixaban: Drug information
(For additional information see "Apixaban: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning
Discontinuation:

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.

Spinal/Epidural hematoma:

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.

Brand Names: US
  • Eliquis;
  • Eliquis DVT/PE Starter Pack
Brand Names: Canada
  • Eliquis
Pharmacologic Category
  • Anticoagulant;
  • Anticoagulant, Factor Xa Inhibitor;
  • Direct Oral Anticoagulant (DOAC)
Dosing: Adult

The adult dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editor: Edith A Nutescu, PharmD, MS, FCCP.

Heparin-induced thrombocytopenia

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 nonheparin anticoagulant (Kunk 2017; Shatzel 2016; Warkentin 2017).

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 nonheparin anticoagulant, can transition to 5 mg twice daily after platelet count recovery. However, if the parenteral nonheparin anticoagulant is administered for <7 days, transition to 10 mg twice daily; then after a total of 7 days with nonheparin anticoagulation, reduce to 5 mg twice daily (Crowther 2021). For patients without thrombosis, some experts start 5 mg twice daily regardless of whether parenteral anticoagulation was used initially (ASH [Cuker 2018]).

Duration: Not well established:

Heparin-induced thrombocytopenia without thrombosis: Typically, 4 weeks to 3 months (ACCP [Linkins 2012]). Some experts allow for discontinuation of anticoagulation after platelet count recovery, potentially resulting in a shorter duration (ASH [Cuker 2018]).

Heparin-induced thrombocytopenia with thrombosis: Typically, 3 to 6 months (ACCP [Linkins 2012]; ASH [Cuker 2018]).

Nonvalvular atrial fibrillation

Nonvalvular atrial fibrillation (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 mcmol/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 mcmol/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 PCI (ACC [Kumbhani] 2021; Khan 2020; Lopes 2019).

Venous thromboembolism

Venous thromboembolism:

Deep vein thrombosis and/or pulmonary embolism treatment:

Note: For initial therapy, without prior treatment with a parenteral anticoagulant (in hemodynamically stable patients without extensive clot burden) or as transition from parenteral anticoagulant. May be used in patients with active cancer (eg, metastatic disease or receiving chemotherapy) (Agnelli 2020; Bauer 2020; Hull 2022; Leader 2020; McBane 2019).

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) (ACCP [Kearon 2016]).

Unprovoked venous thromboembolism: ≥3 months depending on risk of venous thromboembolism (VTE) recurrence and bleeding (ACCP [Kearon 2016]; ACCP [Kearon 2012]; ISTH [Baglin 2012]).

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 (Lip 2021): Oral: 2.5 mg twice daily (Agnelli 2013a).

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 (Eikelboom 2001; ACCP [Falck-Ytter 2012]); 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 (Pai 2018).

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:

General transition recommendation: Initiate apixaban at the time of the next scheduled dose of the parenteral anticoagulant.

Venous thromboembolism initial treatment transition (alternate recommendation): For acute VTE, some experts start apixaban within 6 to 12 hours after the last dose of a twice daily LMWH regimen or within 12 to 24 hours after a once-daily regimen (Hull 2022).

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) (Hull 2022).

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 (Leung 2019).

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 (Leung 2019).

Transitioning between anticoagulants in the perioperative setting: See 2017 AHA scientific statement, "Management of Patients on Non-Vitamin K Antagonist Oral Anticoagulants in the Acute Care and Periprocedural Setting" and/or 2017 ACC expert consensus decision pathway, “Periprocedural Management of Anticoagulation in Patients with Nonvalvular Atrial Fibrillation.”

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

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 (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 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) (Herndon 2019; Schafer 2018; Stanton 2017) and dialysis patients (Chokesuwattanaskul 2018; Reed 2018; Siontis 2018). 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 (Hull 2018; Manning 2018; Pai 2018).

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) (Wang 2016). 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 (Lip 2018): 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) (Wang 2016). 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) (Wang 2016). According to the manufacturer, no dosage adjustment necessary.

Nonvalvular atrial fibrillation (to prevent stroke and systemic embolism):

Serum creatinine <1.5 mg/dL (133 micromol/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 micromol/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 (AHA/ACC/HRS [January 2014]; AHA/ACC/HRS [January 2019]). Some experts recommend apixaban 2.5 mg twice daily for CrCl 15 to 29 mL/minute (ACCP [Lip 2018]).

Hemodialysis, intermittent (thrice weekly): Not dialyzable to minimally dialyzable (AUC decreased by 14% over 4 hours) (Wang 2016). 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 (Wang 2016). 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 (Mavrakanas 2017). 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 (Siontis 2018).

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 (Chang 2019; KDIGO [Herzog 2011]). In patients with ESKD and atrial fibrillation requiring dialysis, in whom a decision is made to anticoagulate, apixaban or warfarin is considered appropriate (AHA/ACC/HRS [January 2014]; AHA/ACC/HRS [January 2019]).

Dosing: Hepatic Impairment: Adult

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.

Dosing: Older Adult

Refer to adult dosing. Nonvalvular atrial fibrillation (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 mcmol/L), then reduce dose to 2.5 mg twice daily.

Dosing: Obesity: Adult

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 (ISTH [Martin 2021]; expert opinion). 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 (ISTH [Martin 2021]; Kido 2020; Piran 2018; Rocca 2018; Sebaaly 2020). 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 (Upreti 2013). 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 (Hohnloser 2019). 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 (Coons 2020; Kushnir 2019).

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 (ISTH [Martin 2021]).

Dosage Forms: US

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)

Generic Equivalent Available: US

No

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Eliquis: 2.5 mg, 5 mg

Medication Guide and/or Vaccine Information Statement (VIS)

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.

Administration: Adult

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.

Use: Labeled Indications

Deep vein thrombosis: Treatment of deep vein thrombosis (DVT); to reduce the risk of recurrent DVT following initial therapy

Nonvalvular atrial fibrillation: To reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF)

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

Use: Off-Label: Adult

Heparin-induced thrombocytopenia (treatment); Recurrent stroke/transient ischemic attacks (prevention)

Medication Safety Issues
Sound-alike/look-alike issues:

Apixaban may be confused with axitinib

High alert medication:

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.

National Patient Safety Goals:

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, renal 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).

Adverse Reactions (Significant): Considerations
Major bleeding

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 risk factors for bleeding with anticoagulant use:

• Older patients (Ref)

• Race (Ref)

• History of stroke (Ref)

• 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)

• Hypertension (Ref)

• Diabetes (Ref)

• Malignancy (Ref)

• Excessive fall risk (Ref)

Spinal or epidural hematomas

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)

Adverse Reactions

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)

Contraindications

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

Warnings/Precautions

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.

• Renal impairment: Systemic exposure increases with worsening renal 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 renal impairment, worsening renal function, and with interventions such as hemodialysis; dosage adjustment may be required. Consult dosing in renal impairment for additional details.

• 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:

• Acutely ill medical patients: In acutely ill patients (eg, heart failure, respiratory failure) at risk for venous thromboembolism (VTE) receiving apixaban for extended VTE prophylaxis, an increased incidence of major bleeding without greater efficacy was observed with extended apixaban therapy (eg, 30 days) versus low molecular weight heparin (enoxaparin) therapy for 1 to 2 weeks (Goldhaber 2011).

• Elderly: 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 mcmol/L).

Other warnings/precautions:

• Appropriate use: In hemodynamically unstable patients with acute PE or patients with PE requiring thrombolysis or pulmonary embolectomy, the use of apixaban is not recommended as an alternative to unfractionated heparin for initial treatment.

• Appropriate use: Surgical patients: When temporary interruption is necessary before surgery, the timing of discontinuation depends on renal 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, discontinue therapy ~48 to 72 hours or longer 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. When there is adequate hemostasis after surgery, may reinstitute therapy after 24 hours if there is low risk for bleeding or after 48 to 72 hours if there is high risk for bleeding. Other specific considerations can be found in expert scientific statements and consensus pathways (ACC [Doherty 2017]; 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 mcmol/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.

Metabolism/Transport Effects

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

Drug Interactions

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

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. Risk C: Monitor therapy

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

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

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

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

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Kanamycin: May enhance the anticoagulant effect of Anticoagulants. 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 (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

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

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: See full drug monograph for guidelines for the use of alteplase for acute ischemic stroke during treatment with oral anticoagulants. 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

Food Interactions

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).

Reproductive Considerations

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.

Pregnancy Considerations

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).

Breastfeeding Considerations

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).

Monitoring Parameters

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).

Reference Range

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).

Mechanism of Action

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.

Pharmacokinetics

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)

Pharmacokinetics: Additional Considerations

Renal function impairment: In subjects with ESRD, the AUC of apixaban was 17% greater compared to those with normal renal function.

Pricing: US

Tablet Therapy Pack (Eliquis DVT/PE Starter Pack Oral)

5 mg (per each): $10.58

Tablets (Eliquis Oral)

2.5 mg (per each): $10.58

5 mg (per each): $10.58

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Apixatrack (EG);
  • Elikvis (UA);
  • Elimbosis (EG);
  • Eliquis (AE, AR, AT, AU, BB, BE, BH, BR, CH, CL, CN, CO, CY, CZ, DE, DK, EE, EG, FI, FR, GB, GR, HK, HR, HU, ID, IE, IL, IS, JP, KR, KW, LB, LT, LU, LV, MT, MY, NL, NO, PH, PL, PT, QA, RO, RU, SA, SE, SG, SI, SK, TH, TR, ZW);
  • Pixcolt (EG);
  • Tevix (VE)


For country abbreviations used in Lexicomp (show table)

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