Apixaban (Lexi-Drugs)

ALERT: US Boxed Warning
  Discontinuation:
  Spinal/Epidural hematoma:
Pronunciation

(a PIX a ban)

Brand Names: US

Eliquis; Eliquis Starter Pack

Brand Names: Canada

Eliquis

Dosing: Adult

Heparin-induced thrombocytopenia (off-label use): Note: For treatment of acute heparin-induced thrombocytopenia (HIT), either as initial therapy in selected hemodynamically-stable patients or after initial therapy with a parenteral non-heparin anticoagulant (Kunk 2017; Shatzel 2016; Warkentin 2017).

HIT 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 (Coutre 2019). 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:

HIT 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]).

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

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, then reduce dose to 2.5 mg twice daily.

Venous thromboembolism (VTE):

Deep vein thrombosis (DVT) and/or pulmonary embolism (PE) 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.

Oral: 10 mg twice daily for 7 days followed by 5 mg twice daily. Note: In patients with active cancer, apixaban has not been well studied; another anticoagulant (eg, LMWH, edoxaban) is likely more appropriate (ACCP [Kearon 2016]; Raskob 2018).

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 VTE: 3 months (provided provoking risk factor is no longer present) (ACCP [Kearon 2016])

Unprovoked PE or DVT (proximal or isolated distal): ≥3 months depending on risk of 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 VTE 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 2018): Oral: 2.5 mg twice daily (Agnelli 2013a)

VTE prophylaxis:

Total hip arthroplasty (THA) or total knee arthroplasty (TKA) (alternative to LMWH): 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 TKA 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 LMWH or fondaparinux (therapeutic dose) to apixaban:

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

VTE 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 2018b).

Transitioning from unfractionated heparin (UFH) 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 2018b).

Transitioning from warfarin to apixaban: Discontinue warfarin and initiate apixaban as soon as the INR falls to <2 (US labeling). Some experts recommend transitioning to apixaban when the INR is therapeutic and as close as possible to 2, particularly if the risk of bleeding may be increased (Hull 2018b).

Transitioning from apixaban to another anticoagulant:

Transitioning from apixaban to UFH continuous infusion, LMWH, 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 and can complicate INR interpretation if therapy is overlapped. Some experts overlap apixaban with warfarin for 2 or more days. Another alternative is to stop apixaban, start warfarin the same day, and bridge with a parenteral anticoagulant if indicated until the desired INR is reached (Manning 2018b).

Transitioning between direct oral anticoagulants (DOACs): Start the new DOAC when the next dose of the previous DOAC was scheduled to be given.

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.”

Dosage adjustment of apixaban with concomitant medications:

Strong dual CYP3A4 and P-glycoprotein inhibitors (eg, ketoconazole, itraconazole, ritonavir):

Recommended apixaban doses >2.5 mg twice daily: Reduce apixaban dose by 50%.

Recommended apixaban dose of 2.5 mg twice daily: Avoid concomitant use.

Strong dual CYP3A4 and P-glycoprotein inducers (eg, rifampin, carbamazepine, phenytoin, St John’s wort): Avoid concomitant use.

Dosing: Geriatric

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, then reduce dose to 2.5 mg twice daily.

Dosing: Renal Impairment: Adult

Deep vein thrombosis (DVT), pulmonary embolism (PE), reduction in the risk of recurrent DVT and PE: No dosage adjustment is recommended by the manufacturer for any degree of renal impairment. However, patients with a serum creatinine >2.5 mg/dL or CrCl <25 mL/minute (as determined by Cockcroft-Gault equation) were excluded from clinical trials (Agnelli 2013a; Agnelli 2013b). Thus, some experts avoid use in severe renal impairment since efficacy remains untested and cannot be assured (Hull 2018a).

ESRD requiring hemodialysis: According to the manufacturer, no dosage adjustment necessary. Some experts avoid use in ESRD requiring hemodialysis (Hull 2018a). Also see Note: ESRD requiring hemodialysis.

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

Serum creatinine <1.5 mg/dL: No dosage adjustment necessary unless ≥80 years of age and body weight ≤60 kg, then reduce dose to 2.5 mg twice daily (also refer to adult dosing).

Serum creatinine ≥1.5 mg/dL and either ≥80 years of age or body weight ≤60 kg: 2.5 mg twice daily. Note: Patients with a serum creatinine >2.5 mg/dL or CrCl <25 mL/minute (as determined by Cockcroft-Gault equation) were excluded from clinical trials (Connolly 2011; Granger 2011).

Severe or ESRD not requiring hemodialysis: Warfarin remains the anticoagulant of choice (AHA/ACC/HRS [January 2014]). However, in patients who cannot take warfarin, some experts consider apixaban to be a reasonable alternative (Manning 2018a).

ESRD requiring hemodialysis: 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. More recent pharmacokinetic data suggest use of a reduced dose (ie, 2.5 mg twice daily) for patients with ESRD requiring thrice weekly hemodialysis sessions since the approved 5 mg twice-daily dosing resulted in significant supratherapeutic exposure (Mavrakanas 2017). However, these data have not determined whether the long-term use of this dosing will reduce systemic embolic events and bleeding risk in patients with ESRD requiring hemodialysis (Fanikos 2017); some experts avoid anticoagulation in this population unless risk of thromboembolism is very high (KDIGO [Herzog 2011], Manning 2018a). In patients with ESRD requiring hemodialysis, in whom a decision is made to anticoagulate, warfarin remains the anticoagulant of choice (AHA/ACC/HRS [January 2014]). Also see Note: ESRD requiring hemodialysis.

Postoperative (hip or knee replacement) venous thromboprophylaxis: No dosage adjustment is recommended by the manufacturer for any degree of renal impairment. However, it should be noted that patients with either clinically significant renal impairment (ADVANCE-1 [Lassen 2009]), impaired renal function (ADVANCE-2 [Lassen 2010b]), or CrCl <30 mL/minute (as determined by Cockcroft-Gault equation) (ADVANCE-3 [Lassen 2010a]) were excluded from the respective clinical trials.

ESRD requiring hemodialysis: According to the manufacturer, no dosage adjustment necessary. Also see Note: ESRD requiring hemodialysis.

Note: ESRD requiring hemodialysis: Not dialyzable to minimally dialyzable (AUC decreased by 14% over 4 hours) (NCS/SCCM [Frontera 2016]; Wang 2016). The above manufacturer’s recommendations are made solely on a single-dose pharmacokinetic and pharmacodynamic (anti-factor Xa activity) study in only 8 patients (Wang 2016). Clinical efficacy and long-term safety studies have not been done in this population; therefore, due to limited available data, use with caution (AHA [Raval 2017).

Additional recommendations: Geriatric patients ≥65 years of age: CrCl <25 mL/minute: Avoid use due to increased risk of bleeding (Beers Criteria [AGS 2015]).

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: Obesity: Adult

The International Society on Thrombosis and Haemostasis (ISTH) 2016 guideline suggests avoiding the use of apixaban (and other direct oral anticoagulants) in patients with a BMI >40 kg/m2 or weight >120 kg due to the lack of clinical data in this population. If used in a patient with a BMI >40 kg/m2 or weight >120 kg, ISTH suggests measuring peak and trough levels using an anti-factor Xa assay or mass spectrometry. If drug level is below the expected range, ISTH suggests changing to a vitamin K antagonist rather than adjusting the dose of apixaban (ISTH [Martin 2016]).

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)Level of Evidence [C, G]

Data from several case reports and retrospective studies suggest that apixaban may be used in the management of patients with heparin-induced thrombocytopenia (HIT) Ref.

Based on the American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia, apixaban is an effective and recommended agent for heparin-induced thrombocytopenia complicated by thrombosis (HITT) or heparin-induced thrombocytopenia without thrombosis (isolated HIT).

  Recurrent stroke/transient ischemic attacks (prevention)Level of Evidence [G]

Based on the American Heart Association/American Stroke Association (AHA/ASA) guidelines for the prevention of stroke in patients with stroke and transient ischemic attack, apixaban may be considered as an alternative to warfarin for the prevention of recurrent stroke or transient ischemic attack in patients with an acute MI complicated by left ventricular mural thrombus formation or anterior or apical wall-motion abnormalities with a left ventricular ejection fraction <40% who are intolerant to warfarin because of nonhemorrhagic adverse events.

Level of Evidence Definitions
  Level of Evidence Scale
Clinical Practice Guidelines

Atrial Fibrillation:

AAN, “Prevention of Stroke in Nonvalvular Atrial Fibrillation,” February 2014

AHA/ACC/HRS, “2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation,” March 2014.

AHA/ASA, “Oral Antithrombotic Agents for the Prevention of Stroke in Nonvalvular Atrial Fibrillation: A Science Advisory for Healthcare Professionals from the American Heart Association/American Stroke Association,” August 2012

“Antithrombotic Therapy for Atrial Fibrillation: CHEST Guideline and Expert Panel Report,” July 2018

Canadian Cardiovascular Society, “2016 Focused Update of the Canadian Cardiovascular Society Guidelines for the Management of Atrial Fibrillation,” 2016

EHRA, “Updated EHRA practical guide for use of the non-VKA oral anticoagulants,” June 2016

Life-Threatening Hemorrhage:

ACC, “2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants” December 2017

AHA/ASA, “Guidelines for the Management of Spontaneous Intracerebral Hemorrhage,” July 2015

EHRA, “Updated European Heart Rhythm Association Practical Guide on the Use of Non-vitamin K Antagonist Anticoagulants in Patients with Non-valvular Atrial Fibrillation,” October 2015

NCS/SCCM, “Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage,” 2016

Stroke:

AHA/ASA, “Guidelines for Prevention of Stroke in Patients with Stroke and Transient Ischemic Attack,” May 2014

Valvular Heart Disease:

“American Society of Hematology 2018 guidelines for management of venous thromboembolism,” December 2018

AHA/ACC, “2017 AHA/ACC Focused Update of the 2014 Guideline for the Management of Patients with Valvular Heart Disease,” 2017

AHA/ACC, “2014 AHA/ACC Guideline for the Management of Patients with Valvular Heart Disease,” March 2014

“British Thoracic Society Guideline for the Initial Management of Pulmonary Embolism” June 2018

VTE:

“American Society of Hematology 2018 Guidelines for Management of Venous Thromboembolism,” December 2018

Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report,” February 2016

Other:

AHA Scientific Statement, “Management of Patients on Non-Vitamin K Antagonist Oral Anticoagulants in the Acute Care and Periprocedural Setting,” 2017

Administration: 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.

Storage/Stability

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Medication Patient Education with HCAHPS Considerations

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Have patient report immediately to prescriber signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), back pain, numbness or tingling feeling, muscle weakness, paralysis, urinary incontinence, fecal incontinence, a fall hitting the head, dizziness, passing out, loss of strength and energy, confusion, headache, joint pain, angina, wheezing, or joint edema (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Medication Safety Issues
  Sound-alike/look-alike issues:
  High alert medication:
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/2017/202155s017lbl.pdf#page=39, must be dispensed with this medication.

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

Concerns related to adverse effects:

• Bleeding: May increase the risk of bleeding, including severe and potentially fatal bleeding. Concomitant use of drugs that affect hemostasis increases the risk of bleeding. Discontinue therapy with active pathological hemorrhage and promptly evaluate for bleeding source. Andexanet alfa is available for reversal of apixaban in patients experiencing life-threatening or uncontrolled bleeding. Apixaban is highly protein-bound; therefore, hemodialysis is ineffective. Depending on the bleeding severity, activated oral charcoal should be considered if ingestion occurred within 1 to 2 hours of presentation. The following alternative options may also be considered depending specific clinical scenario: 4-factor unactivated prothrombin concentrate (PCC) (eg, Kcentra) or 4-factor activated prothrombin complex concentrate (aPCC) (eg, FEIBA). Some studies and case reports have shown moderate success in correcting coagulation tests with some of these agents; however, correction of coagulation tests does not imply reversal of the anticoagulation effect of the medication (AHA/ASA [Hemphill 2015; EHRA [Heidbuchel 2015]; NCS/SCCM [Frontera 2016]).

• Thromboembolic events: [US Boxed Warning]: Premature discontinuation of any oral anticoagulant, including apixaban, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. 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. If apixaban must be discontinued for reasons other than bleeding or completion of a course of therapy, consider the use of another anticoagulant. In patients with non-valvular atrial fibrillation who had an acute ischemic stroke while receiving a 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, non-disabling stroke and longer times for moderate-to-severe stroke) (AHA/ASA [Kernan 2014]).

Disease-related concerns:

• Acute coronary syndrome (ACS): In a clinical trial evaluating the use of apixaban in addition to standard antiplatelet therapy to reduce the risk of recurrent ischemic events post-ACS, an increased incidence of major bleeding (including intracranial and fatal bleeding) without any significant clinical benefit was observed (Alexander 2011).

• 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. Bleeding risk may be increased in severe renal impairment (CrCl <15 to 29 mL/minute); use with caution. Patients with significant renal impairment (eg, CrCl <30 mL/minute) were excluded from clinical trials. Dosage reduction is recommended for patients with nonvalvular atrial fibrillation and 2 of the 3 following risk factors: Serum creatinine ≥1.5 mg/dL, age ≥80 years, or weight ≤60 kg. Compared to warfarin, apixaban has been shown to be associated with less major bleeding among all ranges of estimated GFRs as determined by initial serum creatinine; however, patients with a serum creatinine >2.5 mg/dL or CrCl <25 mL/minute (as determined by Cockcroft-Gault equation) were excluded from the analysis (Hohnloser 2012). Use with caution in patients on hemodialysis; limited information is available. In patients who develop acute kidney injury during use, closely monitor or consider switching to an alternative anticoagulant due to an increased risk of bleeding in this population (AHA [Raval 2017]).

• Valvular disease: Use is not recommended in patients with prosthetic heart valves or significant rheumatic heart disease (eg, mitral stenosis). However, it may be reasonable to use apixaban as an alternative to vitamin K antagonist in patients with atrial fibrillation and native aortic valve disease, tricuspid valve disease, or mitral regurgitation and a CHA2DS2-VASc score ≥2 (AHA/ACC [Nishimura 2017]). Non-valvular atrial fibrillation is defined as atrial fibrillation that occurs in the absence of rheumatic mitral valve disease, mitral valve repair, or prosthetic heart valve (AHA/ACC/HRS [January 2014]).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

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.

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.

• 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.

• Spinal or epidural hematoma: [US Boxed Warning]: Spinal or epidural hematomas resulting in long-term or permanent paralysis may occur with neuraxial anesthesia (epidural or spinal anesthesia) or spinal/epidural puncture; the risk is increased by the use of indwelling epidural catheters with concomitant administration of other drugs that affect hemostasis (eg, NSAIDS, platelet inhibitors, other anticoagulants), in patients with a history of traumatic or repeated epidural or spinal punctures, a history of spinal deformity or surgery, or if optimal timing between the administration of apixaban and neuraxial procedures is not known. Consider the potential benefit versus risk prior to neuraxial intervention in patients who are anticoagulated or scheduled to be anticoagulated for thromboprophylaxis. In patients who receive both apixaban and neuraxial anesthesia, avoid removal of epidural or intrathecal catheter for at least 24 hours following last apixaban dose; avoid apixaban administration for at least 5 hours following catheter removal. If traumatic puncture occurs, delay administration of apixaban for at least 48 hours. Monitor frequently for signs of neurologic impairment (eg, numbness/weakness of legs, bowel/bladder dysfunction). If neurologic impairment is noted, prompt treatment is necessary.

Geriatric Considerations

The median age of subjects in the ARISTOTLE study (apixaban versus warfarin patients with atrial fibrillation) was 70 years and 31% of subjects were 75 years and older. Age did not affect the incidence of major bleeding or efficacy outcomes (Granger, 2011). According to the manufacturer more than 50% of subjects in the ADVANCE-1 (knee), -2 (knee), and -3 (hip) DVT prevention post joint replacement trials were ≥65 years, and 16% were ≥75 years. The mean ages in these trials were ~61, ~66, and ~61 years, respectively. No differences in efficacy or safety were identified between younger and older subjects.

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events were not observed in animal reproduction studies.

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 (Königsbrügge 2014). Because data are insufficient to evaluate the safety of oral factor Xa inhibitors in pregnant females, use during pregnancy should be avoided (Bates 2012).

Breast-Feeding Considerations

It is not known if apixaban is present in breast milk.

Apixaban is not recommended for use in patients who are breastfeeding; use of alternative anticoagulants is preferred (Bates 2012).

Briggs’ Drugs in Pregnancy & Lactation
Adverse Reactions

>10%: Hematologic & oncologic: Hemorrhage (1% to 12%; major: ≤3%; clinically relevant nonmajor bleeding: 2% to 4%)

1% to 10%:

Endocrine & metabolic: Increased gamma-glutamyl transferase (≤1%)

Gastrointestinal: Nausea (3%), gingival hemorrhage (≤1%)

Genitourinary: Hematuria (≤2%), hypermenorrhea (1%)

Hematologic & oncologic: Anemia (3%), bruise (1% to 2%), hematoma (1% to 2%), postprocedural hemorrhage (≤1%), rectal hemorrhage (≤1%)

Hepatic: Increased serum transaminases (≤1%)

Respiratory: Epistaxis (≤4%), hemoptysis (≤1%)

<1%, postmarketing, and/or case reports: Abnormal hepatic function tests, abnormal uterine bleeding, acute posthemorrhagic anemia, allergic edema, anal hemorrhage, anaphylaxis, conjunctival hemorrhage, gastrointestinal hemorrhage, genital bleeding, hematemesis, hematochezia, hematoma, hematoma at injection site, hemophthalmos, hemorrhoidal bleeding, hypersensitivity, hypotension, incision site hemorrhage, increased serum alkaline phosphatase, increased serum AST, increased serum bilirubin, intracranial hemorrhage, melena, muscle hemorrhage, occult blood in urine, perioperative blood loss, periorbital edema (Ahmad 2018), periorbital hematoma, petechia, postoperative hematoma (incision site), postprocedural hemorrhage, puncture site bleeding, retinal hemorrhage, skin rash, syncope, thrombocytopenia, vaginal hemorrhage, wound hemorrhage, wound secretion

Metabolism/Transport Effects

Substrate of BCRP/ABCG2, CYP1A2 (minor), CYP2C19 (minor), CYP2C8 (minor), CYP2C9 (minor), CYP3A4 (major), P-glycoprotein/ABCB1; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions 

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

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. Exceptions: Acenocoumarol; Warfarin. 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

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

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

CYP3A4 Inducers (Strong): May decrease the serum concentration of Apixaban. Risk X: Avoid combination

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

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Risk D: Consider therapy modification

Dasatinib: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). 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

Estrogen Derivatives: May diminish the anticoagulant effect of Anticoagulants. More specifically, the potential prothrombotic effects of some estrogens and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of estrogens against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Exceptions: Tibolone. Risk D: Consider therapy modification

Factor X (Human): Anticoagulants (Inhibitors of Factor Xa) may diminish the therapeutic effect of Factor X (Human). Risk C: Monitor therapy

Fat Emulsion (Fish Oil Based): May enhance the anticoagulant effect of Anticoagulants. 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

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Anticoagulants. Bleeding may occur. Risk D: Consider therapy modification

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

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

Limaprost: May enhance the adverse/toxic effect of Anticoagulants. The risk for bleeding may be increased. Risk C: Monitor therapy

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Risk D: Consider therapy modification

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. 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: 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

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

Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Risk D: Consider therapy modification

Progestins: May diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of progestins against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Risk D: Consider therapy modification

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

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

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). 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

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

Urokinase: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination

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

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).

Monitoring Parameters

Renal function and CBC prior to initiation, when clinically indicated, and at least annually in all patients (AHA/ACC/HRS [January 2014]; AHA [Raval 2017]), hepatic function; signs of bleeding. Routine monitoring of coagulation tests is not required.

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).

Reference Range

Routine coagulation testing is not required or necessary for 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), 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 antifactor Xa activity calibrated specifically for apixaban (undetectable anti-Xa activity likely excludes clinically relevant drug concentrations). An antifactor Xa assay calibrated for low molecular weight heparin can rule out clinically relevant drug concentrations, but is not useful for quantification. (ACC [Tomaselli 2017]; AHA [Raval 2017]).

Advanced Practitioners Physical Assessment/Monitoring

Obtain renal function tests, CBC, and hepatic function tests; dosage adjustment may be needed with severe hepatic or renal impairment. Consider patients age and weight as dose reduction may be needed. Consider using an antifactor Xa assay or mass spectrometry to help guide treatment. Assess other medicines patient may be taking, alternate therapy or dosage adjustments may be needed. Assess for signs and symptoms of bleeding. Evaluate risks vs benefits before spinal puncture or spinal procedure and before utilizing indwelling epidural catheter or neuroaxial anesthesia. Screen for valvular disease. Instruct patients that premature discontinuation of medication increases the risk of thrombotic events.

Nursing Physical Assessment/Monitoring

Check ordered labs and report any abnormalities. Monitor for and educate patient to report signs and symptoms of bleeding. Educate patient that grapefruit juice may increase the effects of the medication. Instruct patients not to discontinue medication prematurely.

Dosage Forms: US

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

Tablet, Oral:

Eliquis: 2.5 mg, 5 mg

Eliquis Starter Pack: 5 mg

Dosage Forms: Canada

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

Tablet, Oral:

Eliquis: 2.5 mg, 5 mg

Anatomic Therapeutic Chemical (ATC) Classification
  • B01AF02
Generic Available (US)

No

Pricing: US

Tablets (Eliquis Oral)

2.5 mg (per each): $8.88

5 mg (per each): $8.88

Tablets (Eliquis Starter Pack Oral)

5 mg (per each): $8.88

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.

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.

Pharmacodynamics/Kinetics

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)

Pharmacodynamics/Kinetics: Additional Considerations

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

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Dental Health Professional Considerations

At this time there are no coagulation parameters for apixaban to predict the extent of bleeding. Increased bleeding may occur during invasive dental procedures in patients taking apixaban. Medical consult is suggested prior to dental invasive procedures. Routine coagulation testing (INR) is not required, or necessary, for Direct-Acting Oral Anticoagulants (DOAC).

Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Surgical site bleeding may occur. See Effects on Bleeding.

Effects on Bleeding

Apixaban inhibits platelet activation and fibrin clot formation via direct, selective, and reversible inhibition of factor Xa. As with all anticoagulants, bleeding is the major adverse effect of apixaban. Hemorrhage may occur at virtually any site; risk is dependent on multiple variables including the intensity of anticoagulation and patient susceptibility. Medical consult is suggested.

Index Terms

Non-Vitamin K Antagonist Oral Anticoagulant (NOAC) (error-prone acronym)

FDA Approval Date
December 28, 2012
References

Agnelli G, Buller HR, Cohen A, et al; AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013a;368(8):699-708. doi: 10.1056/NEJMoa1207541.[PubMed 23216615]

Agnelli G, Buller HR, Cohen A, et al; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013b;369(9):799-808.[PubMed 23808982]

Ahmad A, Steinhilber S. Periorbital edema from apixaban treatment. J Gen Intern Med. 2018;33(2):232.[PubMed 28913641]

Alexander JH, Lopes RD, James S, et al, “Apixaban With Antiplatelet Therapy After Acute Coronary Syndrome,” N Engl J Med, 2011, 365(8):699-708.[PubMed 21780946]

American Geriatrics Society 2015 Beers Criteria Update Expert Panel. American Geriatrics Society 2015 updated Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2015;63(11):2227-2246. doi:10.1111/jgs.13702[PubMed 26446832]

Baglin T, Bauer K, Douketis J, Buller H, Srivastava A, Johnson G; SSC of the ISTH. Duration of anticoagulant therapy after a first episode of an unprovoked pulmonary embolus or deep vein thrombosis: guidance from the SSC of the ISTH. J Thromb Haemost. 2012;10(4):698-702. doi: 10.1111/j.1538-7836.2012.04662.x.[PubMed 22332937]

Bapat P, Pinto LS, Lubetsky A, et al. Examining the transplacental passage of apixaban using the dually perfused human placenta. J Thromb Haemost. 2016;14(7):1436-1441.[PubMed 27149680]

Bates SM, Greer IA, Middeldorp S, et al. “VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines,” Chest, 2012, 141(2 Suppl):e691-736.[PubMed 22315276]

Connolly SJ, Eikelboom J, Joyner C, et al; AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364(9):806-817.[PubMed 21309657]

Coutre S, Crowther M. Management of heparin-induced thrombocytopenia. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed June 13, 2018.

Cuker A, Arepally GM, Chong BH, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia. Blood Adv.2018;2(22):3360-3392. doi: 10.1182/bloodadvances.2018024489.[PubMed 30482768]

Davis KA, Davis DO. Direct acting oral anticoagulants for the treatment of suspected heparin-induced thrombocytopenia. Eur J Haematol. 2017;99(4):332-335. doi: 10.1111/ejh.12921.[PubMed 28672052]

Eikelboom JW, Quinlan DJ, Douketis JD. Extended-duration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of the randomised trials. Lancet. 2001;358(9275):9-15. doi: 10.1016/S0140-6736(00)05249-1.[PubMed 11454370]

Eliquis (apixaban) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; June 2018.

Eliquis (apixaban) [product monograph]. Kirkland, Quebec, Canada: Pfizer Canada Inc; October 2018.

Ezekwudo DE, Chacko R, Gbadamosi B, et al. Apixaban for treatment of confirmed heparin-induced thrombocytopenia: a case report and review of literature. Exp Hematol Oncol. 2017;6:21. doi: 10.1186/s40164-017-0080-7.[PubMed 28725494]

Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2)(suppl):e278S-e325S. doi: 10.1378/chest.11-2404.[PubMed 22315265]

Fanikos J, Burnett AE, Mahan CE, Dobesh PP. Renal function considerations for stroke prevention in atrial fibrillation. Am J Med. 2017;130(9):1015-1023. doi: 10.1016/j.amjmed.2017.04.015.[PubMed 28502818]

Frontera JA, Lewin JJ 3rd, Rabinstein AA, et al. Guideline for reversal of antithrombotics in intracranial hemorrhage: a statement for healthcare professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care. 2016;24(1):6-46. doi: 10.1007/s12028-015-0222-x.[PubMed 26714677]

Goldhaber SZ, Leizorovicz A, Kakkar AK, et al, “Apixaban versus Enoxaparin for Thromboprophylaxis in Medically Ill Patients,” N Engl J Med, 2011, 365(23):2167-77.[PubMed 22077144]

Granger CB, Alexander JH, McMurray JJ, et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-992.[PubMed 21870978]

Heidbuchel H, Verhamme P, Alings M, et al. Updated European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace. 2015;17(10):1467-1507. doi: 10.1093/europace/euv309.[PubMed 26324838]

Hemphill JC 3rd, Greenberg SM, Anderson CS, et al; American Heart Association Stroke Council; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2015;46(7):2032-2060. doi: 10.1161/STR.0000000000000069.[PubMed 26022637]

Herzog CA, Asinger RW, Berger AK, et al. Cardiovascular disease in chronic kidney disease. A clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int.2011;80(6):572-586. doi: 10.1038/ki.2011.223.[PubMed 21750584]

Hohnloser SH, Hijazi Z, Thomas L, et al, “Efficacy of Apixaban When Compared With Warfarin in Relation to Renal Function in Patients With Atrial Fibrillation: Insights From the ARISTOTLE Trial,” Eur Heart J, 2012, 33(22):2821-30.[PubMed 22933567]

Hull RD, Lip G. Overview of the treatment of lower extremity deep vein thrombosis (DVT). Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed January 18, 2018a.

Hull RD, Lip G. Venous thromboembolism: Anticoagulation after initial management. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed June 13, 2018b.

January CT, Wann LS, Alpert JS, et al; ACC/AHA Task Force Members. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society [published online March 28, 2014]. Circulation. doi:10.1161/CIR.0000000000000041.[PubMed 24682347]

Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines [published correction appears in Chest. 2012;142(6):1698-1704]. Chest. 2012;141(2)(suppl):e419S-e496S. doi: 10.1378/chest.11-2301.[PubMed 22315268]

Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149(2):315-352. doi: 10.1016/j.chest.2015.11.026.[PubMed 26867832]

Kernan WN, Ovbiagele B, Black HR, et al; American Heart Association Stroke Council; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Peripheral Vascular Disease. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association [published correction appears in Stroke. 2015;46(2):e54]. Stroke. 2014;45(7):2160-2236. doi: 10.1161/STR.0000000000000024.[PubMed 24788967]

Khalid S, Daw H. The role of apixaban in the treatment of heparin-induced thrombocytopenia. Cureus. 2017;9(7):e1428. doi: 10.7759/cureus.1428.[PubMed 28884054]

Königsbrügge O, Langer M, Hayde M, Ay C, Pabinger I. Oral anticoagulation with rivaroxaban during pregnancy: a case report. Thromb Haemost. 2014;112(6):1323-1324.[PubMed 25055834]

Kunk PR, Brown J, McShane M, et al. Direct oral anticoagulants in hypercoagulable states. J Thromb Thrombolysis. 2017;43(1):79-85. doi: 10.1007/s11239-016-1420-x.[PubMed 27632140]

Lanau N, Mareque J, Giner L, Zabalza M. Direct oral anticoagulants and its implications in dentistry. A review of literature. J Clin Exp Dent. 2017:9(11):e1346-e1354.[PubMed 29302288]

Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement [published correction appears in N Engl J Med. 2009;361(18):1814]. N Engl J Med. 2009;361(6):594-604.[PubMed 19657123]

Lassen MR, Gallus A, Raskob GE, Pineo G, Cen D, Ramirez LM; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med.2010a;363(26):2487-2498.[PubMed 21175312]

Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P; ADVANCE-2 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010b;375(9717):807-815.[PubMed 20206776]

Linkins LA, Dans AL, Moores LK, et al. Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e495S-e530S. doi: 10.1378/chest.11-2303. Review. Erratum in: Chest.2015;148(6):1529.[PubMed 22315270]

Lip G, Hull RD. Rationale and indications for indefinite anticoagulation in patients with venous thromboembolism. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed February 6, 2018.

Manning WJ. Management of thromboembolic risk in patients with atrial fibrillation and chronic kidney disease. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed January 18, 2018a.

Manning WJ, Singer DE, Lip G. Atrial fibrillation: Anticoagulant therapy to prevent embolization. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed June 13, 2018b.

Martin K, Beyer-Westendorf J, Davidson BL, Huisman MV, Sandset PM, Moll S. Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH. J Thromb Haemost. 2016;14(6):1308-1313.[PubMed 27299806]

Mavrakanas TA, Samer CF, Nessim SJ, Frisch G, Lipman ML. Apixaban pharmacokinetics at steady state in hemodialysis patients. J Am Soc Nephrol. 2017;28(7):2241-2248. doi: 10.1681/ASN.2016090980.[PubMed 28302754]

Nishimura RA, Otto CM, Bonow RO, et al. 2017 AHA/ACC focused update of the 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2017;70(2):252-289. doi: 10.1016/j.jacc.2017.03.011.[PubMed 28315732]

Pai M, Douketis JD. Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed June 13, 2018.

Raskob GE, van Es N, Verhamme P, et al; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2018;378(7):615-624. doi: 10.1056/NEJMoa1711948.[PubMed 29231094]

Raval AN, Cigarroa JE, Chung MK, et al; American Heart Association Clinical Pharmacology Subcommittee of the Acute Cardiac Care and General Cardiology Committee of the Council on Clinical Cardiology; Council on Cardiovascular Disease in the Young; Council on Quality of Care and Outcomes Research. Management of patients on non-vitamin K antagonist oral anticoagulants in the acute care and periprocedural setting: a scientific statement from the American Heart Association [published corrections appear in Circulation. 2017;135(10):e647; Circulation. 2017;135(24):e1144]. Circulation. 2017;135(10):e604-e633. doi:10.1161/CIR.0000000000000477.[PubMed 28167634]

Sharifi M, Bay C, Vajo Z, et al. New oral anticoagulants in the treatment of heparin-induced thrombocytopenia. Thromb Res. 2015;135(4):607-609. doi: 10.1016/j.thromres.2015.01.009.[PubMed 25613925]

Shatzel JJ, Crapster-Pregont M, Deloughery TG. Non-vitamin K antagonist oral anticoagulants for heparin-induced thrombocytopenia. A systematic review of 54 reported cases. Thromb Haemost. 2016;116(2):397-400. doi: 10.1160/TH16-02-0101.[PubMed 27075620]

Tomaselli GF, Mahaffey KW, Cuker A, et al. 2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2017;70(24):3042-3067.[PubMed 29203195]

Wang X, Tirucherai G, Marbury TC, et al. Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end-stage renal disease on hemodialysis. J Clin Pharmacol. 2016;56(5):628-636. doi: 10.1002/jcph.628.[PubMed 26331581]

Warkentin TE, Pai M, Linkins LA. Direct oral anticoagulants for treatment of HIT: update of Hamilton experience and literature review. Blood. 2017;130(9):1104-1113. doi: 10.1182/blood-2017-04-778993.[PubMed 28646118]

Brand Names: International

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

Apixaban (Patient Education – Adult Medication)
You must carefully read the “Consumer Information Use and Disclaimer” below in order to understand and correctly use this information
Pronunciation

(a PIX a ban)

Brand Names: US

Eliquis; Eliquis Starter Pack

Brand Names: Canada

Eliquis

Warning
  • Do not stop taking this drug without talking to your doctor. Stopping this drug when you are not supposed to may raise the chance of blood clots. This includes stroke in certain people. You may need to stop this drug before certain types of dental or health care. Your doctor will tell you when to start taking it again. Follow what your doctor tells you closely.
  • People who have any type of spinal or epidural procedure are more likely to have bleeding problems around the spine when already on this drug. This bleeding rarely happens, but can lead to not being able to move body (paralysis) long-term or paralysis that will not go away. The risk is raised in people who have problems with their spine, a certain type of epidural catheter, or have had spinal surgery. The risk is also raised in people who take any other drugs that may affect how the blood clots like blood-thinner drugs (like warfarin), aspirin, or nonsteroidal anti-inflammatory drugs (NSAIDs). Talk with the doctor.
  • Tell your doctor you use this drug before you have a spinal or epidural procedure. Call your doctor right away if you have any signs of nerve problems like back pain, numbness or tingling, muscle weakness, paralysis, or loss of bladder or bowel control.
  • Talk with your doctor if you have recently had or will be having a spinal or epidural procedure. Some time may need to pass between the use of this drug and your procedure. Talk with your doctor.
What is this drug used for?
  • It is used to thin the blood so that clots will not form.
  • It is used to treat blood clots.
What do I need to tell my doctor BEFORE I take this drug?
  • If you have an allergy to apixaban or any other part of this drug.
  • If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
  • If you have any of these health problems: Active bleeding or liver problems.
  • If you have had a heart valve replaced.
  • If you are taking any of these drugs: Carbamazepine, itraconazole, ketoconazole, phenytoin, rifampin, ritonavir, or St. John’s wort.
  • If you are breast-feeding or plan to breast-feed.
  • This is not a list of all drugs or health problems that interact with this drug.
  • Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this drug with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.
What are some things I need to know or do while I take this drug?
  • Tell all of your health care providers that you take this drug. This includes your doctors, nurses, pharmacists, and dentists. This drug may need to be stopped before certain types of surgery as your doctor has told you. If this drug is stopped, your doctor will tell you when to start taking this drug again after your surgery or procedure.
  • Have blood work checked as you have been told by the doctor. Talk with the doctor.
  • Do not run out of this drug.
  • You may bleed more easily. Be careful and avoid injury. Use a soft toothbrush and an electric razor.
  • Very bad and sometimes deadly bleeding problems have happened with this drug. Talk with the doctor.
  • If you fall or hurt yourself, or if you hit your head, call your doctor right away. Talk with your doctor even if you feel fine.
  • Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this drug while you are pregnant.
What are some side effects that I need to call my doctor about right away?
  • WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:
  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Signs of bleeding like throwing up blood or throw up that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; vaginal bleeding that is not normal; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop.
  • Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight.
  • Dizziness or passing out.
  • Feeling tired or weak.
  • Feeling confused.
  • Headache.
  • Joint pain or swelling.
  • Chest pain or pressure.
  • Wheezing.
What are some other side effects of this drug?
  • All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if you have any side effects that bother you or do not go away.
  • These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.
  • You may report side effects to your national health agency.
How is this drug best taken?
  • Use this drug as ordered by your doctor. Read all information given to you. Follow all instructions closely.
  • Take with or without food.
  • If you have trouble swallowing this drug, it can be crushed and mixed in water, apple juice, or applesauce. If you crush and mix this drug, take it within 4 hours of mixing.
  • To gain the most benefit, do not miss doses.
  • Keep taking this drug as you have been told by your doctor or other health care provider, even if you feel well.
  • Those who have feeding tubes may use this drug. Use as you have been told. Flush the feeding tube after this drug is given.
What do I do if I miss a dose?
  • Take a missed dose as soon as you think about it.
  • If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
  • Do not take 2 doses at the same time or extra doses.
  • If you do not think about the missed dose until the next day, skip the missed dose and go back to your normal time.
How do I store and/or throw out this drug?
  • Store at room temperature.
  • Store in a dry place. Do not store in a bathroom.
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Throw away unused or expired drugs. Do not flush down a toilet or pour down a drain unless you are told to do so. Check with your pharmacist if you have questions about the best way to throw out drugs. There may be drug take-back programs in your area.
General drug facts
  • If your symptoms or health problems do not get better or if they become worse, call your doctor.
  • Do not share your drugs with others and do not take anyone else’s drugs.
  • Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
  • Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
  • Some drugs may have another patient information leaflet. If you have any questions about this drug, please talk with your doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.