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Apixaban

Pronunciation

(a PIX a ban)

Dosage Forms

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

Tablet, Oral:

Eliquis: 2.5 mg, 5 mg

Brand Names: U.S.

  • Eliquis

Pharmacologic Category

  • Anticoagulant
  • Anticoagulant, Factor Xa Inhibitor
  • Direct Oral Anticoagulant (DOAC)

Pharmacology

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.

Distribution

Vss: ~21 L

Metabolism

Hepatic predominantly via CYP3A4/5 and to a lesser extent via CYP1A2, 2C8, 2C9, 2C19, and 2J2 to inactive metabolites; substrate of P-glycoprotein (P-gp) and breast cancer resistant protein (BCRP)

Excretion

Urine (~27% as parent drug); feces

Onset of Action

3 to 4 hours

Time to Peak

3 to 4 hours

Half-Life Elimination

~12 hours

Protein Binding

~87%

Special Populations: Renal Function Impairment

In subjects with ESRD, the AUC of apixaban was 17% greater compared to those with normal renal function. The dialysis clearance of apixaban is approximately 18 mL/minute resulting in a 14% decrease in exposure due to hemodialysis compared to off-dialysis period.

Use: Labeled Indications

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

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

Note: The 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society guidelines for the management of AF recommend oral anticoagulation for patients with nonvalvular AF or atrial flutter with prior stroke, TIA, or a CHA2DS2-VASc score ≥2. As an alternative to warfarin, apixaban may also be used for 3 weeks prior and 4 weeks after cardioversion in patients with AF or atrial flutter of ≥48 hours duration or when the duration is unknown (January 2014)

Postoperative venous thromboprophylaxis following hip or knee replacement surgery: Prophylaxis of deep vein thrombosis, which may lead to pulmonary embolism, in patients who have undergone hip or knee replacement surgery

Pulmonary embolism: Treatment of pulmonary embolism; to reduce the risk of recurrent pulmonary embolism following initial therapy

Contraindications

US labeling: Severe hypersensitivity reaction (ie, anaphylaxis) to apixaban or any component of the formulation; active pathological bleeding

Canadian labeling: Hypersensitivity to apixaban or any component of the formulation; clinically-significant active bleeding (including gastrointestinal bleeding); 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

Dosing: Adult

Deep venous thrombosis: Oral:

Treatment: 10 mg twice daily for 7 days followed by 5 mg twice daily

Reduction in the risk of recurrence: 2.5 mg twice daily after at least 6 months of treatment for DVT

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.

Postoperative venous thromboprophylaxis: Oral:

Hip replacement surgery: 2.5 mg twice daily beginning 12 to 24 hours postoperatively; duration: 35 days

Knee replacement surgery: 2.5 mg twice daily beginning 12 to 24 hours postoperatively; duration: 12 days

Pulmonary embolism (PE): Oral:

Treatment: 10 mg twice daily for 7 days followed by 5 mg twice daily

Reduction in the risk of recurrence: 2.5 mg twice daily after at least 6 months of treatment for PE

Conversion:

Conversion from warfarin to apixaban: Discontinue warfarin and initiate apixaban when INR is <2

Conversion from apixaban to warfarin: Note: Apixaban affects the INR; measuring the INR during coadministration with warfarin therapy may not be useful for determining an appropriate dose of warfarin

US labeling: If continuous anticoagulation is necessary, discontinue apixaban and begin both a parenteral anticoagulant with warfarin when the next dose of apixaban is due; discontinue parenteral anticoagulant when INR reaches an acceptable range

Canadian labeling: Initiate warfarin or other vitamin K antagonist (VKA) at usual starting doses and continue apixaban until INR ≥2, then discontinue apixaban. During concomitant therapy, manufacturer recommends initiating INR testing on day 3 and just prior to each dose of apixaban.

Conversion from apixaban to other non-warfarin anticoagulants (oral or parenteral): Discontinue apixaban and begin taking the new non-warfarin anticoagulant at the usual time of the next scheduled dose of apixaban.

Conversion from other non-warfarin anticoagulants (oral or parenteral) to apixaban: Discontinue the other non-warfarin anticoagulant and begin taking apixaban at the usual time of the next scheduled dose of the other non-warfarin anticoagulant.

Dosage adjustment of apixaban with concomitant medications:

US labeling: For patients receiving dual strong CYP3A4 and P-glycoprotein inhibitors (eg, clarithromycin, ketoconazole, itraconazole, ritonavir) and apixaban doses >2.5 mg twice daily, reduce apixaban dose by 50%. Note: Avoid concomitant use with dual strong CYP3A4 and P-glycoprotein inhibitors if patient is already taking apixaban 2.5 mg twice daily or patient meets 2 of the following criteria: Age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL.

Canadian labeling: Dual CYP3A4 and P-glycoprotein inhibitors: No dosage adjustment necessary for moderate dual inhibitors. Use is contraindicated with strong dual inhibitors.

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

Manufacturer’s labeling: Adults:

US labeling:

Deep vein thrombosis (DVT), pulmonary embolism (PE), reduction in the risk of recurrent DVT and PE: No dosage adjustment is recommended by the manufacturer. However, it should be noted that patients with a serum creatinine >2.5 mg/dL or CrCl <25 mL/minute (as determined by Cockcroft-Gault equation) were excluded from the clinical trials (Agnelli, 2013a; Agnelli, 2013b).

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

Serum creatinine <1.5 mg/dL: No dosage adjustment necessary unless age ≥80 years 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 age ≥80 years 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). In patients with severe or end-stage chronic kidney disease, warfarin remains the anticoagulant of choice (AHA/ACC/HRS [January, 2014]).

ESRD requiring hemodialysis: 5 mg twice daily; reduce to 2.5 mg twice daily if age ≥80 years or body weight ≤60 kg. Note: This recommendation is made solely on a single dose pharmacokinetic and pharmacodynamic (anti-Xa activity) study. Clinical efficacy and long-term safety studies have not been done in this population; therefore, use with caution. In patients with severe or end-stage chronic kidney disease, warfarin remains the anticoagulant of choice (AHA/ACC/HRS [January, 2014]).

Postoperative (hip or knee replacement) venous thromboprophylaxis: No dosage adjustment is recommended by the manufacturer. 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.

Canadian labeling: Note: Estimated creatinine clearance (eCrCl) may be calculated using Cockcroft-Gault equation.

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

eCrCl ≥25 mL/minute: No dosage adjustment necessary. Patients with serum creatinine ≥1.5 mg/dL (SI: ≥133 micromole/L) and either age ≥80 years or body weight ≤60 kg: 2.5 mg twice daily

eCrCl 15 to 24 mL/minute: There are no dosage adjustments provided in manufacturer’s labeling (very limited data).

eCrCl <15 mL/minute: Use is not recommended.

Dialysis: Use is not recommended.

Postoperative (hip or knee replacement) venous thromboprophylaxis, deep vein thrombosis (DVT), pulmonary embolism (PE), reduction in the risk of recurrent DVT and PE:

eCrCl ≥30 mL/minute): No dosage adjustment required.

eCrCl 15 to 29 mL/minute: There are no dosage adjustments provided in manufacturer’s labeling; use with caution as bleeding risk may be increased.

eCrCl <15 mL/minute: Use is not recommended.

Dialysis: Use is not recommended.

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

Dosing: Hepatic Impairment

US labeling:

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.

Canadian labeling:

Mild or moderate impairment (Child-Pugh class A or B): No dosage adjustment required; use with caution.

Severe impairment (Child-Pugh class C): Use is not recommended.

Note: Use is contraindicated in patients with hepatic disease associated with coagulopathy and clinically-relevant bleeding risk.

Dosing: Obesity

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 antifactor 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]).

Administration

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

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).

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. 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. 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. 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. Consider therapy modification

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. 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. Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

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

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Apixaban. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Apixaban. Exceptions: Clarithromycin; Cobicistat; Darunavir; Itraconazole; Ketoconazole (Systemic); Lopinavir; Ombitasvir, Paritaprevir, and Ritonavir; Ritonavir; Saquinavir; Telaprevir. 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. Avoid combination

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. 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). Consider therapy modification

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

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. 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. 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. 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. 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. Consider therapy modification

Factor X (Human): Anticoagulants (Inhibitors of Factor Xa) may diminish the therapeutic effect of Factor X (Human). 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. Consider therapy modification

Hemin: May enhance the anticoagulant effect of Anticoagulants. Avoid combination

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

Ibritumomab: Anticoagulants may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to an increased risk of bleeding. Monitor therapy

Ibrutinib: May enhance the adverse/toxic effect of Anticoagulants. 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. Consider therapy modification

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

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. Consider therapy modification

Nintedanib: Anticoagulants may enhance the adverse/toxic effect of Nintedanib. Specifically, the risk for bleeding may be increased. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

NSAID (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. Consider therapy modification

Obinutuzumab: Anticoagulants may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. 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. Avoid combination

Omega-3 Fatty Acids: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Pentosan Polysulfate Sodium: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

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. 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. 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. Avoid combination

Salicylates: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

St John's Wort: May decrease the serum concentration of Apixaban. Avoid combination

Sugammadex: May enhance the anticoagulant effect of Anticoagulants. 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. Monitor therapy

Tibolone: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Tipranavir: May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Tositumomab and Iodine I 131 Tositumomab: Anticoagulants may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse effects may be increased. Monitor therapy

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

Vitamin E (Systemic): May enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Anticoagulants may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Vorapaxar: May enhance the adverse/toxic effect of Anticoagulants. More specifically, this combination is expected to increase the risk of bleeding. Avoid combination

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 uterine bleeding, acute posthemorrhagic anemia, anal hemorrhage, anaphylaxis, conjunctival hemorrhage, gastrointestinal hemorrhage, genital bleeding, hematoma at injection site, hemophthalmos, hemorrhoidal bleeding, hypersensitivity, hypotension, incision site hemorrhage, increased serum alkaline phosphatase, increased serum AST, increased serum bilirubin, intracranial hemorrhage, muscle hemorrhage, occult blood in urine, perioperative blood loss, periorbital hematoma, petechia, postoperative hematoma (incision site), postprocedural hemorrhage, puncture site bleeding, retinal hemorrhage, syncope, thrombocytopenia, traumatic hematoma, vaginal hemorrhage, wound hemorrhage, wound secretion

ALERT: U.S. 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.

Warnings/Precautions

Concerns related to adverse effects:

• Bleeding: May increase the risk of bleeding; serious, potentially fatal bleeding may occur. Concomitant use of drugs that affect hemostasis increases the risk of bleeding. Monitor for signs and symptoms of bleeding. Discontinue therapy with active pathological hemorrhage and promptly evaluate for bleeding source. No specific antidote exists for apixaban reversal; hemodialysis does not appear to have a substantial impact on apixaban exposure. Although not evaluated in clinical trials, in the event of apixaban-related hemorrhage, the use of prothrombin complex concentrate (PCC), activated prothrombin complex concentrate, or recombinant factor VIIa may be considered. A preclinical study evaluated the impact of different clotting factors in reversing actions of apixaban. A high concentration of apixaban (200 ng/mL) was added to blood from healthy donors in vitro and blood-clotting response was evaluated when prothrombin complex concentrates (PCCs; product not specified), activated prothrombin complex concentrates (aPCCs), and recombinant factor VII (rFVIIa) were added. PCC and aPCC seemed to be more efficient in restoring generation of thrombin, while rFVIIa was the quickest to produce a compact blood clot and most effective in studies with blood circulating through a damaged blood vessel. These lab tests indicate that these agents may reverse the effects of apixaban, but more studies are needed to determine their clinical impact (Escolar, 2012). The use of activated oral charcoal may be considered if ingestion occurred within 2 to 6 hours of presentation.

• 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.

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. Hemodialysis does not appear to have a substantial impact in apixaban exposure; patients with ESRD with or without hemodialysis have not been studied. Dosage reduction is recommended for patients with nonvalvular atrial fibrillation with a serum creatinine ≥1.5 mg/dL and are either ≥80 years of age or weigh ≤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).

• Valvular disease: Safety and efficacy have not been established in patients with prosthetic heart valves or significant rheumatic heart disease (eg, mitral stenosis); use is not recommended. 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.

• Hip fracture surgery: Canadian labeling: Use in patients undergoing hip fracture surgery has not been studied; avoid use in these patients.

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.

• Surgery and invasive procedures: Discontinue apixaban at least 48 hours prior to elective surgery or invasive procedures with a moderate-to-high risk of unacceptable or clinically significant bleeding. Discontinue at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding or where bleeding would not be in a critical location and easily controlled. Anticoagulation bridging during the 24 to 48 hours apixaban is interrupted and prior to the intervention is not generally required. Reinitiate apixaban when adequate hemostasis has been achieved unless oral therapy cannot be administered, then consider administration of a parenteral anticoagulant.

Monitoring Parameters

Renal function prior to initiation, when clinically indicated, and at least annually in all patients (AHA/ACC/HRS [January, 2014]), hepatic function; signs of bleeding. Routine monitoring of coagulation tests is not required. Although not recommended to assess effectiveness, the prothrombin time (PT), INR, and aPTT are prolonged with apixaban. Anti-FXa assay may be helpful (plasma concentrations and anti-FXa activity exhibit linear relationship) in guiding clinical decisions.

When converting from apixaban to a vitamin K antagonist (VKA), Canadian labeling recommends INR testing just prior to each dose of apixaban beginning on day 3 of concurrent therapy with the VKA.

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events were not observed in animal reproduction studies. Data are insufficient to evaluate the safety of oral factor Xa inhibitors during pregnancy; use during pregnancy should be avoided (Bates 2012).

Patient Education

• 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), 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.

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