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Apixaban

Medically reviewed on Nov 15, 2018

Pronunciation

See also: Plavix

(a PIX a ban)

Index Terms

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

Dosage Forms

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

Brand Names: U.S.

  • Eliquis
  • Eliquis Starter Pack

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; O-demethylation and hydroxylation are the major sites of transformation; substrate of P-glycoprotein (P-gp) and breast cancer resistant protein (BCRP)

Excretion

Urine (~27% as parent drug); feces (biliary and direct intestinal excretion)

Onset of Action

3 to 4 hours

Time to Peak

3 to 4 hours

Half-Life Elimination

~12 hours (8 to 15 hours) (AHA [Raval 2017])

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.

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

Off Label Uses

Heparin-induced thrombocytopenia (treatment)

Data from several case reports suggest that apixaban may be used in the management of patients with heparin-induced thrombocytopenia (HIT) [Davis 2017], [Ezekwudo 2017], [Khalid 2017], [Shatzel 2016], [Warkentin 2017]. The optimal use of apixaban in management of HIT is unknown and therefore, dosing recommendations cannot be made at this time due to paucity of data. However, some suggest using the dosing regimen recommended for the treatment of acute venous thromboembolism as either initial therapy of acute HIT in selected hemodynamically stable patients or after initial therapy with a parenteral non-heparin anticoagulant [Coutre 2018].

Recurrent stroke/transient ischemic attacks (prevention)

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 less than 40% who are intolerant to warfarin because of nonhemorrhagic adverse events.

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

Dosing: Adult

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

Adults:

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 the clinical trials (Agnelli 2013a; Agnelli 2013b). Some experts avoid use in severe renal impairment (Hull 2018).

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

ESRD requiring hemodialysis: According to the manufacturer, no dosage adjustment necessary unless if ≥80 years of age or body weight ≤60 kg, then reduce to 2.5 mg twice daily. More recent pharmacokinetic data suggests 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 still 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 2018). 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

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

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]).

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 (High risk with Inducers). Monitor therapy

Bromperidol: May enhance the adverse/toxic effect of Anticoagulants. Monitor therapy

Clarithromycin: May increase the serum concentration of Apixaban. 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 (High risk with Inducers). 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. 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 (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). Consider therapy modification

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

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

Fat Emulsion (Fish Oil Based): May enhance the anticoagulant effect of Anticoagulants. 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 Tiuxetan: Anticoagulants may enhance the adverse/toxic effect of Ibritumomab Tiuxetan. 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

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

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

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

MiFEPRIStone: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the risk of bleeding may be increased. 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. 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

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. 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

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. Monitor therapy

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

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

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

Sulodexide: May enhance the anticoagulant effect of Anticoagulants. 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. 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 (High risk with Inducers). 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 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

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, 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.

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).

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).

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), 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.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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