Apixaban

Dosage Forms

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

Tablet, Oral:

Eliquis: 2.5 mg, 5 mg

Eliquis DVT/PE Starter Pack: 5 mg

Pharmacology

Mechanism of Action

Inhibits platelet activation and fibrin clot formation via direct, selective and reversible inhibition of free and clot-bound factor Xa (FXa). FXa, as part of the prothrombinase complex consisting also of factor Va, calcium ions, and phospholipid, catalyzes the conversion of prothrombin to thrombin. Thrombin both activates platelets and catalyzes the conversion of fibrinogen to fibrin.

Pharmacokinetics/Pharmacodynamics

Distribution

V_ss: ~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%

Use in Specific Populations

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

Use: Off Label

Heparin-induced thrombocytopenia (treatment)cyes

Data from several case reports and retrospective studies suggest that apixaban may be used in the management of patients with heparin-induced thrombocytopenia (HIT) Davis 2017, Ezekwudo 2017, Khalid 2017, Kunk 2017, Sharifi 2015, Shatzel 2016, Warkentin 2017.

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)yes

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.

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

Dosage and Administration

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).

Heparin-induced thrombocytopenia with or without thrombosis: Oral: 10 mg twice daily for 7 days or until platelet count recovery, whichever is longer, followed by 5 mg twice daily. Note: If initially treated with a parenteral non-heparin anticoagulant, can transition to 5 mg twice daily after platelet count recovery. However, if the parenteral non-heparin anticoagulant is administered for <7 days, transition to 10 mg twice daily; then after a total of 7 days with non-heparin anticoagulation, reduce to 5 mg twice daily (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:

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

Heparin-induced thrombocytopenia without thrombosis 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 (133 mcmol/L), then reduce dose to 2.5 mg twice daily.

Post-percutaneous coronary intervention with stent placement and nonvalvular atrial fibrillation: Oral: 5 mg twice daily unless patient has any 2 of the following: Age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL (133 mcmol/L), then reduce dose to 2.5 mg twice daily; administer with an appropriate antithrombotic regimen including clopidogrel (preferred P2Y12 inhibitor in this situation) with or without aspirin, depending on risks for thrombosis and bleeding (Lopes 2019; Sarafoff 2019).

Venous thromboembolism:

Deep vein thrombosis and/or pulmonary embolism treatment:

Note: For initial therapy, without prior treatment with a parenteral anticoagulant (in hemodynamically stable patients without extensive clot burden) or as transition from parenteral anticoagulant. May be used in patients with active cancer (eg, metastatic disease or receiving chemotherapy), but data are limited. However, in patients with gastrointestinal cancer, low molecular weight heparin (LMWH) is preferred (ASCO [Key 2019]; Bauer 2020; McBane 2019).

Oral: 10 mg twice daily for 7 days followed by 5 mg twice daily.

Duration of therapeutic anticoagulation (first episode, general recommendations): Optimal duration of therapy is unknown and is dependent on many factors, such as whether provoking events were present, patient risk factors for recurrence and bleeding, and individual preferences:

Provoked pulmonary embolism or deep vein thrombosis: 3 months (provided provoking risk factor is no longer present) (ACCP [Kearon 2016])

Unprovoked pulmonary embolism or deep vein thrombosis (proximal or isolated distal): ≥3 months depending on risk of venous thromboembolism recurrence and bleeding (ACCP [Kearon 2016]; ACCP [Kearon 2012]; ISTH [Baglin 2012])

Note: All patients receiving indefinite therapeutic anticoagulation with no specified stop date should be reassessed at periodic intervals.

Indefinite anticoagulation (reduced-intensity dosing for prophylaxis against venous thromboembolism recurrence): Note: For patients at elevated risk of recurrent VTE following at least 6 months of therapeutic anticoagulation. This reduced-intensity regimen is not recommended if indefinite full anticoagulation is indicated (Lip 2018): Oral: 2.5 mg twice daily (Agnelli 2013a)

Venous thromboembolism prophylaxis:

Total hip arthroplasty or total knee arthroplasty (alternative to low-molecular-weight heparin): Oral: 2.5 mg twice daily beginning 12 to 24 hours postoperatively

Duration: Optimal duration of prophylaxis is unknown but it is usually given for a minimum of 10 to 14 days and can be extended for up to 35 days (Eikelboom 2001; ACCP [Falck-Ytter 2012]); some experts suggest a duration in the lower end of the range (10 to 14 days) for total knee arthroplasty or higher end of range (~30 days) for THA (Pai 2018).

Transitioning between anticoagulants: Note: This provides general guidance on transitioning between anticoagulants; also refer to local protocol for additional detail.

Transitioning from another anticoagulant to apixaban:

Transitioning from low-molecular-weight heparin or fondaparinux (therapeutic dose) to apixaban:

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

Venous thromboembolism initial treatment transition (alternate recommendation): For acute VTE, some experts start apixaban within 6 to 12 hours after the last dose of a twice daily LMWH regimen or within 12 to 24 hours after a once-daily regimen (Hull 2018b).

Transitioning from unfractionated heparin continuous infusion to apixaban: Start apixaban when the parenteral anticoagulant infusion is stopped (consult local protocol if the aPTT is above the target range) (Hull 2018b).

Transitioning from warfarin to apixaban: Discontinue warfarin and initiate apixaban as soon as the INR falls to <2 (US labeling).

Transitioning from apixaban to another anticoagulant:

Transitioning from apixaban to unfractionated heparin continuous infusion, low-molecular-weight heparin, or fondaparinux: Start the parenteral anticoagulant when the next dose of apixaban was scheduled to be given.

Transitioning from apixaban to warfarin: Apixaban can elevate the INR, complicating interpretation if overlapped with warfarin. To minimize interference, check INR near the end of apixaban dosing interval. Some experts suggest overlapping apixaban with warfarin for ≥2 days until INR is therapeutic. An alternative is to stop apixaban, start warfarin the same day, and bridge with a parenteral anticoagulant until the desired INR is reached (Leung 2019).

Transitioning between direct oral anticoagulants: Start the new direct oral anticoagulant (DOAC) when the next dose of the previous DOAC was scheduled to be given (Leung 2019).

Transitioning between anticoagulants in the perioperative setting: See 2017 AHA Scientific Statement, "Management of Patients on Non-Vitamin K Antagonist Oral Anticoagulants in the Acute Care and Periprocedural Setting."

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 (133 mcmol/L), then reduce dose to 2.5 mg twice daily.

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

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

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the adverse/toxic effect of Apixaban. Specifically, the risk for bleeding may be increased. Management: Carefully consider risks and benefits of this combination and monitor closely. 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

Caplacizumab: May enhance the anticoagulant 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 (Strong): May decrease the serum concentration of Apixaban. Management: Avoid concurrent use of apixaban with strong CYP3A4 inducers whenever possible. Use of a strong CYP3A4 inducer with apixaban should be strictly avoided in any patient who is using an agent (either the CYP3A4 inducer or a third drug) that induces P-gp. Exceptions: Apalutamide; CarBAMazepine; Fosphenytoin; Phenytoin; RifAMPin. Consider therapy modification

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

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

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

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. Management: Avoid such combinations when possible. If used concomitantly, increase diligence in monitoring for adverse effects (eg, bleeding, bruising, altered mental status due to CNS bleeds). 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

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

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

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. Consider therapy modification

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

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

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 (COX-2 Selective): 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

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

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

Adverse Reactions

>10%: Hematologic & oncologic: Hemorrhage (≤15%; major: ≤2%; clinically relevant nonmajor bleeding: 4%)

1% to 10%:

Endocrine & metabolic: Heavy menstrual bleeding (1%)

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

Genitourinary: Hematuria (≤2%)

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

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

<1%: Abnormal uterine bleeding, acute posthemorrhagic anemia, allergic angioedema, anal hemorrhage, anaphylaxis, conjunctival hemorrhage, dermal hemorrhage, gastrointestinal hemorrhage, genital bleeding, hematemesis, hematochezia, hematoma at injection site, hemophthalmos, hemorrhoidal bleeding, hypersensitivity reaction, hypotension, incision site hemorrhage, increased gamma-glutamyl transferase, increased serum alkaline phosphatase, increased serum bilirubin, increased serum transaminases, intracranial hemorrhage, melena, muscle hemorrhage, perioperative blood loss, periorbital hematoma, petechia, postoperative hematoma (incision site), postprocedural hemorrhage, puncture site bleeding, retinal hemorrhage, skin rash, syncope, thrombocytopenia, wound hemorrhage, wound secretion

Frequency not defined:

Cardiovascular: Thrombosis (with premature discontinuation)

Central nervous system: Epidural intracranial hemorrhage (in patients receiving neuraxial anesthesia or undergoing spinal puncture)

Hematologic & oncologic: Spinal hematoma (in patients receiving neuraxial anesthesia or undergoing spinal puncture)

Postmarketing: Periorbital edema (Ahmad 2018)

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 direct oral anticoagulant (DOAC) (eg, apixaban), guidelines generally support withholding oral anticoagulation until 1 to 2 weeks after the ischemic stroke (time frame may vary with shorter times for transient ischemic attack or small, non-disabling stroke and longer times for moderate-to-severe stroke) (AHA/ASA [Kernan 2014]).

Disease-related concerns:

• Antiphospholipid syndrome: Use not recommended for patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome; safety and efficacy have not been established. Patients positive for all three antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, and anti-beta 2-glycoprotein I) may have increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.
• Bariatric surgery:

– Altered absorption: Evaluate the risk versus benefit of possible decreased drug absorption against the consideration of alternative anticoagulants; efficacy may be decreased after gastric bypass or sleeve gastrectomy. Apixaban’s absorption appears to occur primarily in the small intestine. Peak apixaban concentrations and total AUC are reduced by 60% when released in the distal small intestine and further reduced to 90% and 84%, respectively, when released in the ascending colon (Frost 2013).

– Rivaroxaban: Peak concentrations and AUC were reduced by 56% and 29%, respectively, when released into the proximal small intestine and further reduced in the distal small intestine or colon (manufacturer labeling 2019). Patients with significantly altered GI tracts are represented by small series and case reports (Hakeam 2017). The available data are conflicting for absorption alterations, derived from small populations, and underrepresent individual direct oral anticoagulants and surgeries (Kroll 2017; Kroll 2018; Lee 2013; Rottenstreich 2018).

• Hepatic impairment: Use with caution in moderate impairment (Child-Pugh class B) as there is limited clinical experience in these patients; dosing recommendations cannot be provided. Use in severe hepatic impairment (Child-Pugh class C) is not recommended.
• Renal impairment: Systemic exposure increases with worsening renal function. 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 (133 mcmol/L), 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 (221 mcmol/L) 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. Avoid use of DOACs in patients with mechanical valves or with moderate to severe mitral stenosis. However, a DOAC may be used in patients with atrial fibrillation and native aortic valve disease, tricuspid valve disease, or mitral regurgitation when anticoagulation is required (AHA/ACC/HRS [January 2014, 2019]; AHA/ACC [Nishimura 2017]).

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 (133 mcmol/L).

Other warnings/precautions:

• Appropriate use: In hemodynamically unstable patients with acute PE or patients with PE requiring thrombolysis or pulmonary embolectomy, the use of apixaban is not recommended as an alternative to unfractionated heparin for initial treatment.
• Body weight: Systemic exposure may be increased by 20% to 30% in patients <50 kg and decreased by 20% to 30% in patients >120 kg; dosage reduction is recommended for patients with nonvalvular atrial fibrillation weighing ≤60 kg and either ≥80 years of age or with a serum creatinine ≥1.5 mg/dL (133 mcmol/L).
• Spinal or epidural hematoma: [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

CBC, aPTT, PT, serum creatinine, and liver function tests prior to initiation, when clinically indicated, and at least annually (AHA/ACC/HRS [January 2014]; Leung 2019)

Routine coagulation testing is not required or necessary for direct oral anticoagulants (DOACs). There are currently no FDA-approved assays or calibration reagents available.

In clinical situations when assessment of the anticoagulant effect is useful (eg, acute care, periprocedural settings, absorption), evaluating a recent creatinine clearance and time since the last dose was ingested is usually sufficient for guiding clinical decisions. No commonly used coagulation tests can definitively exclude the presence of clinically relevant serum concentrations. A prolonged PT suggests clinically relevant serum concentrations are present, but normal PT and aPTT values cannot rule out the presence of apixaban.

If available, the preferred test to rule out clinically significant serum concentrations and quantify anticoagulant effect is 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]; Leung 2019).

When converting from apixaban to a vitamin K antagonist (VKA), it has been recommended to perform INR testing just prior to each dose of apixaban beginning on day 3 of concurrent therapy with the VKA (Eliquis Canadian product monograph).

Pregnancy

Pregnancy Considerations

Based on placenta perfusion studies, apixaban is expected to cross the placenta (Bapat 2016).

Information specific to the use of apixaban in pregnancy is limited (Beyer-Westendorf 2016; Königsbrügge 2014; Lameijer 2018). Use of direct acting oral anticoagulants increases the risk of bleeding in all patients. When used in pregnancy, there is also the potential for fetal bleeding or subclinical placental bleeding which may increase the risk of miscarriage, preterm delivery, fetal compromise, or stillbirth (Cohen 2016).

Data are insufficient to evaluate the safety of direct acting oral anticoagulants during pregnancy (Bates 2012) and use in pregnant females is not recommended (Regitz-Zagrosek [ESC 2018]). Agents other than apixaban are preferred for the treatment of AF, PE, or VTE in pregnant patients (Howard 2018; Kearon 2016; Lip 2018; Regitz-Zagrosek [ESC 2018]). Patients should be switched to an alternative anticoagulant if pregnancy occurs during therapy. Fetal monitoring that includes evaluations for fetal bleeding and assessments for risk of preterm delivery are recommended if the direct acting oral anticoagulant is continued (Cohen 2016).

Until safety data are available, adequate contraception is recommended during therapy for females of childbearing potential. Females planning a pregnancy should be switched to alternative anticoagulants prior to conception (Cohen 2016).

Patient Education

What is this drug used for?

• It is used to treat or prevent blood clots.

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; 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
• Severe cerebrovascular disease like 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
• Leaking of urine
• Leaking of stool
• A fall hitting the head
• Dizziness
• Passing out
• Loss of strength and energy
• Confusion
• Headache
• Joint pain
• Chest pain
• Joint swelling
• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.