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brand eliquis 5 mg tablet

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Uses

Embolism Associated with Atrial Fibrillation

Apixaban is used to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Current evidence suggests that apixaban is more effective than aspirin or warfarin in reducing the risk of these thromboembolic events in patients with atrial fibrillation and at least one additional risk factor for stroke, with a similar risk of bleeding complications as aspirin and a lower risk than with warfarin.

Data are lacking on the use of apixaban in patients with prosthetic heart valves, and the manufacturer recommends that the drug not be used in such patients.(See Patients with Prosthetic Heart Valves under Warning/Precautions: Other Warnings/Precautions, in Cautions.)

The American College of Chest Physicians (ACCP), the American College of Cardiology (ACC), the American Heart Association (AHA), the American Stroke Association (ASA), and other experts currently recommend that antithrombotic therapy be administered to all patients with nonvalvular atrial fibrillation (i.e., atrial fibrillation in the absence of rheumatic mitral stenosis, a prosthetic heart valve, or mitral valve repair) who are considered to be at increased risk of stroke, unless such therapy is contraindicated. Recommendations regarding choice of antithrombotic therapy are based on the patient's risk for stroke and bleeding. In general, oral anticoagulant therapy (traditionally warfarin) is recommended in patients with atrial fibrillation who have a moderate to high risk for stroke and acceptably low risk of bleeding, while aspirin or no antithrombotic therapy may be considered in patients at low risk of stroke. Although many risk stratification methods have been used, patients considered to be at increased risk of stroke generally include those with prior ischemic stroke or transient ischemic attack (TIA), advanced age (e.g., 75 years or older), history of hypertension, diabetes mellitus, or congestive heart failure. In addition, population-based studies suggest that female sex is an important risk factor for stroke in patients with atrial fibrillation, particularly in patients 75 years of age or older, and AHA and ASA recommend the use of risk stratification tools that account for age- and sex-specific differences in stroke risk. One such tool is the CHA2DS2-VASc score, an extension of the CHADS2 system (which considers the risk factors congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, and prior stroke/TIA) that adds extra points for female sex (1 point); previous myocardial infarction, peripheral arterial disease, or aortic plaque (1 point); and age 65-74 years (1 point) or 75 years or older (2 points).

The risk of thromboembolism in patients with atrial flutter is not as well established as it is in those with atrial fibrillation. In addition, many patients with atrial flutter have alternating periods of atrial fibrillation. Experts state that antithrombotic therapy in patients with atrial flutter generally should be managed in the same manner as in patients with atrial fibrillation.

Although warfarin traditionally has been used for oral anticoagulation in patients with atrial fibrillation at increased risk of stroke, some experts suggest that non-vitamin K antagonist oral anticoagulants such as apixaban may provide certain advantages over warfarin (e.g., rapid onset of action, predictable anticoagulant effect, no requirement for coagulation monitoring, less potential for drug-drug and drug-food interactions) and may be considered as alternative therapy in selected patients. The non-vitamin K antagonist oral anticoagulants may be particularly useful in patients at moderate to high risk of stroke who are unable to comply with warfarin monitoring requirements or in whom a consistent therapeutic response to warfarin has not been achieved (e.g., because of drug or food interactions), while warfarin may continue to be preferred in patients who have well-controlled international normalized ratios (INRs) (e.g., INR in therapeutic range more than 70% of the time) and are compliant with regular laboratory monitoring. Warfarin generally should remain the treatment of choice in patients with severe renal impairment pending clinical outcomes data with the non-vitamin K antagonist oral anticoagulants in these patients. Because of the lack of direct, comparative studies, the relative efficacy and safety of apixaban and other non-vitamin K antagonist oral anticoagulants (e.g., dabigatran, edoxaban, rivaroxaban) used for the prevention of stroke in patients with nonvalvular atrial fibrillation remains to be fully elucidated. Some evidence from indirect comparisons suggests that there may be important differences (e.g., bleeding risk) among the non-vitamin K antagonist oral anticoagulants; however, results of such analyses should be interpreted with caution because of possible confounding factors (e.g., differences in study design and methods, patient populations, and anticoagulation control). AHA and ASA state that while clinical trials of non-vitamin K antagonist oral anticoagulants were not designed to determine differences in efficacy compared with warfarin in men versus women, apixaban, dabigatran, or rivaroxaban may be a useful alternative to warfarin for the prevention of stroke and systemic thromboembolism in women with paroxysmal or permanent atrial fibrillation and prespecified risk factors (according to CHA2DS2-VASc) who do not have a prosthetic heart valve or hemodynamically important valve disease, severe renal failure (creatinine clearance less than 15 mL/minute), lower body weight (less than 50 kg), or advanced liver disease (impaired baseline clotting function). When selecting an appropriate anticoagulant for patients with atrial fibrillation, experts recommend that the risks versus benefits of such therapy be considered for individual patients based on the absolute and relative risks of stroke and bleeding; patient compliance, preference, tolerance, and comorbidities; cost; availability of agents to reverse anticoagulant effects in case of bleeding complications; and other clinical factors such as renal function, availability of facilities to monitor INR, and degree of current INR control in patients already receiving warfarin.

Efficacy and safety of apixaban for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation were evaluated in a multinational, randomized, double-blind study (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation [ARISTOTLE]) that was designed to demonstrate noninferiority of apixaban compared with warfarin. The study included a total of 18,201 adults with nonvalvular atrial fibrillation and at least one additional risk factor for stroke (i.e., prior stroke, TIA, or systemic embolism; age 75 years or older; arterial hypertension requiring treatment; diabetes mellitus; symptomatic heart failure as defined by New York Heart Association [NYHA] class 2 or higher; left ventricular ejection fraction of 40% or less). At baseline, patients had a mean Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke (doubled) (i.e., CHADS2) score of 2.1; 19% had a history of a previous embolic event (stroke, TIA, or non-CNS systemic embolism), and 57% had been previously treated with warfarin or another vitamin K antagonist prior to study entry. Patients received apixaban at a dosage of 5 mg orally twice daily (or a reduced dosage of 2.5 mg twice daily in patients with at least 2 of the following characteristics: age of 80 years or older, body weight of 60 kg or less, serum creatinine concentration of 1.5 mg/dL or higher) or warfarin in a dosage adjusted to achieve an INR of 2-3. Approximately 5% of patients in the apixaban group received the reduced dosage of the drug. The primary efficacy outcome of the study was a composite of stroke (ischemic or hemorrhagic) or systemic embolism, and the primary safety end point was major bleeding as defined by the International Society of Thrombosis and Hemostasis (ISTH) criteria; all-cause mortality was evaluated as a secondary outcome. Although the study was designed principally to test for noninferiority of apixaban compared with warfarin in reducing the rate of stroke or systemic embolism, a sequential testing strategy was employed where superiority testing was performed on the key outcome measures if noninferiority was achieved; all efficacy analyses were conducted in the intent-to-treat (per randomization) population.

Results of the study indicated that apixaban was not only noninferior, but also was superior to warfarin in reducing the risk of stroke and systemic embolism. After a median follow-up of 1.8 years, the rate of the primary outcome of stroke or systemic embolism was substantially lower in patients receiving apixaban than in those receiving warfarin (annual rate of 1.27 and 1.6%, respectively; relative risk reduction of 21%). Superiority of apixaban over warfarin was largely attributed to a reduction in the risk of hemorrhagic stroke and ischemic stroke with hemorrhagic conversion; there was no difference in the incidence of purely ischemic strokes between the treatment groups. With respect to the primary safety outcome, apixaban also demonstrated superiority over warfarin; major bleeding, including intracranial hemorrhage, occurred at a substantially lower rate in patients receiving apixaban than in those receiving warfarin (annual rate of 2.13 and 3.09%, respectively; relative risk reduction of 31%). In addition, a significant reduction in all-cause mortality was observed with apixaban versus warfarin therapy (annual rate of 3.52 and 3.94%, respectively), which was primarily due to a reduction in cardiovascular-related deaths. The beneficial effects of apixaban over warfarin on stroke risk reduction, major bleeding, and all-cause mortality were consistent across a variety of patient subgroups defined by geographic region, prior warfarin use, age, baseline body weight, CHADS2 scores, renal function, apixaban dosage, type of atrial fibrillation, history of stroke or TIA, and aspirin use at randomization.

Patients who received warfarin in the ARISTOTLE study had an INR within therapeutic range 62% of the time, which is comparable to or better than that reported in other trials of non-vitamin K antagonist oral anticoagulants (e.g., dabigatran, rivaroxaban). Some clinicians have criticized this level of INR control as not being reflective of current practice and suggest that the benefits of apixaban may be less pronounced when compared with patients who achieve better warfarin control (e.g., INR in therapeutic range at least 70% of the time). However, in a subanalysis of the ARISTOTLE study, the benefits of apixaban relative to warfarin appeared to be consistent regardless of the quality of INR control (based on center-level comparison).

Apixaban was evaluated in another randomized double-blind study (Apixaban Versus Acetylsalicylic Acid to Prevent Stroke [AVERROES]) for the prevention of stroke in patients with atrial fibrillation and at least one additional risk factor for stroke (i.e., prior stroke or TIA; age 75 years or older; arterial hypertension requiring treatment; diabetes mellitus requiring treatment; symptomatic heart failure as defined by NYHA class 2 or higher; left ventricular ejection fraction of 35% or less; documented peripheral arterial disease); the study compared apixaban (5 mg twice daily or 2.5 mg twice daily in selected patients) with aspirin (81-324 mg daily) in such patients who had failed or were considered unsuitable for vitamin K antagonist therapy by their clinician. Approximately 5600 patients were included; a major reason for warfarin unsuitability in these patients was difficulty or anticipated difficulty maintaining therapeutic INRs. The AVERROES study was terminated early after a planned interim analysis demonstrated a clear benefit of apixaban over aspirin in reducing the risk of stroke without substantially increasing the risk of bleeding. After a mean follow-up of 1.1 years, the rate of the primary outcome of stroke (ischemic or hemorrhagic) or systemic embolism was substantially lower in patients receiving apixaban than in those receiving aspirin (annual rate of 1.6 and 3.7%, respectively; relative risk reduction of 55%). Although a modest increase in the risk of major bleeding was observed with apixaban versus aspirin, the difference was not statistically significant. The observed benefits of apixaban over aspirin in this study were consistent across major subgroups of patients.

Deep-Vein Thrombosis and Pulmonary Embolism

Prophylaxis

Major Orthopedic Surgery

Apixaban is used for the prevention of postoperative deep-vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone total hip- or knee-replacement surgery. Evidence from randomized, controlled studies suggests that apixaban (2.5 mg twice daily) is more effective than once-daily subcutaneous enoxaparin sodium (40 mg once daily) in reducing the risk of venous thromboembolism in patients undergoing total hip- or knee-replacement surgery, without increasing bleeding risk. Noninferiority of apixaban (2.5 mg twice daily) and the currently recommended US dosing regimen for subcutaneous enoxaparin sodium in knee-replacement surgery (30 mg twice daily) was not established in a controlled study comparing these 2 anticoagulant regimens, although clinically relevant bleeding rates in this study were lower with apixaban. Data currently are lacking on the efficacy and safety of apixaban in patients undergoing hip-fracture surgery.

ACCP recommends routine thromboprophylaxis in all patients undergoing major orthopedic surgery, including total hip- or knee-replacement surgery, because of the high risk of postoperative venous thromboembolism. According to ACCP, thromboprophylaxis with an appropriate antithrombotic agent or an intermittent pneumatic compression device should be continued for at least 10-14 days, and potentially for up to 35 days after surgery in all patients undergoing major orthopedic surgery. Apixaban is considered by ACCP and other clinicians to be an acceptable option for pharmacologic thromboprophylaxis in patients undergoing total hip- or knee-replacement surgery. Although ACCP states a low molecular weight heparin generally is preferred for this use because of relative efficacy and safety and extensive clinical experience, apixaban may be a reasonable choice in situations in which a low molecular weight heparin is not available or cannot be used (e.g., in patients with a history of heparin-induced thrombocytopenia or in those who refuse or are uncooperative with subcutaneous injections). When selecting an appropriate thromboprophylaxis regimen for patients undergoing major orthopedic surgery, factors such as relative efficacy and bleeding risk as well as logistics and compliance issues should be considered. For additional details on prevention of venous thromboembolism in patients undergoing major orthopedic surgery, consult the most recent ACCP Evidence-based Clinical Practice Guidelines on Antithrombotic Therapy and Prevention of Thrombosis available at http://www.chestnet.org.

Apixaban was evaluated for the prevention of venous thromboembolism following total hip- or knee-replacement surgery in 3 multicenter randomized double-blind studies known as the ADVANCE (Apixaban Dose Orally versus Anticoagulation with Enoxaparin) studies. In these studies, apixaban was compared with subcutaneous enoxaparin therapy in patients undergoing elective total knee-replacement (ADVANCE 1 and 2) or total hip-replacement surgery (ADVANCE 3). The primary efficacy end point in all 3 studies consisted of a composite of asymptomatic and symptomatic DVT, nonfatal PE, and all-cause mortality; the primary safety outcome was bleeding. These studies were designed principally to test for noninferiority of apixaban compared with enoxaparin in reducing the rate of the primary efficacy end point; superiority testing was performed if noninferiority was achieved. In all 3 studies, apixaban was administered orally at the same dosage (2.5 mg twice daily, initiated 12-24 hours after surgery), but dosage and timing of enoxaparin sodium administration varied between the studies. In ADVANCE 1, enoxaparin sodium was administered at a dosage of 30 mg twice daily (initiated 12-24 hours after surgery), while in ADVANCE 2 and 3, enoxaparin sodium was administered at a dosage of 40 mg once daily (initiated 12 hours before surgery and continued after surgery according to the investigator's standard of care). Anticoagulant prophylaxis (with apixaban or enoxaparin) was continued postoperatively for 10-14 days in the knee-replacement studies and for 32-38 days in the hip-replacement study. These studies demonstrated that apixaban was more effective than enoxaparin sodium 40 mg once daily in reducing the risk of venous thromboembolism without increasing the risk of bleeding; the improved efficacy of apixaban over enoxaparin was due principally to a reduction in asymptomatic proximal DVT. When compared with enoxaparin sodium 30 mg twice daily (the approved US regimen for enoxaparin thromboprophylaxis after knee-replacement surgery) in the ADVANCE 1 study, apixaban did not meet the noninferiority criteria for the primary efficacy outcome, although apixaban was associated with lower rates of clinically relevant bleeding.

Treatment and Secondary Prevention

Apixaban is used for the treatment of acute DVT and/or PE and for reduction in the risk of recurrent DVT and PE (secondary prevention) following initial anticoagulant therapy.

Efficacy and safety of apixaban for the treatment of acute DVT and/or PE has been established in a randomized, controlled study (Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy [AMPLIFY]) in more than 5000 adults with symptomatic proximal DVT and/or PE. In this study, therapy with apixaban (10 mg orally twice daily for 7 days, followed by 5 mg twice daily for 6 months) was noninferior to conventional anticoagulant therapy (subcutaneous enoxaparin sodium 1 mg/kg every 12 hours for at least 5 days with overlapping warfarin therapy until INR was therapeutic (2 or greater), followed by daily warfarin therapy adjusted to maintain an INR of 2-3 and continued for 6 months) in reducing the incidence of the primary efficacy outcome (composite of symptomatic recurrent venous thromboembolism [defined as fatal or nonfatal PE and DVT] or death related to venous thromboembolism) and superior to the conventional regimen in reducing the incidence of major bleeding. The primary efficacy outcome occurred in 2.3% of patients receiving apixaban and 2.7% of those receiving the conventional regimen, and major bleeding occurred in 0.6 and 1.8% of patients in these respective groups (relative risk reduction of 69%).

Efficacy and safety of apixaban for reducing the risk of recurrent deep-vein thrombosis and pulmonary embolism (i.e., secondary prevention) has been established in another randomized, placebo-controlled study (AMPLIFY-EXT) in approximately 2500 patients who had received 6-12 months of anticoagulant therapy for venous thromboembolism. Some patients in the AMPLIFY-EXT study (approximately one-third) were participants in the AMPLIFY study who had received apixaban or enoxaparin and warfarin therapy and in whom clinicians were uncertain about the need for continuing anticoagulation. In the AMPLIFY-EXT study, extended treatment with apixaban 2.5 or 5 mg twice daily for 1 year reduced the incidence of the primary efficacy outcome (composite of symptomatic recurrent venous thromboembolism [defined as fatal and nonfatal PE and DVT] or death from any cause) without increasing the rate of major bleeding. The 2.5-mg (thromboprophylactic) and 5-mg (treatment) dosages of apixaban used in the extension study showed similar efficacy, and rates of adverse events in the 2 treatment groups were similar to those with placebo. The incidence of thromboembolism in the placebo group in the extension study was 8.8%, indicating an appreciable continuing risk of recurrent venous thromboembolism in the study population following an initial 6-12 months of anticoagulant therapy. Patients with provoked venous thromboembolism related to a transient risk factor (e.g., surgery) were not enrolled in the AMPLIFY and AMPLIFY-EXT studies unless they had another irreversible risk factor requiring 6 months of anticoagulant treatment (e.g., prior venous thromboembolism, immobilization, history of or active cancer, known prothrombotic genotype). In addition, these studies included relatively few patients with cancer, low body weight (less than 60 kg), or renal insufficiency (creatinine clearance less than 50 mL/minute); additional data on efficacy and safety of apixaban therapy in such patients with venous thromboembolism are needed. The relative efficacy and safety of apixaban versus other non-vitamin K antagonist oral anticoagulants (e.g., dabigatran, rivaroxaban) for the treatment of venous thromboembolism remains to be established in controlled, comparative trials.

The manufacturer states that apixaban is not recommended as initial therapy (as an alternative to heparin) in patients with PE who have hemodynamic instability or who may receive thrombolytic therapy or undergo pulmonary embolectomy.

Acute Medical Illness

Current evidence suggests that extended treatment with apixaban is not superior to short-term treatment with subcutaneous enoxaparin for thromboprophylaxis in patients with acute medical illness and is associated with a small but statistically significant increase in the risk of major bleeding. In a randomized, double-dummy placebo-controlled study (Apixaban Dosing to Optimize Protection from Thrombosis [ADOPT]), patients with an acute medical illness (e.g., congestive heart failure, respiratory failure) and moderately to severely restricted mobility received apixaban 2.5 mg twice daily for 30 days or subcutaneous enoxaparin sodium 40 mg once daily for 6-14 days or until hospital discharge; treatment was initiated within 72 hours of hospital admission. The primary efficacy outcome was the 30-day composite of death related to venous thromboembolism, PE, symptomatic DVT, or asymptomatic proximal-leg DVT (determined by systematic bilateral compression ultrasonography on day 30); the primary safety outcome was major bleeding. In approximately 4500 evaluable patients, the primary efficacy outcome occurred in 2.71% of those receiving apixaban and 3.06% who received enoxaparin (13% relative risk reduction with apixaban), a difference that was not statistically significant. However, the rapid increase in the rate of thromboembolic events following discontinuance of enoxaparin treatment suggests the benefits of some type of extended thromboembolism prophylaxis in this patient population; additional study and experience are needed. Apixaban therapy was associated with an increased risk of major bleeding; by day 30, major bleeding had occurred in 0.47% of the patients in the apixaban group and in 0.19% of the enoxaparin-treated patients (2.58-fold risk increase with apixaban).

Acute Coronary Syndrome

Current evidence suggests that addition of apixaban to standard antiplatelet therapy (e.g., aspirin, clopidogrel) does not substantially reduce the rate of recurrent ischemic events in patients with acute coronary syndrome (ACS) and may increase the risk of major, sometimes fatal, bleeding. In a randomized, phase 2, dose-ranging study (Apixaban for Prevention of Acute Ischemic and Safety Events [APPRAISE]), approximately 1700 patients with recent ST-segment elevation or non-ST-segment elevation ACS received apixaban (2.5 mg twice daily, 10 mg once daily, 10 mg twice daily, or 20 mg once daily) or placebo. Nearly all patients also received aspirin (up to 165 mg daily), and 76% of patients also received clopidogrel according to clinician discretion. The primary outcome of the study was major bleeding or clinically relevant nonmajor bleeding. The 2 higher-dose arms of apixaban therapy were discontinued early because of excess total bleeding events. Compared with placebo, apixaban (2.5 mg twice daily or 10 mg once daily for approximately 6 months) increased bleeding in a dose-dependent fashion. There was a trend toward fewer ischemic events (cardiovascular death, myocardial infarction, severe recurrent ischemia, ischemic stroke) in patients given apixaban; overall ischemic event rates and bleeding events in the apixaban group were greater in patients receiving dual antiplatelet therapy (adjunctive aspirin plus clopidogrel) compared with those receiving only adjunctive aspirin. In a follow-up randomized, phase 3 trial (APPRAISE-2), high-risk patients with ACS received apixaban (5 mg twice daily or a reduced dosage of 2.5 mg twice daily in those with a creatinine clearance less than 40 mL/minute) or placebo as adjuncts to antiplatelet therapy with aspirin with or without a P2Y12-receptor antagonist (e.g., clopidogrel, prasugrel, ticagrelor) for prevention of recurrent ischemic events. The trial was stopped early because of excess bleeding, including intracranial and fatal bleeding events, when apixaban was given in conjunction with dual antiplatelet therapy, without evidence of efficacy.

Dosage and Administration

General

Routine coagulation monitoring (e.g., prothrombin time [PT], activated partial thromboplastin time [aPTT], international normalized ratio [INR]) is not necessary with apixaban therapy because of the drug's predictable pharmacokinetic and pharmacodynamic effects. However, in certain situations, such as in the case of overdosage or in patients with hemorrhagic or thromboembolic complications or those requiring emergency surgery, it may be useful to assess the degree of anticoagulation. Although apixaban produces concentration-dependent increases in aPTT, PT, INR, and the Heptest (used to measure inhibition of exogenous activated factor X [factor Xa]), these tests generally are not useful for monitoring the anticoagulant effects of apixaban because of a high degree of inconsistency and variability in results. A chromogenic anti-factor Xa assay (Rotachrom Heparin chromogenic assay) was used during the apixaban development program to measure the effect of apixaban on factor Xa activity. Although the chromogenic assay appears to correlate well with apixaban activity and may produce less variable results than other coagulation tests, a standardized assay specifically calibrated for apixaban currently is not available in most healthcare facilities. The manufacturer does not recommend use of this chromogenic assay for assessing the anticoagulant effects of apixaban.

Apixaban is administered orally twice daily without regard to food. In patients who are unable to swallow whole tablets, apixaban 2.5- or 5-mg tablets may be crushed and suspended in 60 mL of 5% dextrose in water and immediately delivered through a nasogastric feeding tube. The manufacturer states there is no information on administration of crushed or suspended tablets by mouth.

If a dose is missed, the missed dose should be taken as soon as possible on the same day, followed by resumption of the regular twice-daily dosing schedule; the dose should not be doubled to make up for the missed dose.(See Advice to Patients.)

Dosage

Embolism Associated with Atrial Fibrillation

The recommended dosage of apixaban to reduce the risk of stroke and systemic embolism in adults with nonvalvular atrial fibrillation is 5 mg twice daily.

Dosage should be reduced to 2.5 mg twice daily in patients with at least 2 of the following characteristics that can increase drug exposure and thus, increase the risk of bleeding: age 80 years or older, body weight of 60 kg or less, or serum creatinine concentration of 1.5 mg/dL or greater.(See Dosage and Administration: Special Populations.)

Deep-Vein Thrombosis and Pulmonary Embolism

Thromboprophylaxis in Hip- or Knee-Replacement Surgery

For the prevention of deep-vein thrombosis (DVT) and associated pulmonary embolism (PE) in patients who have undergone hip- or knee-replacement surgery, the recommended dosage of apixaban is 2.5 mg twice daily. The initial dose should be administered at least 12-24 hours after surgery, provided hemostasis has been established. The recommended duration of apixaban therapy is 35 days for patients undergoing hip-replacement surgery and 12 days for patients undergoing knee-replacement surgery. In clinical studies, the initial dose of apixaban was administered 12-24 hours after wound closure, and treatment was continued postoperatively for 10-14 days after knee-replacement surgery and for 32-38 days after hip-replacement surgery.

Treatment and Secondary Prevention

For the treatment of acute DVT and/or PE, the recommended dosage of apixaban is 10 mg twice daily for 7 days, followed by 5 mg twice daily; in the principal efficacy trial, apixaban therapy was administered for 6 months. For reduction in the risk of recurrent DVT and PE (secondary prevention) in patients who have received at least 6 months of initial anticoagulant therapy, the recommended dosage of apixaban is 2.5 mg twice daily.

Transitioning to or from Other Anticoagulant Therapy

When transitioning from warfarin to apixaban therapy, the manufacturer states that warfarin should be discontinued and apixaban initiated as soon as the INR is less than 2.

When transitioning from apixaban to warfarin therapy, INR measurements may not be useful for determining an appropriate dose of warfarin because apixaban also can prolong the INR. If continuous anticoagulation is necessary during the conversion, the manufacturer recommends that apixaban be discontinued and a parenteral anticoagulant and warfarin initiated simultaneously at the time of the next scheduled dose of apixaban; the parenteral anticoagulant can then be discontinued once an acceptable INR is achieved with warfarin. Some clinicians have suggested other strategies for transitioning from non-vitamin K antagonist oral anticoagulants (e.g., apixaban, rivaroxaban) to warfarin based on the patient's creatinine clearance and the warfarin start date.

When transitioning to or from therapy with anticoagulants other than warfarin, the manufacturer recommends discontinuing the current anticoagulant and initiating the other anticoagulant at the time of the next scheduled dose.

Managing Anticoagulation in Patients Requiring Invasive Procedures

Apixaban therapy should be temporarily interrupted prior to elective surgery or other invasive procedure to decrease the risk of bleeding; the recommended time interval for discontinuance is based on the anticipated risk of bleeding associated with the procedure and the elimination half-life of the drug. For procedures associated with a moderate to high risk of unacceptable or clinically important bleeding, the manufacturer recommends that apixaban be discontinued at least 48 hours prior to the procedure; some experts suggest a longer time interval for discontinuance (e.g., 5 days prior to a scheduled procedure) to ensure that apixaban has been completely eliminated. For procedures associated with a low risk of bleeding or bleeding in a noncritical location that can be easily controlled, the manufacturer recommends that apixaban be discontinued at least 24 hours prior to the procedure. Bridging anticoagulation generally is not required prior to the procedure or during the 24-48 hours after stopping apixaban. Apixaban therapy should be resumed postoperatively as soon as adequate hemostasis has been established; although experience is limited, some experts suggest that timing of reinitiation be based on procedural bleeding risk and hemostasis.

Coadministration with Dual Inhibitors of Cytochrome P-450 Isoenzyme 3A4 and P-glycoprotein

In patients receiving apixaban dosages exceeding 2.5 mg twice daily (e.g., 5 mg twice daily) who are on concomitant therapy with drugs that are potent inhibitors of both cytochrome P-450 (CYP) isoenzyme 3A4 and P-glycoprotein (e.g., ketoconazole, itraconazole, ritonavir, clarithromycin), the dosage of apixaban should be reduced by 50% (e.g., from 5 mg twice daily to 2.5 mg twice daily). Patients who are already receiving an apixaban dosage of 2.5 mg twice daily should avoid the use of such potent dual inhibitors of CYP3A4 and P-glycoprotein.(See Drug Interactions: Drugs Affecting P-glycoprotein Transport and CYP3A4.)

Special Populations

Hepatic Impairment

No dosage adjustment is necessary in patients with mild hepatic impairment. Because of limited experience, the manufacturer states that dosage recommendations cannot be provided in patients with moderate hepatic impairment. Patients with severe hepatic impairment have not been evaluated; therefore, apixaban should not be used in this population.(See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Renal Impairment

The manufacturer states that dosage adjustment of apixaban based solely on renal impairment is not necessary; however, a reduced dosage of 2.5 mg twice daily is recommended in patients with an elevated serum creatinine concentration of 1.5 mg/dL or greater if they also are 80 years of age or older and/or weigh 60 kg or less.(See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

In patients with nonvalvular atrial fibrillation who have end-stage renal disease (ESRD) and are maintained on hemodialysis, the recommended dosage of apixaban is 5 mg twice daily. In such ESRD patients who are 80 years of age or older or who weigh 60 kg or less, the dosage of apixaban should be reduced to 2.5 mg twice daily. The manufacturer states that these dosage recommendations are based on pharmacokinetic and pharmacodynamic (anti-factor Xa activity) data in ESRD patients maintained on hemodialysis; such patients were not studied in clinical efficacy and safety trials of apixaban.

Geriatric Patients

The manufacturer states that dosage adjustment based solely on age is not necessary in geriatric patients 65 years of age or older; however, a reduced dosage of 2.5 mg twice daily is recommended in patients 80 years of age or older if they also weigh 60 kg or less and/or have a serum creatinine concentration of 1.5 mg/dL or greater.

Body Weight

The manufacturer states that dosage adjustment based solely on body weight is not necessary; however, a reduced dosage of 2.5 mg twice daily is recommended in patients who weigh 60 kg or less if they also are 80 years of age or older and/or have a serum creatinine concentration of 1.5 mg/dL or greater.

Although extremes of body weight (less than 50 kg or more than 120 kg) may alter peak plasma concentrations of and systemic exposure to apixaban, the manufacturer states that no dosage adjustment is necessary based on extremes of body weight. In the principal efficacy study, patients with high body weight (exceeding 120 kg) had decreased drug exposure (approximately 25% lower), but this did not result in loss of efficacy.

Race/Ethnicity

No dosage adjustment is necessary based on race or ethnicity.

Cautions

Contraindications

Active pathologic bleeding.

Severe hypersensitivity reaction (e.g., anaphylactic reactions) to apixaban.

Warnings/Precautions

Warnings

Risk of Thrombosis Following Premature Discontinuance of Anticoagulation

Premature discontinuance of any oral anticoagulant, including apixaban, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events (e.g., stroke). An increased incidence of stroke was observed during the transition from apixaban to warfarin in clinical trials in patients with atrial fibrillation. If discontinuance of apixaban is required for reasons other than pathologic bleeding or completion of a course of therapy, anticoagulant coverage with an alternative anticoagulant should be considered. When transitioning patients from one anticoagulant therapy to another, it is important to ensure continuous anticoagulation while minimizing the risk of bleeding. Particular caution is advised when switching patients from a factor Xa inhibitor to warfarin therapy because of the slow onset of action of warfarin.(See Transitioning to or from Other Anticoagulant Therapy under Dosage and Administration: Dosage.) Patients should be advised about the importance of adhering to the therapeutic regimen and instructed on steps to take if doses are missed.(See Advice to Patients.)

Spinal/Epidural Hematoma

Patients receiving anticoagulants are at risk of developing an epidural or spinal hematoma when concomitant neuraxial (epidural/spinal) anesthesia or spinal puncture is employed; such complications can result in long-term or permanent paralysis. The risk of these complications is increased by postoperative use of indwelling epidural catheters for administration of analgesia or by concomitant use of drugs affecting hemostasis, such as nonsteroidal anti-inflammatory agents (NSAIAs), platelet-aggregation inhibitors, or other anticoagulants. Risk also may be increased in patients with a history of traumatic or repeated epidural or spinal punctures, spinal deformity, or spinal surgery.

Removal of an indwelling epidural or intrathecal catheter should be delayed for at least 24 hours after a dose of apixaban, and at least 5 hours should elapse following removal of the catheter prior to administration of the next apixaban dose. If traumatic puncture occurs, the administration of apixaban should be delayed for 48 hours.

Patients receiving apixaban in the setting of epidural or spinal anesthesia should be monitored frequently for manifestations of neurologic impairment (e.g., numbness or weakness of the legs, bowel or bladder dysfunction). If neurologic compromise is noted, urgent diagnosis and treatment are necessary. Clinicians should consider the potential benefits versus risks of neuraxial intervention in patients who are currently receiving or will receive anticoagulant prophylaxis.

Sensitivity Reactions

Hypersensitivity

Hypersensitivity reactions, including skin rash, allergic edema, and anaphylactic reactions, have been reported in less than 1% of patients receiving apixaban.(See Cautions: Contraindications.)

Other Warnings and Precautions

Bleeding

Apixaban increases the risk of hemorrhage and can cause serious, potentially fatal, bleeding. The drug should be discontinued if active pathological hemorrhage occurs. (See Cautions: Contraindications and also see Advice to Patients.) However, minor or ''nuisance'' bleeding is a common occurrence in patients receiving any anticoagulant and should not readily lead to treatment discontinuance.(See Risk of Thrombosis Following Premature Discontinuance of Anticoagulation under Warnings/Precautions: Warnings, in Cautions.)

In the principal efficacy study of apixaban in patients with nonvalvular atrial fibrillation (ARISTOTLE), major bleeding occurred at an annual rate of 2.13% (327 out of 9088 patients) in patients who received the drug, although the rate was substantially lower with apixaban than with warfarin therapy (rate of 2.13% per year versus 3.09% per year). In this study, bleeding was assessed according to the International Society on Thrombosis and Hemostasis (ISTH) criteria, which defines major bleeding as clinically overt bleeding that is accompanied by one or more of the following events: decrease in hemoglobin of at least 2 g/dL, transfusion of at least 2 units of packed red blood cells, bleeding at a critical site (i.e., intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, or retroperitoneal) or resulting in death.

Risk of bleeding may be increased in patients with renal impairment and in those receiving concomitant therapy with drugs that affect hemostasis (e.g., aspirin or other antiplatelet drugs, fibrinolytics, heparin or other anticoagulants, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, chronic use of NSAIAs) or drugs that are inhibitors of both P-glycoprotein and cytochrome P-450 (CYP) isoenzyme 3A4. (See Drug Interactions.)

Apixaban therapy should be temporarily interrupted prior to any elective surgery or other invasive procedure to reduce the risk of bleeding.(See Managing Anticoagulation in Patients Requiring Invasive Procedures under Dosage and Administration: Dosage.)

There is no specific antidote or reversal agent for apixaban; anticoagulant effects may persist for up to 24 hours or longer after the drug is discontinued. If a serious bleeding event occurs during therapy, the drug should be discontinued and appropriate supportive measures provided. Procoagulant reversal agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (also known as anti-inhibitor coagulant complex), or factor VIIa (recombinant) may be considered for immediate reversal of anticoagulation; however, efficacy and safety of these agents have not been established in clinical studies of patients receiving apixaban. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of apixaban, and there is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) or systemic hemostatics (desmopressin, aprotinin [no longer commercially available in the US]) in patients receiving apixaban. Because of high plasma protein binding, apixaban is not expected to be dialyzable. In the event of an overdosage, activated charcoal may be used to decrease plasma concentrations of apixaban more rapidly.

Patients with Prosthetic Heart Valves

Safety and efficacy of apixaban have not been established in patients with prosthetic heart valves, and use of apixaban is not recommended in such patients.

Specific Populations

Pregnancy

Category B.

There are no adequate or well-controlled studies of apixaban in pregnant women. Animal studies have not demonstrated any evidence of fetotoxic effects; however, increased maternal bleeding was observed when apixaban was administered to pregnant animals at doses ranging from 1-19 times the human exposure at the maximum recommended dose. Because use of apixaban is likely to increase the risk of bleeding during pregnancy and delivery, the manufacturer states that the drug should be used during pregnancy only if the potential benefits justify the potential risks to the mother and fetus.

Lactation

Apixaban is distributed into milk in rats; it is not known whether the drug is distributed into human milk. Because of the potential for serious adverse reactions to apixaban in nursing infants, the manufacturer states that a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Pediatric Use

Safety and efficacy have not been established in pediatric patients younger than 18 years of age

Geriatric Use

No substantial differences in efficacy and safety were observed in geriatric patients 65 years of age or older relative to younger adults in clinical trials. In clinical trials of apixaban in patients with nonvalvular atrial fibrillation or deep-vein thrombosis/pulmonary embolism, no clinically important differences in efficacy or safety were observed among different age groups. Pharmacokinetic effects (systemic exposure and peak plasma concentrations) of apixaban were similar in patients 65 years of age or older and younger adults (18-40 years of age) receiving the drug.

Hepatic Impairment

Pharmacokinetic (systemic exposure and peak plasma concentrations) and pharmacodynamic (inhibition of factor Xa activity) effects of apixaban do not appear to be substantially altered in patients with mild or moderate hepatic impairment.(See Dosage and Administration: Special Populations.) Patients with moderate hepatic impairment may have intrinsic coagulation abnormalities that can affect response to apixaban therapy; however, the impact of this effect is not clear.

Data are lacking in patients with severe hepatic impairment, and the manufacturer recommends that apixaban not be used in such patients.

Renal Impairment

Pharmacokinetic (systemic exposure and peak plasma concentrations) and pharmacodynamic (inhibition of factor Xa activity) effects of apixaban do not appear to be substantially altered in patients with renal impairment (mild, moderate, or severe) compared with those with normal renal function. Although results of a pharmacokinetic study showed an approximate 44% increase in systemic exposure to apixaban in patients with severe renal impairment (i.e., creatinine clearance of 15 mL/minute) compared with those with normal renal function, this degree of change was considered to be modest. In the principal clinical study of the drug, patients with moderate to severe renal impairment had higher rates of bleeding regardless of treatment (apixaban or warfarin). Dosage adjustment based on renal function alone does not appear to be necessary, but is recommended in patients with renal impairment who meet additional criteria for dosage modification.(See Dosage and Administration: Special Populations.)

The manufacturer states that recommendations regarding use of apixaban in patients with creatinine clearance less than 15 mL/minute or in those receiving dialysis cannot be made.

Race/Ethnicity

Pharmacokinetics of apixaban do not appear to be substantially altered by race or ethnicity. In several studies in which healthy individuals of different ethnic or racial origins (Caucasian, Asian, and African-American) received apixaban, pharmacokinetic parameters (e.g., peak plasma concentrations, half-life, time to steady state) of the drug were similar regardless of race or ethnicity.

Common Adverse Effects

Bleeding was the most common adverse effect reported in clinical trials of apixaban.

Drug Interactions

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Apixaban is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4/5, and to a lesser extent by CYP isoenzymes 1A2, 2C8, 2C9, 2C19, and 2J2. Although pharmacokinetic interactions are possible with drugs that inhibit or induce CYP3A4/5, in vitro studies indicate that the potential may be low because of apixaban's multiple routes of elimination.(See Drug Interactions: Drugs Affecting P-glycoprotein Transport and CYP3A4.)

In vitro studies indicate that apixaban does not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 3A4/5, or 2C19 nor induce CYP isoenzymes 1A2, 2B6, or 3A4/5; therefore, pharmacokinetic interactions are not expected with drugs that are metabolized by these isoenzymes.

Drugs Affecting P-glycoprotein Transport

Apixaban is a substrate of the efflux transporter P-glycoprotein; inhibitors or inducers of this transport protein may potentially alter apixaban exposure.(See Drug Interactions: Drugs Affecting P-glycoprotein Transport and CYP3A4.) Apixaban does not substantially inhibit P-glycoprotein.

Drugs Affecting P-glycoprotein Transport and CYP3A4

Since apixaban is a substrate of both P-glycoprotein and CYP3A4, concomitant use of drugs that inhibit P-glycoprotein and CYP3A4 can increase exposure (peak plasma concentrations and area under the plasma concentration-time curve [AUC]) to apixaban and increase the risk of bleeding. In patients receiving apixaban dosages exceeding 2.5 mg twice daily (e.g., 5 mg twice daily), the dosage of apixaban should be reduced by 50% (e.g., from 5 mg twice daily to 2.5 mg twice daily) if concomitant therapy with potent dual inhibitors of P-glycoprotein and CYP3A4 (e.g., clarithromycin, itraconazole, ketoconazole, ritonavir) is administered. In patients already receiving apixaban 2.5 mg twice daily, concomitant administration of potent dual inhibitors of P-glycoprotein and CYP3A4 should be avoided. Although concomitant administration of other, less potent inhibitors of CYP3A4 and P-glycoprotein (e.g., diltiazem, naproxen) also may increase exposure to apixaban, dosage adjustments generally are not necessary.

Conversely, drugs that induce P-glycoprotein and CYP3A4 can reduce plasma concentrations of apixaban and increase the risk of stroke. Concomitant use of apixaban and potent dual inducers of P-glycoprotein and CYP3A4 (e.g., carbamazepine, phenytoin, rifampin, St. John's wort [Hypericum perforatum]) should be avoided.

Diltiazem

Concomitant administration of apixaban and diltiazem (a moderate CYP3A4 and weak P-glycoprotein inhibitor) increased AUC and peak plasma concentrations of apixaban by 1.4- and 1.3-fold, respectively; however, the manufacturer of apixaban states that no dosage adjustments are necessary.

Ketoconazole

Concomitant administration of apixaban and ketoconazole (a strong inhibitor of both P-glycoprotein and CYP3A4) substantially increased the AUC and peak plasma concentration of apixaban by 2- and 1.6-fold, respectively. Dosage of apixaban should be reduced to 2.5 mg twice daily with such concomitant therapy.(See Dosage and Administration: Dosage.) Concomitant use of apixaban and ketoconazole should be avoided in patients who have 2 or more of the following characteristics: age 80 years or older, body weight 60 kg or less, serum creatinine concentration of 1.5 mg/dL or greater.

Naproxen

Concomitant administration of apixaban and naproxen (a P-glycoprotein inhibitor) increased AUC and peak plasma concentrations of apixaban by 1.5- and 1.6-fold, respectively; however, no dosage adjustment is necessary.

Apixaban did not substantially alter the pharmacokinetics of naproxen; however, a 50-60% increase in anti-factor Xa activity was observed with such concomitant therapy.

Rifampin

Concomitant administration of apixaban and rifampin (a strong inducer of both P-glycoprotein and CYP3A4) decreased AUC and peak plasma concentrations of apixaban by 54 and 42%, respectively; concomitant use of these drugs should be avoided.

Drugs Affecting Hemostasis

Concomitant use of apixaban and drugs that affect hemostasis (e.g., aspirin or other antiplatelet drugs, heparin or other anticoagulants, fibrinolytics, selective serotonin reuptake inhibitors [SSRIs], serotonin norepinephrine reuptake inhibitors [SNRIs], nonsteroidal anti-inflammatory agents [NSAIAs]) increases the risk of bleeding.

Amiodarone

Efficacy and safety end points for apixaban compared with warfarin did not appear to be altered by concomitant administration of amiodarone in the principal efficacy study of apixaban in patients with nonvalvular atrial fibrillation.

Aspirin

In the principal efficacy study of apixaban, bleeding risk was increased in patients who received concomitant apixaban and aspirin therapy. Additionally, a placebo-controlled study of patients with acute coronary syndromes was terminated early after an increased risk of bleeding was observed in patients receiving apixaban in combination with aspirin and clopidogrel.

In drug interaction studies in healthy individuals, apixaban did not substantially alter the pharmacokinetics of aspirin, and a pharmacodynamic interaction was not observed with such concomitant therapy.

Atenolol

Concomitant administration of apixaban and atenolol in healthy individuals did not appreciably alter the pharmacokinetics of either drug.

Clopidogrel

No pharmacodynamic interactions (e.g., anti-factor Xa activity) were observed with concomitant apixaban and clopidogrel therapy. However, a placebo-controlled study (APPRAISE-2) of patients with acute coronary syndromes was terminated early after an increased risk of bleeding was observed in patients receiving apixaban in combination with aspirin and clopidogrel.

Digoxin

In drug interaction studies conducted in healthy individuals, apixaban did not substantially alter the pharmacokinetics of digoxin.

Enoxaparin

In a study in healthy individuals, concomitant administration of apixaban and enoxaparin had no effect on the pharmacokinetics of apixaban, but had an additive effect on anti-factor Xa activity. The increased pharmacodynamic effect was considered to be modest. When administration of apixaban and enoxaparin was separated by 6 hours in this study, the additive effect on anti-factor Xa activity was attenuated.

Famotidine

Famotidine did not substantially alter the pharmacokinetics of apixaban in healthy individuals.

Prasugrel

Concomitant administration of apixaban and prasugrel in healthy individuals did not appreciably alter the pharmacokinetics of either drug.

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