Eliquis

Apixaban.

ELIQUIS film-coated tablets are available for oral administration in strengths of 2.5 mg and 5 mg of apixaban.
Excipients/Inactive Ingredients: Anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate. Film-coating: Lactose monohydrate, hypromellose, titanium dioxide, triacetin, and yellow iron oxide (2.5 mg tablets) or red iron oxide (5 mg tablets).

Pharmacology: Pharmacodynamics: Apixaban, a selective inhibitor of the coagulation factor Xa (FXa), is chemically described as 1-(4-Methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide. Its molecular formula is C₂₅H₂₅N₅O₄, which corresponds to a molecular weight of 459.5.
Apixaban is a white to pale yellow powder. At physiological pH (1.2-6.8), apixaban does not ionize; its aqueous solubility across the physiological pH range is ~0.04 mg/mL.
The pharmacodynamic effects of apixaban are reflective of the mechanism of action (FXa inhibition). As a result of FXa inhibition, apixaban prolongs clotting tests such as prothrombin time (PT), INR and activated partial thromboplastin time (aPTT). Changes observed in these clotting tests at the expected therapeutic dose are small and subject to a high degree of variability. They are not recommended to assess the pharmacodynamic effects of apixaban. In the thrombin time generation assay, apixaban reduced endogenous thrombin potential, a measure of thrombin generation in human plasma.
Apixaban also demonstrates anti-FXa activity as evident by reduction in FXa enzyme activity in the Rotachrom Heparin chromogenic assay data from clinical studies. Anti-FXa activity exhibits a close direct linear relationship with apixaban plasma concentration, reaching maximum values at the time of apixaban peak plasma concentrations. The relationship between apixaban plasma concentration and anti-FXa activity is linear over a wide dose range of apixaban. The dose- and concentration-related changes observed following apixaban administration are more pronounced, and less variable, with anti-FXa activity compared with clotting tests.
Table 1 shows the predicted steady-state exposure and anti-Factor Xa activity for each indication. In patients taking apixaban for the prevention of VTE following hip or knee replacement surgery, the results demonstrate a less than 1.6-fold fluctuation in peak-to-trough levels. In non-valvular atrial fibrillation patients taking apixaban for the prevention of stroke and systemic embolism, the results demonstrate a less than 1.7-fold fluctuation in peak-to-trough levels. In patients taking apixaban for the treatment of VTE or prevention of recurrence of VTE, the results demonstrate a less than 2.2-fold fluctuation in peak-to-trough levels. (See Table 1.)

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Although treatment with apixaban does not require routine monitoring of exposure, a calibrated quantitative anti-FXa assay may be useful in situations where knowledge of apixaban exposure may help to inform clinical decisions.
Mechanism of Action: Apixaban is a potent, oral, reversible, direct and highly selective active site inhibitor of FXa. It does not require antithrombin III for antithrombotic activity. Apixaban inhibits free and clot-bound FXa, and prothrombinase activity. Apixaban has no direct effects on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting FXa, apixaban prevents thrombin generation and thrombus development. Preclinical studies of apixaban in animal models have demonstrated antithrombotic efficacy in the prevention of arterial and venous thrombosis at doses that preserved hemostasis.
Clinical Studies: Clinical Trial Information: Prevention of VTE: Elective Hip or Knee Replacement Surgery: The apixaban clinical program was designed to demonstrate the efficacy and safety of apixaban for the prevention of VTE in a broad range of adult patients undergoing elective hip or knee replacement. A total of 8464 patients were randomized in two pivotal, double-blind, multi-national studies, comparing apixaban 2.5 mg given orally twice daily or enoxaparin 40 mg once daily. Included in this total were 1262 patients of age 75 or older, 1004 patients with low body weight (≤60 kg), 1495 patients with BMI ≥33 kg/m² and 437 patients with severe or moderate renal impairment. The ADVANCE-3 study included 5407 patients undergoing elective hip replacement, and the ADVANCE-2 study included 3057 patients undergoing elective knee replacement. Subjects received either apixaban 2.5 mg given orally twice daily (po bid) or enoxaparin 40 mg administered subcutaneously once daily (sc od). The first dose of apixaban was given 12 to 24 hours post-surgery, whereas enoxaparin was started 9 to 15 hours prior to surgery. Both apixaban and enoxaparin were given for 32-38 days in the ADVANCE-3 study and for 10 14 days in the ADVANCE-2 study.
Apixaban demonstrated a statistically superior reduction in the primary endpoint, a composite of all VTE/all cause death, and in the Major VTE endpoint, a composite of proximal DVT, non-fatal PE, and VTE-related death, compared to enoxaparin in both elective hip or knee replacement surgery (see Table 2).

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The safety endpoints of major bleeding, the composite of major and clinically relevant non-major (CRNM) bleeding, and all bleeding showed similar rates for patients treated with apixaban 2.5 mg compared with enoxaparin 40 mg (see Table 3). All the bleeding criteria included surgical site bleeding.
In both Phase III studies, bleeding was assessed beginning with the first dose of double-blind study drug, which was either enoxaparin or injectable placebo, given 9 to 15 hours before surgery. Bleeding during the treatment period included events that occurred before the first dose of apixaban, which was given 12-24 hours after surgery. Bleeding during the post-surgery treatment period only included events occurring after the first dose of study drug after surgery. Over half the occurrences of major bleeding in the apixaban group occurred prior to the first dose of apixaban. Table 3 shows the bleeding results from the treatment period and the post-surgery treatment period. (See Table 3.)

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Prevention of Stroke and Systemic Embolism: NVAF: The clinical program was designed to demonstrate the efficacy and safety of apixaban for the prevention of stroke and systemic embolism in patients suitable for VKA (ARISTOTLE) and in patients unsuitable for VKA (AVERROES). Both studies were active-controlled (vs warfarin in ARISTOTLE and vs ASA in AVERROES), randomized, double-blind, parallel-arm, multi-national trials in patients with nonvalvular, persistent, paroxysmal, or permanent atrial fibrillation (AF) or atrial flutter (AFl) and one or more of the following additional risk factors: Prior stroke or transient ischemic attack (TIA) (also prior systemic embolism in ARISTOTLE), age ≥75 years, arterial hypertension requiring treatment, diabetes mellitus, heart failure New York Heart Association Class 2, decreased left ventricular ejection fraction (LVEF), documented peripheral arterial disease (AVERROES only). (See Table 4.)

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ARISTOTLE Study: Patients were randomized to treatment with apixaban 5 mg orally twice daily (or 2.5 mg twice daily in selected patients, 4.7%) or warfarin (target INR range 2.0-3.0) and followed for a median of 89.86 weeks for apixaban and 87.79 weeks for warfarin. The apixaban 2.5 mg twice daily dose was assigned to patients with at least 2 of the following characteristics: Age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL (133 micromole/L). 43% were VKA naive, defined as not previously received or have received ≤30 consecutive days of treatment with warfarin or another VKA. Coronary artery disease was present in 33.2% of patients.
For patients randomized to warfarin, the median percentage of time in therapeutic range (INR 2-3) was 66%.
The primary objective of the study was to determine if apixaban 5 mg twice daily (or 2.5 mg twice daily in selected patients) was noninferior to warfarin for the prevention of stroke (ischemic, hemorrhagic, or unspecified) and systemic embolism. Assessments of superiority of apixaban versus warfarin were also prespecified for the primary endpoint and for death due to any cause.
The key study outcomes were prespecified and tested in a sequential, hierarchical manner to conserve overall type 1 error. Apixaban was tested compared to warfarin for: (1) non-inferiority on the composite endpoint of stroke and systemic embolism, (2) superiority on the composite endpoint of stroke and systemic embolism, (3) superiority on major bleeding, and (4) superiority on all-cause death.
In the study, apixaban achieved statistically significant superiority in the primary endpoint of prevention of stroke (hemorrhagic or ischemic) and systemic embolism (see Table 5 and Figure 1). Statistically significant superiority was also achieved in all-cause death (see Table 5), Numeric reductions were observed for both CV and non-CV deaths.
Apixaban reduced the incidence of strokes compared to warfarin within each stroke severity category, including less severe strokes [Rankin score 0 to 2, HR=0.89 (CI=0.64, 1.26)] and the more clinically important fatal or disabling strokes [Rankin score 3 to 6, HR=0.71 (CI=0.54, 0.94)]. The reduction in the stroke and systemic embolism incidence was seen regardless of the stroke risk at entry as categorized by CHADS₂ score. (See Table 5.)

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The rate of myocardial infarction was similar between the apixaban and warfarin treatment groups (0.53%/year and 0.61%/year, respectively). (See Figure 1.)

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ARISTOTLE study: Centers were ranked post hoc by the percentage of time that warfarin-treated patients were in therapeutic range (INR 2-3). Findings for stroke/systemic embolism, major bleeds, and all-cause mortality are shown for centers above and below the median level of INR control in Table 6. The benefits of apixaban relative to warfarin were consistent in patients enrolled at centers with INR control below or above the median. (See Table 6.)

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AVERROES Study: Patients were randomized to treatment with apixaban 5 mg orally twice daily (or 2.5 mg twice daily in selected patients, 6.4%) or ASA 81 to 324 mg once daily. The selection of an ASA dose of 81, 162, 243, or 324 mg was at the discretion of the investigator with 90.5% of subjects receiving either an 81 mg (64.3%) or 162 mg (26.2%) dose at randomization.
In the study, VKA therapy had been tried but discontinued in 40% of patients prior to enrollment. Common reasons for unsuitability for VKA therapy in the AVERROES study included unable/unlikely to obtain INRs at requested intervals (42.6%), patient refused treatment with VKA (37.4%), CHADS₂ score=1 and physician did not recommend VKA (21.3%), patient could not be relied on to adhere to VKA medication instruction (15.0%), and difficulty/expected difficulty in contacting patient in case of urgent dose change (11.7%).
The primary objective of the study was to determine if apixaban 5 mg twice daily (2.5 mg twice daily in selected patients) was superior to ASA (81-324 mg QD) for preventing the composite outcome of stroke or systemic embolism. Assessments of superiority of apixaban versus ASA were also pre-specified for major vascular events (composite outcome of stroke, systemic embolism, myocardial infarction or vascular death) and for death due to any cause.
AVERROES was stopped early upon the recommendation of the trial's independent Data Monitoring Committee which found that a predefined interim analysis revealed clear evidence of apixaban providing a clinically important reduction in stroke and systemic embolism and acceptable safety profile.
In the study, apixaban demonstrated statistically significant superiority in the primary endpoint of prevention of stroke (hemorrhagic or ischemic) and systemic embolism (see Table 7 and Figure 2). A clinically important reduction was observed in the key secondary composite endpoint of stroke, systemic embolism, myocardial infarction, or vascular death (see Table 7).
Apixaban reduced the incidence of strokes compared to ASA within each stroke severity category [(modified Rankin score 0 to 2, HR=0.51 (CI=0.29, 0.91); modified Rankin score 3 to 6, HR=0.43 (CI=0.28, 0.65)]. The reduction in the stroke incidence was seen regardless of the stroke risk at entry as categorized by CHADS₂ score.
Apixaban also reduced the incidence of cardiovascular hospitalizations relative to ASA (HR =0.79, CI=0.69, 0.91). (See Table 7 and Figure 2.)

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Bleeding in Patients with Atrial Fibrillation: In the ARISTOTLE and AVERROES studies, the primary safety endpoint was major bleeding, which was defined as acute clinically overt bleeding that was accompanied by one or more of the following: A decrease in hemoglobin of 2 g/dL or more; a transfusion of 2 or more units of packed red blood cells; bleeding that occurred in at least one of the following critical sites, intracranial, intraspinal, intraocular (within the corpus of the eye; thus, a conjunctival bleed is not an intraocular bleed), pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal; bleeding that is fatal. Intracranial hemorrhage included intracerebral (including hemorrhagic stroke), subarachnoid, and subdural bleeds.
Clinically relevant non-major bleeding (CRNM) was defined as acute clinically overt bleeding that does not satisfy additional criteria required for the bleeding event to be defined as a major bleeding event and meets at least one of the following criteria: Hospital admission for bleeding; physician guided medical or surgical treatment for bleeding; change in antithrombotic treatment (anticoagulant or antiplatelet) therapy.
ARISTOTLE Study: There was a statistically superior reduction in the incidence of ISTH major bleeding between the apixaban and warfarin treatment groups (see Table 8). There was also a substantial reduction in the incidence of ISTH major+CRNM and all bleeding. (See Table 8.)

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Intracranial hemorrhage was reduced >50% with apixaban. GUSTO severe and TIMI major bleeding were reduced >40% with apixaban. Fatal bleeding was reduced >70% with apixaban.
Treatment discontinuation due to bleeding related adverse reactions occurred in 1.7% and 2.5% of patients treated with apixaban and warfarin, respectively.
The incidence of ISTH major gastrointestinal bleeds (including upper GI, lower GI, and rectal bleeding) was lower with apixaban (0.76%/year) compared to warfarin (0.86%/year).
The incidence of ISTH major intraocular bleeding was higher with apixaban (0.18%/year) compared to warfarin (0.13%/year).
AVERROES Study: There was an increase in the incidence of major bleeding between the apixaban and ASA treatment group, which was not statistically significant (see Table 9). The frequency of fatal and intracranial bleeding was similar in the 2 treatment groups. (See Table 9.)

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Treatment discontinuation due to bleeding related adverse reactions occurred in 1.5% and 1.3% of patients treated with apixaban and ASA, respectively.
Subpopulation Analysis: In the ARISTOTLE study, the results for the primary efficacy endpoint and major bleeding results were generally consistent across all major subgroups including age, weight, CHADS₂ score, warfarin naive status, level of renal impairment, assignment to reduced dose apixaban, and ASA at randomization (see Figure 3).
Similarly, in the AVERROES study, the results for the primary efficacy endpoint and major bleeding results were consistent across all major subgroups including age, CHADS₂ score, level of renal impairment, and previous VKA use or VKA refusal (see Figure 4).
Notably, the efficacy and safety results for both studies in elderly patients (including those ≥75 years) were consistent with the overall population. (See Figure 3 and Figure 4.)

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Patients undergoing cardioversion: EMANATE, an open-label, multi-center study, enrolled 1500 patients who were either oralanticoagulant naïve or pre-treated less than 48 hours, and scheduled for cardioversion for NVAF.
Patients were randomized 1:1 to apixaban or to heparin and/or VKA for the prevention of cardiovascular events. Electrical and/or pharmacologic cardioversion was conducted after at least5 doses of 5 mg twice daily apixaban [or 2.5 mg twice daily in selected patients (see Dosage & Administration) or at least 2 hours after a 10 mg loading dose [or a 5 mg loading dose in selected patients (see Dosage & Administration)] if earlier cardioversion was required. In the apixaban group, 342 patients received a loading dose (331 patients received the 10 mg dose and 11 patients received the 5 mg dose).
There were no strokes (0%) in the apixaban group (n=753) and 6 (0.80%) strokes in the heparin and/or VKA group (n=747; RR 0, 95% CI 0.0, 0.64) (nominal p-value = 0.0151). All-cause death occurred in 2 patients (0.27%) in the apixaban group and 1 patient (0.13%) in the heparin and/or VKA group (RR 1.98, 95% CI 0.19, 54.00). No systemic embolism events were reported.
Major bleeding and CRNM bleeding events occurred in 3 (0.41%) and 11 (1.50%) patients,respectively, in the apixaban group, compared to 6 (0.83%) and 13 (1.80%) patients in the heparin and/or VKA group.
This exploratory study showed comparable efficacy and safety between apixaban and heparin and/or VKA treatment groups in the setting of cardioversion.
Treatment of VTE: The clinical program was designed to demonstrate the efficacy and safety of apixaban for the treatment of DVT and PE (AMPLIFY), and extended therapy for the prevention of recurrent DVT and PE following 6 to 12 months of anticoagulant treatment for DVT and/or PE (AMPLIFY-EXT). Both studies were randomized, parallel-group, double-blind multinational trials in patients with symptomatic proximal DVT and/or symptomatic PE. All key safety and efficacy endpoints were adjudicated by an independent blinded committee. (See Table 10 and Table 11.)

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AMPLIFY Study: Patients were randomized to treatment with apixaban 10 mg twice daily orally for 7 days followed by apixaban 5 mg twice daily orally for 6 months, or enoxaparin 1 mg/kg twice daily subcutaneously for at least 5 days (until INR ≥2) and warfarin (target INR range 2.0-3.0) orally for 6 months. Patients who required thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent, and patients with creatinine clearance <25 mL/min, significant liver disease, or active bleeding were excluded from the studies. Patients were allowed to enter the study with or without prior parenteral anticoagulation (up to 48 hours).
For patients randomized to warfarin, the mean percentage of time in therapeutic range (INR 2.0 3.0) was 60.9.
The primary objective of the study was to determine if apixaban was noninferior to enoxaparin/warfarin therapy in the combined endpoint of adjudicated recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) or VTE-related death over 6 months of therapy.
In the study, apixaban was shown to be noninferior to enoxaparin/warfarin in the combined endpoint of adjudicated recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) or VTE-related death (see Table 12).

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Figure 5 is a plot of the time from randomization to the occurrence of the first primary efficacy endpoint event in the two treatment groups in the AMPLIFY study. (See Figure 5.)

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Apixaban efficacy in initial treatment of VTE was consistent between patients who were treated for a PE [Relative Risk 0.9, 95% confidence interval (0.5, 1.6)] or DVT [Relative Risk 0.8, 95% confidence interval (0.5, 1.3)]. Efficacy across subgroups, including age, gender, renal function, body mass index (BMI), extent of index PE, location of DVT thrombus, and prior parenteral heparin use was generally consistent (see Figure 6).

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The primary safety endpoint was major bleeding. In the study, apixaban was statistically superior to enoxaparin/warfarin in the primary safety endpoint [Relative Risk 0.31, 95% confidence interval (0.17, 0.55), P-value <0.0001] (see Table 13).

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The adjudicated major bleeding and CRNM bleeding at any anatomical site was generally lower in the apixaban group compared to the enoxaparin/warfarin group. Adjudicated ISTH major gastrointestinal bleeding occurred in 6 (0.2%) apixaban-treated patients and 17 (0.6%) enoxaparin/warfarin-treated patients.
During the 6 months of the study, fewer patients were hospitalized in the apixaban group [153 (5.7%)] compared to the warfarin treated patients [190 (7.1%)].
AMPLIFY-EXT Study: Patients were randomized to treatment with apixaban 2.5 mg twice daily orally, apixaban 5 mg twice daily orally, or placebo for 12 months after completing 6 to 12 months of initial anticoagulant treatment. Approximately one-third of patients participated in the AMPLIFY study prior to enrollment in the AMPLIFY-EXT study.
The primary objective of the study was to determine if apixaban was superior to placebo in the combined endpoint of symptomatic, recurrent VTE (nonfatal DVT or nonfatal PE) or all-cause death.
In the study, both doses of apixaban were statistically superior to placebo in the primary endpoint of symptomatic, recurrent VTE or all-cause death (see Table 14).

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Figure 7 is a plot of the time from randomization to the occurrence of the first primary efficacy endpoint event in the three treatment groups in the AMPLIFY-EXT study. (See Figure 7.)

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Apixaban efficacy for prevention of a recurrence of a VTE was maintained across subgroups, including age, gender, BMI, and renal function.
The primary safety endpoint was major bleeding during the treatment period. In the study, the incidence in major bleeding was similar between the apixaban and placebo groups, there was no statistically significant difference in the incidence of major + CRNM, minor, and all bleeding between the apixaban 2.5 mg twice daily and placebo treatment groups. The frequency of major + CRNM bleeding in the apixaban 5 mg twice daily group was not statistically different from the placebo group. The frequency of CRNM, minor bleeding, and all bleeding in the apixaban 5 mg twice daily group was statistically different from the placebo group (see Table 15).

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Figure 8 is a plot of the time from randomization to the occurrence of the first major or clinically relevant non-major bleeding event in the three treatment groups in the AMPLIFY-EXT study. (See Figure 8.)

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ISTH major gastrointestinal bleeding occurred in 1 (0.1%) apixaban-treated patient at the 5 mg twice daily dose, no patients at the 2.5 mg twice daily dose, and 1 (0.1%) placebo-treated patient.
During the 12 months of the study, fewer patients were hospitalized in the apixaban groups [42 (5%) in the 2.5 mg twice daily group; 34 (4.2%) in the 5 mg twice daily group] compared to the placebo treated patients [62 (7.5%)].
Pharmacokinetics: Absorption: The absolute bioavailability of apixaban is approximately 50% for doses up to 10 mg. Apixaban is rapidly absorbed with maximum concentrations (C_max) appearing 3 to 4 hours after tablet intake. Intake with food does not affect apixaban AUC or C_max at the 10 mg dose. Apixaban can be taken with or without food. Apixaban demonstrates linear pharmacokinetics with dose proportional increases in exposure for oral doses up to 10 mg. At doses ≥25 mg, apixaban displays dissolution limited absorption with decreased bioavailability. Apixaban exposure parameters exhibit low to moderate variability reflected by a within-subject and inter-subject variability of ~20% CV and ~30% CV, respectively.
Following oral administration of 10 mg of apixaban as 2 crushed 5 mg tablets suspended in 30 mL of water, exposure was comparable to exposure after oral administration of 2 intact 5 mg tablets.
Following oral administration of 10 mg of apixaban as 2 crushed 5 mg tablets mixed with 30 g of apple sauce, the C_max and AUC were 21% and 16% lower, respectively, when compared to administration of 2 intact 5 mg tablets.
Following administration of a crushed 5 mg apixaban tablet suspended in 60 mL of D5W and delivered via a nasogastric tube, exposure was similar to exposure seen in other clinical trialsinvolving healthy subjects receiving a single oral 5 mg apixaban tablet dose.
Distribution: Plasma protein binding in humans is approximately 87%. The volume of distribution (Vss) is approximately 21 liters.
Metabolism and Elimination: Apixaban has multiple routes of elimination. Of the administered apixaban dose in humans, approximately 25% was recovered as metabolites, with the majority recovered in feces. Renal excretion of apixaban accounts for approximately 27% of total clearance. Additional contributions from biliary and direct intestinal excretion were observed in clinical and nonclinical studies, respectively.
Apixaban has a total clearance of about 3.3 L/h and a half-life of approximately 12 hours.
O-demethylation and hydroxylation at the 3-oxopiperidinyl moiety are the major sites of biotransformation. Apixaban is metabolized mainly via CYP3A4/5 with minor contributions from CYP1A2, 2C8, 2C9, 2C19, and 2J2. Unchanged apixaban is the major drug-related component in human plasma with no active circulating metabolites present. Apixaban is a substrate of transport proteins, P-gp and breast cancer resistance protein (BCRP).
Renal Impairment: There was no impact of impaired renal function on peak concentration of apixaban. There was an increase in apixaban exposure correlated to decrease in renal function, as assessed via measured creatinine clearance. In individuals with mild (creatinine clearance 51-80 mL/min), moderate (creatinine clearance 30-50 mL/min) and severe (creatinine clearance 15-29 mL/min) renal impairment, apixaban plasma concentrations (AUC) were increased 16, 29, and 44%, respectively, compared to individuals with normal creatinine clearance. Renal impairment had no evident effect on the relationship between apixaban plasma concentration and anti-FXa activity. No dose adjustment is necessary in patients with mild, moderate or severe renal impairment, except as described in Dosage & Administration.
In subjects with end-stage renal disease (ESRD), the AUC of apixaban was increased by 36% when a single dose of apixaban 5 mg was administered immediately after hemodialysis, compared to that seen in subjects with normal renal function. Hemodialysis, started two hours after administration of a single dose of apixaban 5 mg, decreased apixaban AUC by 14% in these ESRD subjects, corresponding to an apixaban dialysis clearance of 18 mL/min.
Hepatic Impairment: Apixaban has not been studied in patients with severe hepatic impairment or active hepatobiliary disease. Apixaban is not recommended in patients with severe hepatic impairment (see Precautions).
In a study comparing subjects with mild and moderate hepatic impairment (classified as Child Pugh A and B, respectively) to healthy control subjects, the single-dose pharmacokinetics and pharmacodynamics of apixaban 5 mg were not altered in subjects with hepatic impairment. Changes in anti-FXa activity and INR were comparable between subjects with mild to moderate hepatic impairment and healthy subjects. No dose adjustment is required in patients with mild or moderate hepatic impairment; however, given the limited number of subjects studied, caution is advised when using ELIQUIS in this population (see Dosage & Administration and Precautions).
Elderly: Elderly patients (above 65 years) exhibited higher plasma concentrations than younger patients, with mean AUC values being approximately 32% higher. No dose adjustment is required, except as described in Dosage & Administration.
Gender: Exposure to apixaban was approximately 18% higher in females than in males. No dose adjustment is required.
Ethnic Origin and Race: The results across phase 1 studies showed no discernible difference in apixaban pharmacokinetics between White/Caucasian, Asian and Black/African American subjects. Findings from a population pharmacokinetic analysis in patients who received apixaban were generally consistent with the phase 1 results. No dose adjustment is required.
Body Weight: Compared to apixaban exposure in subjects with body weight of 65 to 85 kg, body weight >120 kg was associated with approximately 30% lower exposure and body weight <50 kg was associated with approximately 30% higher exposure. No dose adjustment is required, except as described in Dosage & Administration.
Pharmacokinetic/Pharmacodynamic Relationship: The pharmacokinetic/pharmacodynamic (PK/PD) relationship between apixaban plasma concentration and several PD endpoints (anti-FXa activity, INR, PT, aPTT) has been evaluated after administration of a wide range of doses (0.5-50 mg). The relationship between apixaban plasma concentration and anti-FXa activity was best described by a linear model. The PK/PD relationship observed in patients who received apixaban in Phase 2 or Phase 3 clinical trials was consistent with that established in healthy subjects.
Toxicology: Non-Clinical Safety: Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, fertility and embryo fetal development (see Use in Pregnancy & Lactation). In the offspring of pregnant rats treated with apixaban there were decreases in mating and fertility. These effects were minimal and observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

Prevention of VTE: Elective Hip or Knee Replacement Surgery: Prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective hip or knee replacement surgery.
Prevention of Stroke and Systemic Embolism: Non-valvular Atrial Fibrillation: ELIQUIS is indicated to reduce the risk of stroke, systemic embolism, and death in patients with non-valvular atrial fibrillation with one or more risk factors, including patients unsuitable for warfarin. Compared to warfarin, ELIQUIS also results in less bleeding, including intracranial hemorrhage.
Treatment of VTE: ELIQUIS is indicated for: treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), prevention of recurrent DVT and PE.

ELIQUIS can be taken with or without food.
If a dose is missed, the patient should take ELIQUIS immediately and then continue with twice daily administration as before.
Prevention of VTE: Elective Hip or Knee Replacement Surgery: The recommended dose of ELIQUIS is 2.5 mg taken orally twice daily. The initial dose should be taken 12 to 24 hours after surgery.
In patients undergoing hip replacement surgery, the recommended duration of treatment is 32 to 38 days.
In patients undergoing knee replacement surgery, the recommended duration of treatment is 10 to 14 days.
Prevention of Stroke and Systemic Embolism: NVAF: The recommended dose of ELIQUIS is 5 mg taken orally twice daily.
Age, body weight, serum creatinine: In patients with at least 2 of the following characteristics, age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL (133 micromole/L), the recommended dose of ELIQUIS is 2.5 mg twice daily.
Treatment of DVT and PE: The recommended dose of ELIQUIS is 10 mg taken orally twice daily for 7 days, followed by 5 mg taken orally twice daily.
Prevention of recurrent DVT and PE: The recommended dose of ELIQUIS is 2.5 mg taken orally twice daily after at least 6 months of treatment for DVT or PE.
Renal Impairment: Prevention of VTE: Elective Hip or Knee Replacement Surgery: No dose adjustment is necessary in patients with mild, moderate or severe (creatinine clearance 15-29 mL/min) renal impairment (see Pharmacology: Pharmacokinetics: Renal impairment under Actions). Because there is limited clinical experience in patients with creatinine clearance <15 mL/min and no data in patients undergoing dialysis, apixaban is not recommended in these patients (see Renal Impairment: Prevention of VTE: Elective Hip or Knee Replacement Surgery under Precautions and Pharmacology: Pharmacokinetics: Renal Impairment under Actions).
Prevention of Stroke and Systemic Embolism: NVAF: No dose adjustment is recommended in patients with creatinine clearance 15 to 29 mL/min, except as described in Prevention of Stroke and Systemic Embolism: NVAF under Dosage & Administration. Because there is no clinical experience in patients with creatinine clearance <15 mL/min, a dosing recommendation cannot be provided.
There are no data in patients undergoing dialysis, therefore, ELIQUIS is not recommended in these patients (see Pharmacology: Pharmacokinetics: Renal Impairment under Actions).
Treatment of VTE: No dose adjustment is necessary in patients with mild, moderate, or severe (creatinine clearance 15-29 mL/min) renal impairment (see Pharmacology: Pharmacokinetics: Renal impairment under Actions). Because there is limited clinical experience in patients with creatinine clearance <15 mL/min and no data in patients undergoing dialysis, apixaban is not recommended in these patients (see Pharmacology: Pharmacokinetics: Renal Impairment under Actions).
Hepatic Impairment: ELIQUIS may be used with caution in patients with mild or moderate hepatic impairment (Child Pugh A or B). No dose adjustment is required in patients with mild or moderate hepatic impairment (see Hepatic Impairment under Precautions and Pharmacology: Pharmacokinetics: Hepatic Impairment under Actions).
ELIQUIS is not recommended in patients with severe hepatic impairment (see Hepatic Impairment under Precautions and Pharmacology: Pharmacokinetics: Hepatic Impairment under Actions).
Body Weight: Prevention of VTE: Elective Hip or Knee Replacement Surgery: No dose adjustment required (see Pharmacology: Pharmacokinetics under Actions).
Prevention of Stroke and Systemic Embolism: NVAF: See Prevention of stroke and systemic embolism: NVAF under Dosage & Administration.
Treatment of VTE: No dose adjustment required (see Pharmacology: Pharmacokinetics under Actions).
Gender: No dose adjustment required (see Pharmacology: Pharmacokinetics under Actions).
Pediatric and Adolescent: The efficacy and safety of ELIQUIS in children below age 18 have not been established. No data are available.
Elderly: Prevention of VTE: Elective hip or knee replacement surgery: No dose adjustment required (see Pharmacology: Pharmacokinetics under Actions).
Prevention of Stroke and Systemic Embolism: NVAF: See Prevention of stroke and systemic embolism: NVAF under Dosage & Administration.
Treatment of VTE: No dose adjustment required (see Pharmacology: Pharmacokinetics under Actions).
Converting From or to Parenteral Anticoagulants: In general, switching treatment from parenteral anticoagulants to ELIQUIS (and vice versa) can be done at the next scheduled dose.
Converting From or to Warfarin or Other vitamin K Antagonists (VKA): When converting patients from warfarin or other VKA therapy to ELIQUIS, discontinue warfarin or other VKA therapy and start ELIQUIS when the international normalized ratio (INR) is below 2.0.
When converting from ELIQUIS to warfarin or other VKA therapy, continue ELIQUIS for 48 hours after the first dose of warfarin or other VKA therapy.
Surgery and Invasive Procedures: ELIQUIS should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of unacceptable or clinically significant bleeding. ELIQUIS should be discontinued at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding or where the bleeding would be non-critical in location and easily controlled. If surgery or invasive procedures cannot be delayed, exercise appropriate caution taking into consideration an increased risk of bleeding. This risk of bleeding should be weighed against the urgency of intervention. In non-valvular atrial fibrillation patients, bridging anticoagulation during the 24 to 48 hours after stopping ELIQUIS and prior to the intervention is not generally required.
ELIQUIS should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established.
ELIQUIS can be initiated or continued in NVAF patients who may require cardioversion.
For patients not previously treated with anticoagulants, at least 5 doses of ELIQUIS 5 mg twice daily [2.5 mg twice daily in patients who qualify for a dose reduction (see Dosage & Administration)] should be given before cardioversion to ensure adequate anticoagulation (see Precautions).
If cardioversion is required before 5 doses of ELIQUIS can be administered, a 10 mg loading dose should be given, followed by 5 mg twice daily. The dosing regimen should be reduced to a 5 mg loading dose followed by 2.5 mg twice daily if the patient meets the criteria for dose reduction (see Dosage & Administration). The administration of the loading dose should be given at least 2 hours before cardioversion (see Precautions).
Confirmation should be sought prior to cardioversion that the patient has taken ELIQUIS as prescribed. Decisions on initiation and duration of treatment should take established guideline recommendations for anticoagulant treatment in patients undergoing cardioversion into account.
Administration options: For patients who are unable to swallow whole tablets, ELIQUIS tablets may be crushed and suspended in water, 5% dextrose in water (D5W), or apple juice, or mixed with apple sauce and promptly administered orally (see Precautions). Alternatively, ELIQUIS tablets may be crushed and suspended in 60 mL of water or D5W and promptly delivered through a nasogastric tube (see Precautions).
Crushed ELIQUIS tablets are stable in water, D5W, apple juice, and apple sauce for up to 4 hours.
Mode of Administration: Oral administration.

There is no antidote to ELIQUIS. Overdose of ELIQUIS may result in a higher risk of bleeding.
In controlled clinical trials, orally-administered apixaban in healthy subjects at doses up to 50 mg daily for 3 to 7 days (25 mg twice a day for 7 days or 50 mg once a day for 3 days) had no clinically relevant adverse effects.
Administration of activated charcoal 2 and 6 hours after ingestion of a 20-mg dose of apixaban reduced mean apixaban AUC by 50% and 27%, respectively, and had no impact on C_max. Mean half-life of apixaban decreased from 13.4 hours when apixaban was administered alone to 5.3 hours and 4.9 hours, respectively, when activated charcoal was administered 2 and 6 hours after apixaban. Thus, administration of activated charcoal may be useful in the management of apixaban overdose or accidental ingestion.
Hemodialysis is unlikely to be an effective means of managing apixaban overdose (see Pharmacology: Pharmacokinetics under Actions).

Hypersensitivity to the active substance or to any of the excipients.
Clinically significant active bleeding.
Hepatic disease associated with coagulopathy and clinically relevant bleeding risk.
Lesion or condition if considered a significant risk factor for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenousmalformations, vascular aneurysms or major intraspinal or intracerebral vascularabnormalities.
Concomitant treatment with any other anticoagulant agent, e.g., unfractionated heparin (UFH),low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives(fondaparinux, etc.), oral anticoagulants (warfarin, rivaroxaban, dabigatran, etc.) except underspecific circumstances of switching anticoagulant therapy (see Dosage & Administration) or when UFH isgiven at doses necessary to maintain an open central venous or arterial catheter (see Interactions).

Hemorrhage risk: As with other anticoagulants, patients taking ELIQUIS are to be carefully observed for signs of bleeding. ELIQUIS is recommended to be used with caution in conditions with increased risk of hemorrhage, such as: congenital or acquired bleeding disorders; active ulcerative gastrointestinal disease; bacterial endocarditis; thrombocytopenia; platelet disorders; history of hemorrhagic stroke; severe uncontrolled hypertension; and recent brain, spinal, or ophthalmological surgery. ELIQUIS is not recommended in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk. ELIQUIS administration should be discontinued if severe hemorrhage occurs (see Overdosage).
In the event of hemorrhagic complications, treatment must be discontinued and the source of bleeding investigated. The initiation of appropriate treatment, e.g., surgical hemostasis or the transfusion of fresh frozen plasma, should be considered. If life-threatening bleeding cannot be controlled by the above measures, administration of prothrombin complex concentrates (PCCs) or recombinant factor VIIa may be considered. Reversal of ELIQUIS pharmacodynamic effects, as demonstrated by changes in the thrombin generation assay, has been demonstrated after administration of 4-factor PCCs in healthy subjects. However, there is no clinical experience with the use of 4-factor PCC products to reverse bleeding in individuals who have received ELIQUIS. Currently, there is no experience with the use of recombinant factor VIIa in individuals receiving apixaban.
Temporary discontinuation of ELIQUIS: Discontinuing anticoagulants, including ELIQUIS, for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of thrombosis. Avoid lapses in therapy, and if anticoagulation with ELIQUIS must be temporarily discontinued for any reason, restart therapy as soon as possible.
Renal impairment: Prevention of VTE: elective hip or knee replacement surgery: Because there is limited clinical experience in patients with creatinine clearance <15 mL/min and no data in patients undergoing dialysis, apixaban is not recommended in these patients (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Prevention of stroke and systemic embolism: NVAF: There are no data in patients undergoing dialysis, therefore, ELIQUIS is not recommended in these patients (see Pharmacology: Pharmacokinetics under Actions).
Treatment of VTE: Because there is limited clinical experience in patients with creatinine clearance <15 mL/min and no data in patients undergoing dialysis, apixaban is not recommended in these patients (see Pharmacology: Pharmacokinetics under Actions).
Hepatic impairment: ELIQUIS is not recommended in patients with severe hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
ELIQUIS may be used with caution in patients with mild or moderate hepatic impairment (Child Pugh A or B) (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions)
Interaction with strong inhibitors of both cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp): ELIQUIS can be administered with caution in patients receiving concomitant systemic treatment with strong inhibitors of both Cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp), such as azole-antimycotics (e.g., ketoconazole, itraconazole, voriconazole and posaconazole), HIV protease inhibitors (e.g., ritonavir). These medicinal products may increase apixaban exposure by 2-fold) (see Interactions).
Interaction with strong inducers of both CYP3A4 and P-gp: Prevention of VTE: elective hip or knee replacement surgery The concomitant use of ELIQUIS with strong CYP3A4 and P-gp inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital or St. John's Wort) may lead to a ~50% reduction in apixaban exposure. Use caution when co-administering ELIQUIS with strong inducers of both CYP3A4 and P-gp (see Interactions).
Prevention of stroke and systemic embolism: NVAF: The concomitant use of ELIQUIS with strong CYP3A4 and P-gp inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital or St. John's Wort) may lead to a ~50% reduction in apixaban exposure. Use caution when co-administering ELIQUIS with strong inducers of both CYP3A4 and P-gp (see Interactions).
Treatment of VTE: The concomitant use of ELIQUIS with strong CYP3A4 and P-gp inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital or St. John's Wort) may lead to a ~50% reduction in apixaban exposure. For the treatment of DVT or PE, ELIQUIS is not recommended in patients receiving concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp (see Interactions). For prevention of recurrent DVT and PE, use caution when co-administering ELIQUIS with strong inducers of both CYP3A4 and P-gp (see Interactions).
Interaction with other medicinal products affecting hemostasis: The concomitant use of ELIQUIS with antiplatelet agents increases the risk of bleeding. Care is to be taken if patients are treated concomitantly with non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid (ASA). Other platelet aggregation inhibitors or other antithrombotic agents are not recommended concomitantly with ELIQUIS following surgery (see Interactions).
In patients with atrial fibrillation and a condition that warrants mono or dual antiplatelet therapy, a careful assessment of the potential benefits against the potential risks should be made before combining this therapy with ELIQUIS. In a clinical trial of patients with atrial fibrillation, concomitant use of ASA increased the major bleeding risk on apixaban from 1.8% per year to 3.4% per year and increased the bleeding risk on warfarin from 2.7% per year to 4.6% per year. In this clinical trial, there was limited (2.3%) use of concomitant dual antiplatelet therapy with apixaban.
In a clinical trial of high-risk post-acute coronary syndrome patients, characterized by multiple cardiac and non-cardiac comorbidities, who received ASA or the combination of ASA and clopidogrel, a significant increase in bleeding risk was reported for apixaban compared to placebo.
Spinal/epidural anesthesia or puncture: Prevention of VTE: elective hip or knee replacement surgery When neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis. The risk of these events may be increased by the post-operative use of indwelling epidural catheters or the concomitant use of medicinal products affecting hemostasis. Indwelling epidural or intrathecal catheters must be removed at least 5 hours prior to the first dose of ELIQUIS. The risk may also be increased by traumatic or repeated epidural or spinal puncture. Patients are to be frequently monitored for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, bowel or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention, the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis.
Hip fracture surgery: Prevention of VTE: elective hip or knee replacement surgery Apixaban has not been studied in clinical trials in patients undergoing hip fracture surgery to evaluate efficacy and safety in these patients. Therefore, ELIQUIS is not recommended in these patients.
Patients with prosthetic heart valves: Safety and efficacy of Eliquis have not been studied in patients with prostethic heart valves, with or without atrial fibrillation. Therefore, the use of ELIQUIS is not recommended in this setting.
Acute PE in hemodynamically unstable patients or patients who require thrombolysis or pulmonary embolectomy: Treatment of VTE: Initiation of ELIQUIS is not recommended as an alternative to unfractionated heparin for the initial treatment of patients with PE who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.
Patients with antiphospholipid syndrome: Direct acting oral anticoagulants (DOACs), including ELIQUIS, are not recommended for patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome (APS). In particular for patients who are triple positive (for lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies), treatment with DOACs could be associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy. The efficacy and safety of ELIQUIS in patients with APS have not been established.
Effect on ability to drive and to use machines: ELIQUIS has no or negligible influence on the ability to drive and use machines.
Use in Children: The efficacy and safety of ELIQUIS in children below age 18 have not been established. No data are available.

Pregnancy: There are limited data from the use of apixaban in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. Apixaban is not recommended during pregnancy.
Breastfeeding: It is unknown whether apixaban or its metabolites are excreted in human milk. Available data in animals have shown excretion of apixaban in milk. In rat milk, a high milk to maternal plasma ratio (C_max about 8, AUC about 30) was found, possibly due to active transport into the milk. A risk to newborns and infants cannot be excluded.
A decision must be made to either discontinue breast-feeding or to discontinue/abstain from apixaban therapy.
Fertility: Studies in animals dosed directly with apixaban have shown no effect on fertility. However, in the female offspring of pregnant rats treated with apixaban, there were decreases in mating and fertility (see Pharmacology: Toxicology: Non-clinical safety under Actions).

Clinical Experience: Prevention of VTE: Elective Hip or Knee Replacement Surgery: The safety of apixaban has been evaluated in one phase II and three phase III studies including 5,924 patients exposed to apixaban 2.5 mg twice daily undergoing major orthopedic surgery of the lower limbs (Elective Hip Replacement or Elective Knee Replacement) treated for up to 38 days.
In total, 11% of the patients treated with apixaban 2.5 mg twice daily experienced adverse reactions. As with other anticoagulants, bleeding may occur during apixaban therapy in the presence of associated risk factors such as organic lesions liable to bleed. Common adverse reactions were anemia, hemorrhage, contusion, and nausea. The overall incidences of adverse reactions of bleeding, anemia and abnormalities of transaminases (e.g., alanine aminotransferase levels) were numerically lower in patients on apixaban compared to enoxaparin in the phase II and phase III studies in elective hip and knee replacement surgery. The adverse reactions should be interpreted within the surgical setting.
As with any anticoagulant, the use of ELIQUIS may be associated with an increased risk of occult or overt bleeding from any tissue or organ, which may result in post-hemorrhagic anemia. The signs, symptoms, and severity will vary according to the location and degree or extent of the bleeding (see Hemorrhage risk under Precautions and Pharmacology: Pharmacodynamics: Clinical Trial Information under Actions).
Adverse reactions in the one phase II study and the three phase III studies are listed in Table 16 by system organ classification (MedDRA) and by frequency. (See Table 16.)

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Prevention of Stroke and Systemic Embolism: NVAF: The safety of apixaban has been evaluated in the ARISTOTLE and AVERROES studies, including 11284 patients exposed to apixaban 5 mg twice daily and 602 patients to 2.5 mg twice daily. The apixaban exposures were ≥12 months for 9375 patients and ≥24 months for 3369 patients in the two studies. In ARISTOTLE, the mean duration of exposure was 89.2 weeks on apixaban and 87.5 weeks on warfarin; total patient years for exposure was 15534 on apixaban and 15184 on warfarin. In AVERROES, the mean duration of exposure was approximately 59 weeks in both treatment groups; total patient years for exposure was 3193 on apixaban and 3150 on ASA.
The overall discontinuation rate due to adverse reactions was 1.8% for apixaban and 2.6% for warfarin in the ARISTOTLE study, and was 1.5% for apixaban and 1.3% for ASA in the AVERROES study. The overall incidence of adverse reactions related to bleeding was numerically lower in patients on apixaban compared to warfarin in the ARISTOTLE study (24.3% vs 31.0%). and was similar in patients on apixaban compared to ASA in the AVERROES study (9.6% vs 8.5%).
Adverse reactions in the ARISTOTLE and AVERROES studies are listed in Table 17 by system organ classification (MedDRA) and by frequency. The frequency assignments in Table 17 are primarily based on the frequencies observed in the ARISTOTLE study. The adverse reactions observed in the AVERROES study were consistent with those observed in the ARISTOTLE study. (See Table 17.)

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Treatment of VTE: The safety of apixaban has been evaluated in the AMPLIFY and AMPLIFY-EXT studies, including 2676 patients exposed to apixaban 10 mg twice daily, 3359 patients exposed to apixaban 5 mg twice daily, and 840 patients exposed to apixaban 2.5 mg twice daily. The mean duration of exposure to apixaban was 154 days and to enoxaparin/warfarin was 152 days in the AMPLIFY study. The mean duration of exposure to apixaban was approximately 330 days and to placebo was 312 days in the AMPLIFY-EXT study.
In the AMPLIFY study, adverse reactions related to bleeding occurred in 417 (15.6%) of apixaban treated patients compared to 661 (24.6%) of enoxaparin/warfarin-treated patients. The discontinuation rate due to bleeding events was 0.7% in the apixaban-treated patients compared to 1.7% in enoxaparin/warfarin-treated patients in the AMPLIFY study.
In the AMPLIFY-EXT study, adverse reactions related to bleeding occurred in 219 (13.3%) of apixaban-treated patients compared to 72 (8.7%) of placebo-treated patients. The discontinuation rate due to bleeding events was approximately 1% in the apixaban-treated patients compared to 0.4% in those patients in the placebo group in the AMPLIFY-EXT study.
Common adverse reactions (≥1%) were gingival bleeding, epistaxis, contusion, hematuria, hematoma, and menorrhagia.
Adverse reactions in the AMPLIFY and AMPLIFY-EXT studies are listed in Table 18 by system organ classification (MedDRA) and by frequency. (See Table 18.)

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Effect of Other Drugs on Apixaban: Inhibitors of CYP3A4 and P-gp: Co-administration of apixaban with ketoconazole (400 mg once a day), a strong inhibitor of both CYP3A4 and P-gp, led to a 2-fold increase in mean apixaban AUC and a 1.6 fold increase in mean apixaban C_max. No dose adjustment for apixaban is required with concomitant ketoconazole therapy, however apixaban should be used with caution in patients receiving concomitant systemic treatment with azole-antimycotics such as ketoconazole or other strong inhibitors of both CYP3A4 and P-gp (see Precautions).
Active substances that are not considered strong inhibitors of both CYP3A4 and P-gp (e.g., diltiazem, naproxen, amiodarone, verapamil, quinidine) are expected to increase apixaban plasma concentration to a lesser extent. No dose adjustment for apixaban is required when co-administered with agents that are not strong inhibitors of both CYP3A4 and P-gp. For example, diltiazem (360 mg once a day), considered a moderate CYP3A4 and a weak P-gp inhibitor, led to a 1.4 fold increase in mean apixaban AUC and a 1.3 fold increase in C_max. Naproxen (500 mg, single dose), an inhibitor of P-gp but not an inhibitor of CYP3A4, led to a 1.5- fold and 1.6-fold increase in mean apixaban AUC and C_max, respectively. Clarithromycin (500 mg, twice a day), an inhibitor of P-gp and a strong inhibitor of CYP3A4, led to a 1.6-fold and 1.4-fold increase in mean apixaban AUC and C_max, respectively.
Inducers of CYP3A4 and P-gp: Co-administration of apixaban with rifampin, a strong inducer of both CYP3A4 and P-gp, led to an approximate 54% and 42% decrease in mean apixaban AUC and C_max, respectively. The concomitant use of apixaban with other strong CYP3A4 and P-gp inducers (e.g., phenytoin, carbamazepine, phenobarbital or St. John's Wort) may also lead to reduced apixaban plasma concentrations. No dose adjustment for apixaban is required during concomitant therapy with such agents for the prevention of VTE following elective hip or knee replacement surgery or for the prevention of stroke or systemic embolism in non-valvular atrial fibrillation patients, however strong inducers of both CYP3A4 and P-gp should be co-administered with caution (see Precautions).
For the treatment of DVT and PE, concomitant therapy with strong inducers of both CYP3A4 and P-gp is not recommended (see Precautions). For the prevention of recurrent DVT and PE, strong inducers of both CYP3A4 and P-gp should be co-administered with caution (see Precautions).
Anticoagulants, platelet aggregation inhibitors, and NSAIDs: After combined administration of enoxaparin (40 mg single dose) with apixaban (5 mg single dose), an additive effect on anti-FXa activity was observed.
Pharmacokinetic or pharmacodynamic interactions were not evident in healthy subjects when apixaban was co-administered with ASA 325 mg once a day.
Apixaban co-administered with clopidogrel (75 mg once daily) or with the combination of clopidogrel 75 mg and ASA 162 mg once daily, or with prasugrel (60 mg followed by 10 mg once daily) in phase 1 studies did not show a relevant increase in bleeding time or further inhibition of platelet aggregation compared to administration of the antiplatelet agents without apixaban. Increases in clotting tests (PT, INR, and aPTT) were consistent with the effects of apixaban alone.
Naproxen (500 mg), an inhibitor of P-gp, led to a 1.5-fold and 1.6-fold increase in mean apixaban AUC and C_max, in healthy subjects, respectively. Corresponding increases in clotting tests were observed for apixaban. No changes were observed in the effect of naproxen on arachidonic acid-induced platelet aggregation and no clinically relevant prolongation of bleeding time was observed after concomitant administration of apixaban and naproxen.
Despite these findings, ELIQUIS should be used with caution when coadministered with NSAIDs (including ASA) because these medicinal products typically increase the bleeding risk.
Agents associated with serious bleeding are not recommended concomitantly with ELIQUIS, such as: unfractionated heparins and heparin derivatives (including low molecular weight heparins (LMWH)), FXa inhibiting oligosaccharides (e.g., fondaparinux), direct thrombin II inhibitors (e.g., desirudin), thrombolytic agents, GPIIb/IIIa receptor antagonists, dipyridamole, dextran, sulfinpyrazone, vitamin K antagonists, and other oral anticoagulants. It should be noted that unfractionated heparin can be administered at doses necessary to maintain a patent central venous or arterial catheter (see Precautions).
In patients with atrial fibrillation and a condition that warrants mono or dual antiplatelet therapy, a careful assessment of the potential benefits against the potential risks should be made before combining this therapy with ELIQUIS (see Precautions).
Other concomitant therapies: No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when apixaban was co-administered with atenolol or famotidine. Co-administration of apixaban 10 mg with atenolol 100 mg did not have a clinically relevant effect on the pharmacokinetics of apixaban. Following administration of the two drugs together, mean apixaban AUC and C_max were 15% and 18% lower than when administered alone. The administration of apixaban 10 mg with famotidine 40 mg had no effect on apixaban AUC or C_max.
Laboratory parameters: Clotting tests (e.g., PT, INR, and aPTT) are affected as expected by the mechanism of action of apixaban (see Pharmacology: Pharmacodynamics under Actions). Changes observed in these clotting tests at the expected therapeutic dose are small and subject to a high degree of variability (see Pharmacology: Pharmacokinetics under Actions).
Pediatric population: Interaction studies have only been performed in adults.
Effect of apixaban on other drugs: In vitro apixaban studies showed no inhibitory effect on the activity of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6 or CYP3A4 (IC50 >45 μM) and weak inhibitory effect on the activity of CYP2C19 (IC50 >20 μM) at concentrations that are significantly greater than peak plasma concentrations observed in patients. Apixaban did not induce CYP1A2, CYP2B6, CYP3A4/5 at a concentration up to 20 μM. Therefore, apixaban is not expected to alter the metabolic clearance of co-administered drugs that are metabolized by these enzymes. Apixaban is not a significant inhibitor of P-gp.
In studies conducted in healthy subjects, as described below, apixaban did not meaningfully alter the pharmacokinetics of digoxin, naproxen, or atenolol.
Digoxin: Co-administration of apixaban (20 mg once a day) and digoxin (0.25 mg once a day), a P-gp substrate, did not affect digoxin AUC or C_max. Therefore, apixaban does not inhibit P-gp mediated substrate transport.
Naproxen: Co-administration of single doses of apixaban (10 mg) and naproxen (500 mg), a commonly used NSAID, did not have any effect on the naproxen AUC or C_max.
Atenolol: Co-administration of a single dose of apixaban (10 mg) and atenolol (100 mg), a common beta-blocker, did not alter the pharmacokinetics of atenolol.

Store below 30°C.
Shelf-Life: 3 years.

Anticoagulants, Antiplatelets & Fibrinolytics (Thrombolytics)

B01AF02 - apixaban ; Belongs to the class of direct factor Xa inhibitors. Used in the treatment of thrombosis.

S