Eluxa: detailed information

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ELYXA® (ELUXA)

Composition:

Active substance: apixaban;

1 tablet contains 2.5 mg of apixaban;

Excipients: lactose, silicified microcrystalline cellulose, sodium croscarmellose, sodium lauryl sulfate, magnesium stearate;

Film coating: Opadry II Yellow 85F220087 (polyvinyl alcohol, titanium dioxide (E 171), macrogol, talc, yellow iron oxide (E 172), red iron oxide (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: round, biconvex, film-coated tablets of a cinnamon-yellow color.

Pharmacotherapeutic group. Antithrombotic medicinal agents.

Direct factor Xa inhibitors. ATC code B01AF02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Apixaban is a potent, reversible, direct, and highly selective oral inhibitor of the active site of factor Xa. For its antithrombotic effect, it does not require antithrombin III. Apixaban inhibits both free and thrombus-bound factor Xa and also suppresses the activity of prothrombinase. Apixaban does not directly affect platelet aggregation but indirectly inhibits thrombin-induced platelet aggregation. By inhibiting factor Xa, apixaban prevents thrombin generation and thrombus formation. Preclinical studies of apixaban in animals demonstrated the efficacy of the drug's antithrombotic effect in preventing arterial and venous thrombosis at doses that did not impair hemostatic processes.

Pharmacodynamic effects.

The pharmacodynamics of apixaban reflect its mechanism of action (inhibition of factor Xa). As a result of factor Xa inhibition, apixaban increases the values of prothrombin time (PT), international normalized ratio (INR), and activated partial thromboplastin time (aPTT). Changes observed in coagulation parameters during therapeutic dosing are minimal and highly variable, and are not recommended for assessing the pharmacodynamic properties of apixaban. In thrombin generation assays, apixaban reduced endogenous thrombin potential—a quantitative measure of thrombin generation in human plasma.

Apixaban also demonstrates activity in inhibiting factor Xa, as confirmed by reduced enzymatic activity of factor Xa in various commercial factor Xa activity assays, although specific results varied between different assay systems. Clinical study data are available only for the chromogenic assay Rotachrom® heparin. Factor Xa inhibitory activity correlates with plasma concentrations of apixaban. This relationship is approximately linear, with maximum factor Xa inhibition observed at peak plasma concentrations of apixaban. The relationship between plasma concentration of apixaban and factor Xa inhibitory activity is approximately linear over a wide dose range.

Table 1 shows the predicted steady-state concentrations and factor Xa inhibitory activity for each indication. In patients receiving apixaban for prevention of venous thromboembolism (VTE) after knee or hip replacement surgery, less than a 1.6-fold fluctuation was observed between peak and trough levels. In patients with non-valvular atrial fibrillation (NVAF) receiving apixaban for stroke and systemic embolism prevention, results indicated less than a 1.7-fold fluctuation between peak and trough levels. In patients receiving apixaban for treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), or for prevention of recurrent DVT and PE, less than a 2.2-fold fluctuation between peak and trough levels was observed.

Predicted steady-state concentrations of apixaban and factor Xa inhibitory activity

Table 1

Dosing	Apixaban, Cmax (ng/mL)	Apixaban, Cmin (ng/mL)	Maximum anti-Factor Xa activity of apixaban (IU/mL)	Minimum anti-Factor Xa activity of apixaban (IU/mL)
Dosing	Median [5th, 95th percentile]
Prevention of VTE after elective knee or hip replacement surgery
2.5 mg twice daily	77 [41, 146]	51 [23, 109]	1.3 [0.67; 2.4]	0.84 [0.37; 1.8]
Prevention of stroke and systemic embolism in patients with NVAF
2.5 mg twice daily*	123 [69, 221]	79 [34, 162]	1.8 [1.0; 3.3]	1.2 [0.51; 2.4]
5 mg twice daily	171 [91, 321]	103 [41, 230]	2.6 [1.4; 4.8]	1.5 [0.61; 3.4]
Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (EVTt)
2.5 mg twice daily	67 [30, 153]	32 [11, 90]	1.0 [0.46; 2.5]	0.49 [0.17; 1.4]
5 mg twice daily	132 [59, 302]	63 [22, 177]	2.1 [0.91; 5.2]	1.0 [0.33; 2.9]
10 mg twice daily	251 [111, 572]	120 [41, 335]	4.2 [1.8; 10.8]	1.9 [0.64; 5.8]

* Dose adjustment for the population was based on meeting 2 out of 3 dose-reduction criteria in the ARISTOTLE study.

2 r.d. – twice daily.

Although apixaban treatment does not require routine monitoring of exposure levels, in exceptional circumstances when information on apixaban exposure levels may assist in making a clinical decision (e.g., in cases of overdose or emergency surgery), a calibrated method for quantitative determination of anti-factor Xa activity may be used.

Clinical efficacy and safety.

Prevention of venous thromboembolism (VTEp) following hip or knee replacement surgery.

The clinical development program for apixaban was designed to demonstrate the efficacy and safety of apixaban for the prevention of venous thromboembolism in various populations of adult patients undergoing elective hip or knee replacement surgery. Overall, 8,464 patients were randomized in two pivotal, double-blind, multinational studies comparing oral apixaban 2.5 mg twice daily (4,236 patients) with enoxaparin 40 mg once daily (4,228 patients). The total population included 1,262 patients aged 75 years and older (of whom 618 were in the apixaban treatment group), 1,004 patients with low body weight (≤ 60 kg) (of whom 499 were in the apixaban treatment group), 1,495 patients with a body mass index ≥ 33 kg/m² (of whom 743 were in the apixaban treatment group), and 415 patients with moderate renal impairment (of whom 203 were in the apixaban treatment group).

The ADVANCE-3 study included 5,407 patients undergoing elective hip replacement surgery, and the ADVANCE-2 study included 3,057 patients undergoing elective knee replacement surgery. Participants received either oral apixaban 2.5 mg twice daily (p.o. 2 r.d.), or subcutaneous enoxaparin 40 mg once daily (s.c. 1 r.d.). The first dose of apixaban was administered 12–24 hours after surgery, whereas enoxaparin was initiated 9–15 hours before surgery. Apixaban and enoxaparin were administered for 32–38 days in the ADVANCE-3 study and for 10–14 days in the ADVANCE-2 study.

Based on medical history data from the 8,464 patients enrolled in the ADVANCE-3 and ADVANCE-2 studies, 46% of patients had hypertension, 10% had hyperlipidemia, 9% had diabetes, and 8% had coronary artery atherosclerosis.

Apixaban demonstrated a statistically significant greater reduction in the incidence of the primary efficacy endpoint (composite endpoint of all venous thromboembolism events and all-cause mortality) and in the "Major venous thromboembolism" endpoint (composite endpoint of proximal deep vein thrombosis, non-fatal pulmonary embolism, and deaths related to venous thromboembolism) compared to enoxaparin in patients undergoing both elective hip and knee replacement surgery (see Table 2).

Efficacy results from the pivotal Phase III studies

Table 2

Study	ADVANCE-3 (hip joint)			ADVANCE-2 (knee joint)
Investigated treatment Dose Treatment duration	Apixaban 2.5 mg p.o. 2 times daily 35 ± 3 days	Enoxaparin 40 mg s.c. once daily 35 ± 3 days	p value	Apixaban 2.5 mg p.o. 2 times daily 12 ± 2 days	Enoxaparin 40 mg s.c. once daily 12 ± 2 days	p value
Total number of venous thromboembolism events / overall mortality
Number of events / participants Incidence rate	27/1949 1.39 %	74/1917 3.86 %	<0.0001	147/976 15.06 %	243/997 24.37 %	<0.0001
Relative risk 95 % CI	0.36 (0.22, 0.54)	- -	<0.0001	0.62 (0.51, 0.74)	-	<0.0001
Major venous thromboembolic events
Number of events / participants Incidence rate	10/2199 0.45 %	25/2195 1.14 %	0.0107	13/1195 1.09 %	26/1199 2.17 %	0.0373
Relative risk (%)	0.40		0.0107	0.50		0.0373
95 % CI	(0.15; 0.80)			(0.26; 0.97)

In patients who received 2.5 mg apixaban or 40 mg enoxaparin, similar rates were observed for safety endpoints such as major bleeding, the composite endpoint of major bleeding and clinically relevant non-major bleeding (CRNM), and the endpoint of all bleeding. All bleeding criteria included bleeding at the surgical site.

In Phase II and III studies involving patients undergoing elective hip or knee replacement surgery, the overall incidence of adverse events such as bleeding, anemia, and elevations in transaminase levels (e.g., alanine aminotransferase) was numerically lower in patients in the apixaban treatment group compared to those in the enoxaparin treatment group.

Among patients undergoing knee replacement surgery, 4 cases of pulmonary embolism were reported in the apixaban treatment group during the planned treatment period, compared to no cases in the enoxaparin treatment group. The reason for this increased number of pulmonary embolism cases cannot be explained.

Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF).

In the clinical program (ARISTOTLE study: apixaban compared with warfarin; and AVERROES study: apixaban compared with acetylsalicylic acid), a total of 23,799 patients were randomized, of whom 11,927 were assigned to apixaban treatment groups. The program was designed to demonstrate the efficacy and safety of apixaban for the prevention of stroke and systemic embolism in patients with NVAF and the presence of one or more additional risk factors, namely:

prior history of stroke or transient ischemic attack (TIA);
age ≥ 75 years;
arterial hypertension;
diabetes mellitus;
symptomatic heart failure (NYHA class ≥ II).

ARISTOTLE study.

In the ARISTOTLE study, a total of 18,201 patients were randomized; participants were assigned to double-blind treatment with either apixaban 5 mg twice daily (or 2.5 mg twice daily in some patients (4.7%)—see section "Posology and method of administration") or warfarin (target INR range 2.0–3.0). Patients received the study drug for a median duration of 20 months.

The mean age of participants was 69.1 years, and the mean CHADS₂ score was 2.1. A history of stroke or TIA was present in 18.9% of patients.

In this study, apixaban treatment demonstrated a statistically significant benefit over warfarin for the primary efficacy endpoint of prevention of stroke (hemorrhagic or ischemic) and systemic embolism (see Table 3).

Efficacy in patients with atrial fibrillation enrolled in the ARISTOTLE study

Table 3

Parameter	Apixaban N=9120 n (%/year)	Warfarin N=9081 n (%/year)	Hazard ratio (95 % CI)	p-value
Stroke or systemic embolism	212 (1.27)	265 (1.60)	0.79 (0.66; 0.95)	0.0114
Ischemic or undetermined stroke	162 (0.97)	175 (1.05)	0.92 (0.74; 1.13)
Hemorrhagic stroke	40 (0.24)	78 (0.47)	0.51 (0.35; 0.75)
Systemic embolism	15 (0.09)	17 (0.10)	0.87 (0.44; 1.75)

In patients assigned to warfarin treatment, the median time (%) during which the INR was within the range of 2.0–3.0 while on therapeutic treatment was 66%.

Apixaban demonstrated a reduction in the rate of stroke and systemic embolism (compared to warfarin treatment) across various levels of average time in the therapeutic range. For the highest quartile, the relative risk ratio for apixaban versus warfarin was 0.73 (95% CI 0.38, 1.40).

The key secondary endpoints of major bleeding and all-cause mortality were evaluated using a pre-specified hierarchical hypothesis testing strategy to control the overall type I error rate in the study. Statistically significant advantages were also observed for apixaban over warfarin regarding the key secondary endpoints of major bleeding and all-cause mortality (see Table 4). However, with more stringent INR control, the advantage of apixaban over warfarin in terms of all-cause mortality was reduced.

Secondary endpoints in patients with atrial fibrillation in the ARISTOTLE study

Table 4

Parameter	Apixaban N = 9088 n (%/year)	Warfarin N = 9052 n (%/year)	Hazard ratio (95 % CI)	p-value
Bleeding endpoints
Major*	327 (2.13)	462 (3.09)	0.69 (0.60; 0.80)	<0.0001
Fatal	10 (0.06)	37 (0.24)
Intracranial	52 (0.33)	122 (0.80)
Major + clinically non-major bleeding	613 (4.07)	877 (6.01)	0.68 (0.61; 0.75)	<0.0001
All events	2356 (18.1)	3060 (25.8)	0.71 (0.68; 0.75)	<0.0001
Other endpoints
Total mortality	603 (3.52)	669 (3.94)	0.89 (0.80; 1.00)	0.0465
Myocardial infarction	90 (0.53)	102 (0.61)	0.88 (0.66; 1.17)

*Major bleeding, defined according to the criteria of the International Society on Thrombosis and Haemostasis (ISTH).

The cumulative incidence of treatment discontinuation due to adverse reactions in the ARISTOTLE trial was 1.8% with apixaban and 2.6% with warfarin.

Efficacy results in pre-specified subgroups (including subgroups based on CHADS2 score, age, body weight, sex, renal function, prior history of stroke, transient ischemic attack [TIA], and diabetes) were consistent with the primary efficacy outcomes in the overall study population.

The rate of major gastrointestinal bleeding according to ISTH classification (including bleeding from upper and lower gastrointestinal tract and rectal bleeding) was 0.76% per year with apixaban and 0.86% per year with warfarin.

The rate of major bleeding in pre-specified subgroups (including subgroups based on CHADS2 score, age, body weight, sex, renal function, prior history of stroke, TIA, and diabetes) was consistent with results in the overall population.

AVERROES trial.

A total of 5,598 patients were randomized in the AVERROES trial, all of whom were unsuitable for vitamin K antagonist (VKA) therapy. Study participants were assigned to receive either apixaban 5 mg twice daily (or 2.5 mg twice daily in certain patients (6.4%) (see section "Dosage and administration")) or acetylsalicylic acid (ASA). ASA was administered once daily at doses of 81 mg (64%), 162 mg (26.9%), 243 mg (2.1%), or 324 mg (6.6%), as determined by the investigator. The mean duration of study drug exposure was 14 months. The mean age of participants was 69.9 years, and the mean CHADS2 score was 2.0. A history of prior stroke or TIA was reported in 13.6% of patients.

Common reasons for unsuitability for VKA therapy included: inability/low likelihood of achieving required INR levels within the required timeframe (42.6%), patient refusal of VKA therapy (37.4%), CHADS2 score = 1 and physician recommendation against VKA therapy (21.3%), inability to ensure patient compliance with VKA dosing instructions (15%), and difficulty/predicted difficulty in contacting the patient promptly when immediate dose adjustment was needed (11.7%).

The AVERROES trial was terminated prematurely based on the recommendation of the independent Data Monitoring Committee due to compelling evidence of reduced incidence of stroke and systemic embolism combined with a favorable safety profile.

The cumulative incidence of treatment discontinuation due to adverse reactions in the AVERROES trial was 1.5% with apixaban and 1.3% with ASA. In this trial, apixaban treatment demonstrated a statistically significant advantage over ASA for the primary efficacy endpoint of prevention of stroke (hemorrhagic, ischemic, or unspecified) or systemic embolism (see Table 5).

Key efficacy results in patients with atrial fibrillation who participated in the AVERROES trial

Table 5

Parameter	Apixaban N = 2807 n (%/year)	ASA N = 2791 n (%/year)	Risk ratio (95 % CI)	p-value
Stroke or systemic embolism*	51 (1.62)	113 (3.63)	0.45 (0.32; 0.62)	<0.0001
Ischemic or undetermined stroke	43 (1.37)	97 (3.11)	0.44 (0.31; 0.63)
Hemorrhagic stroke	6 (0.19)	9 (0.28)	0.67 (0.24; 1.88)
Systemic embolism	2 (0.06)	13 (0.41)	0.15 (0.03; 0.68)
Stroke, systemic embolism, myocardial infarction, or vascular death*†	132 (4.21)	197 (6.35)	0.66 (0.53; 0.83)	0.003
Myocardial infarction	24 (0.76)	28 (0.89)	0.86 (0.50; 1.48)
Vascular death	84 (2.65)	96 (3.03)	0.87 (0.65; 1.17)
Total mortality†	111 (3.51)	140 (4.42)	0.79 (0.62; 1.02)	0.068

* Assessment using a sequential testing strategy designed to control the overall type I error rate in the study.

† Secondary endpoint.

There was no statistically significant difference in the rate of major bleeding between apixaban and aspirin.

Patients with non-valvular atrial fibrillation (NVAF) with acute coronary syndrome (ACS) and/or undergoing percutaneous coronary intervention (PCI)

In the AUGUSTUS trial—a double-blind, randomized, controlled 2×2 factorial design study—4,614 patients with NVAF who had ACS (43%) and/or underwent PCI (56%) were enrolled. All patients received background therapy with a P2Y12 inhibitor (clopidogrel: 90.3%), administered according to local treatment standards.

Patients within 14 days after ACS and/or PCI were randomized to receive either apixaban 5 mg twice daily (2.5 mg twice daily if the patient met two or more dose-reduction criteria; 10% received the lower dose) or a vitamin K antagonist (VKA) and aspirin (81 mg once daily) or placebo. The mean age of patients was 69.9 years, 94% of randomized patients had a CHA2DS2-VASc score >2, and 47% had a HAS-BLED score >3. For patients randomized to VKA, the time in therapeutic range (TTR) (INR 2–3) was 56%, with 32% of time below TTR and 12% above TTR.

The primary objective of the AUGUSTUS trial was to evaluate safety, and the primary endpoint was major or clinically relevant non-major bleeding according to ISTH criteria. In the apixaban versus VKA comparison, the primary endpoint—major or clinically relevant non-major bleeding according to ISTH criteria at 6 months—occurred in 241 (10.5%) and 332 (14.7%) patients in the apixaban and VKA groups, respectively (RR = 0.69, 95% CI: 0.58, 0.82; two-sided p<0.0001 for non-inferiority and p<0.0001 for superiority). For VKA, an additional analysis using TTR subgroups showed that the highest bleeding rate was associated with the lowest TTR quartile. The bleeding rate was similar when comparing apixaban with VKA in the highest TTR quartile subgroup.

In the comparison of aspirin versus placebo, the primary endpoint—major or non-major clinically relevant bleeding according to ISTH criteria at 6 months—occurred in 367 (16.1%) and 204 (9.0%) patients in the aspirin and placebo groups, respectively (RR = 1.88, 95% CI: 1.58, 2.23; two-sided p<0.0001).

Specifically, in patients receiving apixaban treatment, major or clinically relevant non-major bleeding occurred in 157 (13.7%) and 84 (7.4%) patients in the aspirin and placebo groups, respectively. In patients receiving VKA treatment, major or clinically relevant non-major bleeding occurred in 208 (18.5%) and 122 (10.8%) patients in the aspirin and placebo groups, respectively.

Other treatment effects were evaluated as a secondary trial objective using composite endpoints.

In the comparison of apixaban with VKA, the composite endpoint—death or recurrent hospitalization—occurred in 541 (23.5%) and 632 (27.4%) patients in the apixaban and VKA groups, respectively. The composite endpoint—death or ischemic event (stroke, myocardial infarction, stent thrombosis, or urgent revascularization)—occurred in 170 (7.4%) and 182 (7.9%) patients in the apixaban and VKA groups, respectively.

In the comparison of aspirin with placebo, the composite endpoint—death or recurrent hospitalization—occurred in 604 (26.2%) and 569 (24.7%) patients in the aspirin and placebo groups, respectively. The composite endpoint—death or ischemic event (stroke, myocardial infarction, stent thrombosis, or urgent revascularization)—occurred in 163 (7.1%) and 189 (8.2%) patients in the aspirin and placebo groups, respectively.

Patients undergoing cardioversion

EMANATE was an open-label, multicenter trial involving 1,500 patients with NVAF who were not receiving anticoagulation or had received treatment for less than 48 hours and were scheduled for cardioversion.

Patients were randomized in a 1:1 ratio to receive either apixaban or heparin and/or VKA for prevention of cardiovascular events. Electrical and/or pharmacological cardioversion was performed after at least 5 doses of apixaban 5 mg twice daily (or 2.5 mg twice daily in selected patients)* or at least 2 hours after a 10 mg loading dose (or 5 mg loading dose in selected patients)*, if earlier cardioversion was required (* see section "Dosage and administration").

In the apixaban treatment group, 342 patients received a loading dose (331 patients received a 10 mg dose and 11 received a 5 mg dose).

In the apixaban treatment group (n = 753), there were no strokes (0%), whereas in the heparin and/or VKA treatment group (n = 747, RR 0.00, 95% CI 0.00, 0.64), 6 (0.80%) strokes occurred.

Fatal events (unspecified cause) occurred in 2 patients (0.27%) in the apixaban group and 1 patient (0.13%) in the heparin and/or VKA group. No cases of systemic embolism were reported.

Cases of major and clinically relevant non-major bleeding were observed 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.

A prespecified analysis demonstrated comparable efficacy and safety between the apixaban and heparin and/or VKA treatment groups during cardioversion.

Treatment of DVT, treatment of PE, and prevention of recurrent DVT and PE (VTE).

The clinical program (AMPLIFY: apixaban vs. enoxaparin/warfarin; AMPLIFY-EXT: apixaban vs. placebo) was designed to demonstrate the efficacy and safety of apixaban for the treatment of DVT and/or PE (AMPLIFY) and the extended use of the drug for prevention of recurrent DVT and/or PE after 6–12 months of anticoagulant treatment for DVT and/or PE (AMPLIFY-EXT). Both studies were randomized, double-blind, international, parallel-group trials conducted in patients with symptomatic proximal DVT or symptomatic PE. All primary efficacy and safety endpoints were adjudicated by an independent committee based on blinded data.

AMPLIFY study.

In the AMPLIFY study, 5,395 patients were randomized to: the apixaban treatment group receiving oral apixaban 10 mg twice daily for 7 days followed by oral apixaban 5 mg twice daily for 6 months; the enoxaparin treatment group receiving subcutaneous enoxaparin 1 mg/kg twice daily for at least 5 days (until INR ≥ 2 was achieved); and the warfarin treatment group receiving oral warfarin (target INR range 2.0–3.0) for 6 months.

The mean patient age was 56.9 years, and 89.8% of randomized patients had unprovoked VTE events.

In patients assigned to the warfarin treatment group, the mean percentage of time in the INR therapeutic range (TTR) of 2.0–3.0 was 60.9%. Apixaban demonstrated reduced rates of recurrent symptomatic VTE or VTE-related death across different TTR values. For the highest quartile relative to the mean, the risk ratio for apixaban versus enoxaparin/warfarin was 0.79 (95% CI: 0.39; 1.61).

This study demonstrated that apixaban was non-inferior to enoxaparin/warfarin for the primary composite efficacy endpoint of adjudicated recurrent symptomatic VTE (DVT or PE without fatal outcome) or VTE-related death.

The efficacy of apixaban during initial VTE treatment was comparable in patients receiving the drug for the treatment of PE [relative risk 0.9; 95% CI (0.5, 1.6)] and DVT [relative risk 0.8; 95% CI (0.5, 1.3)]. Efficacy across subgroups, including those stratified by age, sex, body mass index (BMI), renal function, size of PE, location of DVT thrombus, and prior parenteral heparin use, was generally consistent.

The primary safety endpoint was bleeding. In this study, apixaban demonstrated statistically significant advantages compared to enoxaparin/warfarin for the primary safety endpoint [relative risk 0.31, 95% CI (0.17, 0.55), p <0.0001] (see Table 6).

Bleeding outcomes in the AMPLIFY study

Table 6

Outcome	Apixaban N=2676 n (%)	Enoxaparin /warfarin N=2689 n (%)	Relative risk (95 % CI)
Major	15 (0.6)	49 (1.8)	0.31 (0.17; 0.55)
Major + CRNM	115 (4.3)	261 (9.7)	0.44 (0.36; 0.55)
Minor	313 (11.7)	505 (18.8)	0.62 (0.54; 0.70)
All types	402 (15.0)	676 (25.1)	0.59 (0.53; 0.66)

Significant bleeding and clinically relevant non-major bleeding (CRNMB) at any anatomical site were generally lower in the apixaban group compared to the enoxaparin/warfarin group. According to ISTH classification, significant gastrointestinal bleeding occurred in 6 patients (0.2%) receiving apixaban and in 17 patients (0.6%) receiving enoxaparin/warfarin.

AMPLIFY-EXT study.

In the AMPLIFY-EXT study, 2482 patients were randomized to receive either apixaban 2.5 mg orally twice daily, apixaban 5 mg orally twice daily, or placebo for 12 months following completion of an initial 6–12 month course of anticoagulant therapy. Of these, 836 patients (33.7%) had participated in the AMPLIFY study prior to enrollment in AMPLIFY-EXT. The mean patient age was 56.7 years, and 91.7% of the randomized patients had experienced unprovoked VTE events.

In this study, both apixaban doses demonstrated statistically significant efficacy advantages compared to placebo for the primary efficacy outcome of symptomatic recurrent VTE (DVT or non-fatal PE) or death from any cause (see Table 7).

Efficacy results in the AMPLIFY-EXT study

Table 7

Indicator	Apixaban	Apixaban	Placebo	Relative risk (95% CI)
	2.5 mg (N=840)	5.0 mg (N=813)	(N=829)	apixaban 2.5 mg compared with placebo	apixaban 5.0 mg compared with placebo
	n (%)			apixaban 2.5 mg compared with placebo	apixaban 5.0 mg compared with placebo
Death due to recurrent VTE or any cause	19 (2.3)	14 (1.7)	77 (9.3)	0.24 (0.15; 0.40)¥	0.19 (0.11; 0.33)¥
DVT*	6 (0.7)	7 (0.9)	53 (6.4)
PE*	7 (0.8)	4 (0.5)	13 (1.6)
Death from any cause	6 (0.7)	3 (0.4)	11 (1.3)
Death related to recurrent VTE or to PE	14 (1.7)	14 (1.7)	73 (8.8)	0.19 (0.11, 0.33)	0.20 (0.11; 0.34)
Death related to recurrent VTE or cardiovascular events	14 (1.7)	14 (1.7)	76 (9.2)	0.18 (0.10; 0.32)	0.19 (0.11; 0.33)
Non-fatal DVT†	6 (0.7)	8 (1.0)	53 (6.4)	0.11 (0.05; 0.26)	0.15 (0.07; 0.32)
Non-fatal PE†	8 (1.0)	4 (0.5)	15 (1.8)	0.51 (0.22; 1.21)	0.27 (0.09; 0.80)
Death related to PE	2 (0.2)	3 (0.4)	7 (0.8)	0.28 (0.06; 1.37)	0.45 (0.12; 1.71)

¥ p <0.0001.

* For patients who experienced more than one event contributing to the composite endpoint, only the first event was reported (e.g., if a study participant experienced DVT first and then PE, only DVT was recorded in the report).

† Individual patients may have experienced more than one event, and events could be counted in both classifications.

Apixaban efficacy for prevention of VTE recurrence remained consistent across various subgroups, including those classified by age, sex, body mass index, and renal function.

The primary safety endpoint was major bleeding during the treatment period. In this study, the rate of major bleeding with both apixaban doses did not differ statistically from placebo. There was no statistically significant difference in the incidence of major, clinically non-major bleeding, CRNM, or all bleeding between the apixaban 2.5 mg twice daily and placebo groups.

ISTH-defined major gastrointestinal bleeding occurred in 1 (0.1%) patient receiving apixaban 5 mg twice daily, did not occur in any patient receiving apixaban 2.5 mg twice daily, and was observed in 1 patient (0.1%) receiving placebo.

Children.

The European Medicines Agency has deferred the obligation to submit the results of studies with apixaban involving pediatric patients in one or more pediatric subgroups with venous or arterial thromboembolism (information on pediatric use can be found in section “Posology and method of administration”).

Pharmacokinetics.

Absorption.

The absolute bioavailability of apixaban following doses up to and including 10 mg is approximately 50%. Apixaban is rapidly absorbed, with peak plasma concentration (Cmax) reached within 3–4 hours after tablet intake. Food intake does not affect the AUC or Cmax of apixaban when administered at a dose of 10 mg. Apixaban may be taken with or without food.

Following oral administration at doses not exceeding 10 mg, apixaban pharmacokinetics are linear, with dose-proportional increases in exposure. At doses ≥ 25 mg, apixaban exhibits solubility-limited absorption and reduced bioavailability. Apixaban exposure parameters show low to moderate variability, reflected by an intra-participant variability of approximately 20% coefficient of variation (CV) and inter-participant variability of approximately 30% CV.

Following oral administration of 10 mg apixaban as 2 crushed 5 mg tablets suspended in 30 mL of water, exposure was comparable to that following administration of 2 whole 5 mg tablets. Following oral administration of 10 mg apixaban as 2 crushed 5 mg tablets mixed with 30 g of apple puree, Cmax and AUC were 20% and 16% lower, respectively, compared to administration of 2 whole 5 mg tablets.

This reduction in exposure is not considered clinically significant.

Following administration of a crushed 5 mg apixaban tablet suspended in 60 mL of 5% aqueous dextrose solution and administered via nasogastric tube, exposure was similar to that observed in other clinical studies in healthy volunteers receiving a single 5 mg apixaban tablet orally.

Given the predicted dose-proportional pharmacokinetic profile of apixaban, the results of the bioavailability studies are applicable to lower doses of apixaban.

Distribution.

Plasma protein binding in humans is approximately 87%. The volume of distribution is approximately 21 liters.

Biotransformation and elimination.

Apixaban is eliminated from the body through multiple pathways. Approximately 25% of the administered dose of apixaban is excreted as metabolites, with the majority of metabolites eliminated in feces. Renal clearance of apixaban accounts for approximately 27% of total clearance. Additional roles of biliary and direct intestinal elimination pathways were observed in clinical and preclinical studies.

Total clearance of apixaban is approximately 3.3 L/h, and the elimination half-life is approximately 12 hours.

The main biotransformation pathways are O-demethylation and hydroxylation of the 3-oxopiperidinyl moiety. Apixaban metabolism is primarily mediated by CYP3A4/5. CYP1A2, 2C8, 2C9, 2C19, and 2J2 play minor roles in drug metabolism. In human plasma, unchanged apixaban is the main circulating compound associated with this medicinal product. There are no circulating active metabolites in plasma. Apixaban is a substrate of transport proteins P-gp and breast cancer resistance protein (BCRP).

Renal impairment.

Renal impairment did not affect the peak concentration of apixaban. Based on creatinine clearance assessment, increased apixaban exposure correlated with decreased renal function. 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, plasma concentrations of apixaban increased by 16%, 29%, and 44%, respectively, compared to individuals with normal creatinine clearance. Renal impairment did not have a pronounced effect on the relationship between apixaban plasma concentration and the degree of factor Xa inhibition.

Hepatic impairment.

In a study comparing 8 participants with mild hepatic impairment (Child–Pugh class A, score 5 (n=6) and 6 (n=2)) and 8 participants with moderate hepatic impairment (Child–Pugh class B, score 7 (n=6) and 8 (n=2)) to 16 healthy volunteers in the control group, the pharmacokinetics and pharmacodynamics of a single 5 mg dose of apixaban were not altered by hepatic impairment. Changes in factor Xa inhibition activity and changes in INR were comparable between healthy volunteers and patients with mild or moderate hepatic impairment.

Geriatric patients.

Higher drug concentrations in plasma were observed in geriatric patients (over 65 years of age) compared to younger patients; mean AUC values in elderly patients were approximately 32% higher, with no change in Cmax.

Sex.

Apixaban exposure in females was approximately 18% higher than in males.

Ethnic origin and race.

Phase I study results indicate no notable differences in apixaban pharmacokinetic parameters among Caucasian, Mongoloid, and Negroid populations. Population pharmacokinetic analysis results from patients receiving apixaban after elective hip or knee replacement surgery were consistent with Phase I study findings.

Body weight.

When comparing apixaban exposure in individuals with different body weights, exposure decreased by approximately 30% in those with body weight above 120 kg compared to normal weight (65–85 kg), while body weight below 50 kg was associated with approximately 30% higher exposure.

Pharmacodynamic/pharmacokinetic relationship.

The pharmacokinetic/pharmacodynamic (PK/PD) relationship between apixaban plasma concentration and certain PD endpoints (factor Xa inhibition activity, INR, PT, aPTT) was evaluated after administration of various apixaban doses across a wide range from 0.5 to 50 mg. The concentration of apixaban in plasma and factor Xa inhibition activity were best described by a linear model. The PK/PD relationships observed in patients receiving apixaban after elective hip or knee replacement surgery were consistent with those in healthy volunteers.

Clinical characteristics.

Indications.

Prevention of venous thromboembolism in adult patients who have undergone elective knee or hip replacement surgery.

Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation who have one or more risk factors such as prior history of stroke or transient ischemic attack, age 75 years or older, hypertension, diabetes mellitus, or symptomatic heart failure (at least NYHA Class II).

Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as prevention of recurrent DVT and PE in adults (information regarding patients with PE and hemodynamic instability is provided in the section "Special precautions").

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Clinically significant active bleeding.

Liver disease associated with coagulopathy and clinically significant risk of bleeding.

Pathological condition or state associated with a high risk of major bleeding (e.g. current or recent peptic ulcer disease of the gastrointestinal tract, presence of malignant neoplasms with a high risk of bleeding, recent head or spinal cord trauma, recent surgery on the brain, spinal cord or eye, recent intracranial hemorrhage, diagnosed or suspected esophageal varices, arteriovenous malformations, vascular aneurysms, significant intraspinal or intracranial vascular abnormalities).

Concomitant use of any other anticoagulants, such as unfractionated heparin, low-molecular-weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), or oral anticoagulants (warfarin, rivaroxaban, dabigatran, etc.), except in specific circumstances of switching anticoagulant therapy (see section "Dosage and administration"): administration of unfractionated heparin at doses required to maintain patency of a central venous or arterial catheter, or administration of unfractionated heparin during catheter ablation for treatment of atrial fibrillation (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Inhibitors of CYP3A4 and P-gp.

Concomitant administration of apixaban and ketoconazole (400 mg once daily), a potent inhibitor of CYP3A4 and P-gp, resulted in a doubling of the mean AUC and a 1.6-fold increase in the mean Cmax of apixaban.

Eluxa® must not be prescribed to patients receiving systemic treatment with potent inhibitors of CYP3A4 and P-gp, such as azole antifungals (e.g. ketoconazole, itraconazole, voriconazole, posaconazole) or HIV protease inhibitors (e.g. ritonavir) (see section "Special precautions").

Active substances not considered potent inhibitors of CYP3A4 and P-gp (e.g. amiodarone, clarithromycin, diltiazem, fluconazole, naproxen, quinidine, verapamil) are expected to increase plasma concentrations of apixaban to a lesser extent. Dose adjustment of apixaban is not required when co-administered with substances that are not strong inhibitors of CYP3A4 and/or P-gp. For example, diltiazem (360 mg once daily), considered a moderate inhibitor of CYP3A4 and a weak inhibitor of P-gp, increased the mean AUC and Cmax of apixaban by 1.4- and 1.3-fold, respectively. Naproxen (single dose 500 mg), an inhibitor of P-gp but not affecting CYP3A4, increased the mean AUC and Cmax of apixaban by 1.5- and 1.6-fold, respectively. Clarithromycin (500 mg twice daily), an inhibitor of P-gp and a strong inhibitor of CYP3A4, increased the mean AUC and Cmax of apixaban by 1.6- and 1.3-fold, respectively.

Inducers of CYP3A4 and P-gp.

Concomitant administration of apixaban and rifampicin (a potent inducer of CYP3A4 and P-gp) resulted in approximately 54% and 42% reduction in mean AUC and Cmax of apixaban, respectively. Concomitant use of apixaban with other potent inducers of CYP3A4 and P-gp (e.g. phenytoin, carbamazepine, phenobarbital, or St. John's wort) may also lead to reduced plasma concentrations of apixaban. Dose adjustment of apixaban is not required when co-administered with such agents. However, for prevention of VTE during elective hip or knee replacement surgery, prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation, and prevention of recurrent DVT and PE, apixaban should be used with caution in patients receiving concomitant treatment with potent inducers of CYP3A4 and P-gp.

Apixaban is not recommended for the treatment of DVT and PE in patients receiving concomitant systemic treatment with potent inducers of CYP3A4 and P-gp, as its efficacy may be compromised (see section "Special precautions").

Anticoagulants, antiplatelet agents, selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs), and nonsteroidal anti-inflammatory drugs (NSAIDs).

Due to increased risk of bleeding, concomitant use of any other anticoagulants is contraindicated, except in specific circumstances of switching anticoagulant therapy, when unfractionated heparin is administered at doses required to maintain patency of a central venous or arterial catheter, or unfractionated heparin is administered during catheter ablation for treatment of atrial fibrillation (see section "Contraindications").

After combined administration of enoxaparin (single dose 40 mg) and apixaban (single dose 5 mg), an additive effect on anti-Xa activity was observed.

Concomitant administration of apixaban and acetylsalicylic acid (ASA) (325 mg once daily) did not result in significant pharmacokinetic or pharmacodynamic interactions.

Concomitant administration of apixaban with clopidogrel (75 mg once daily), or with a combination of 75 mg clopidogrel and 162 mg ASA once daily, or with prasugrel (initial dose 60 mg, subsequent dose 10 mg once daily) in Phase I studies did not show a significant increase in modeled bleeding time or additional inhibition of platelet aggregation compared to antiplatelet agents alone. Changes in coagulation parameters (PT, INR, and aPTT) were consistent with the effects of apixaban as monotherapy.

Naproxen (500 mg), an inhibitor of P-gp, increased the mean AUC and Cmax of apixaban by 1.5- and 1.6-fold, respectively. Apixaban caused corresponding increases in coagulation parameters. Concomitant administration of naproxen and apixaban did not alter the effect of naproxen on platelet aggregation induced by arachidonic acid and did not result in clinically significant prolongation of bleeding time. Nevertheless, in individual patients, a more pronounced pharmacodynamic response to concomitant administration of antiplatelet agents and apixaban may occur. Eluxa® should be used with caution when combined with SSRIs/SNRIs, NSAIDs, ASA, and/or P2Y12 inhibitors, as these medicinal products generally increase the risk of bleeding (see section "Special precautions").

Limited experience exists with concomitant use of other antiplatelet agents (such as GPIIb/IIIa receptor antagonists, dipyridamole, dextran, or sulfinpyrazone) or thrombolytic agents. Since these agents increase the risk of bleeding, their concomitant use with Eluxa® is not recommended (see section "Special precautions").

Other concomitant medications.

No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when apixaban was co-administered with atenolol or famotidine. Concomitant administration of 10 mg apixaban and 100 mg atenolol had no clinically significant effect on the pharmacokinetics of apixaban. After repeated co-administration of both drugs, mean AUC and Cmax of apixaban were 15% and 18% lower, respectively, compared to monotherapy. Concomitant administration of 10 mg apixaban and 40 mg famotidine did not affect AUC or Cmax of apixaban.

Effect of apixaban on other medicinal products.

In vitro studies with apixaban showed no inhibitory effect on the activity of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6, or CYP3A4 (IC50 > 45 µmol/L), and weak inhibitory effect on CYP2C19 activity (IC50 > 20 µmol/L) at concentrations significantly higher than peak plasma concentrations in patients. Apixaban at concentrations up to 20 µmol/L does not induce the activity of CYP1A2, CYP2B6, or CYP3A4/5. Therefore, apixaban is not expected to alter the metabolic clearance of concomitant drugs metabolized by these enzymes. Apixaban does not significantly inhibit P-gp activity.

As described below, in studies involving healthy volunteers, apixaban did not cause significant changes in the pharmacokinetics of digoxin, naproxen, or atenolol.

Digoxin. Concomitant administration of apixaban (20 mg once daily) and digoxin, a P-gp substrate (0.25 mg once daily), did not alter AUC or Cmax of digoxin. Thus, apixaban does not inhibit P-gp-mediated transport of substrates.

Naproxen. Concomitant administration of single doses of apixaban (10 mg) and the typical NSAID naproxen (500 mg) did not affect AUC or Cmax of naproxen.

Atenolol. Concomitant administration of single doses of apixaban (10 mg) and the typical beta-blocker atenolol (100 mg) did not affect the pharmacokinetics of atenolol.

Activated charcoal.

Administration of activated charcoal reduces exposure levels of apixaban (see section "Overdose").

Special precautions for use.

Bleeding risk.

As with other anticoagulants, patients taking the medicinal product Eluxa® require careful monitoring for signs of bleeding. The drug should be used with caution in conditions associated with an increased risk of bleeding. In case of severe bleeding, administration of Eluxa® should be discontinued (see section "Adverse reactions" and "Overdose").

Although apixaban therapy does not require routine monitoring of drug exposure levels, in exceptional circumstances when information on apixaban exposure may assist in clinical decision-making (e.g., in cases of overdose or emergency surgery), a quantitative assay to measure factor Xa inhibition activity, Rotachrom®, may be used (see section "Pharmacodynamics").

There is an available medicinal product for neutralizing the activity of factor Xa inhibitors.

Interactions with other medicinal products affecting blood coagulation.

Concomitant treatment with any other anticoagulants is contraindicated due to increased bleeding risk (see section "Contraindications").

Concurrent use of Eluxa® with antiplatelet agents increases the risk of bleeding (see section "Interaction with other medicinal products and other forms of interaction").

Caution should be exercised if patients are concurrently receiving SSRIs, SNRIs, or NSAIDs, including acetylsalicylic acid (ASA).

Concomitant administration of other platelet aggregation inhibitors with apixaban after surgical intervention is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

For patients with atrial fibrillation requiring single or dual antiplatelet therapy, the potential benefits and risks should be carefully weighed before combining such therapy with apixaban.

In a clinical trial involving patients with atrial fibrillation, concomitant use of ASA increased the risk of major bleeding associated with apixaban treatment from 1.8% per year to 3.4% per year, and with warfarin from 2.7% per year to 4.6% per year. In this clinical trial, concomitant use of dual antiplatelet therapy was limited (2.1%) (see section "Pharmacodynamics").

The clinical trial included patients with atrial fibrillation and/or those undergoing PCI with a planned treatment period with a P2Y12 inhibitor, with or without ASA, and an oral anticoagulant (apixaban or VKA) for 6 months. Concomitant use of ASA in subjects receiving apixaban increased the risk of major or non-major clinically relevant bleeding according to ISTH criteria by 16.4–33.1% per year (see section "Pharmacodynamics").

In a clinical trial involving high-risk patients after acute coronary syndrome without atrial fibrillation, who had multiple concomitant cardiovascular and non-cardiovascular conditions and received ASA or a combination of ASA and clopidogrel, apixaban use was associated with a significant increase in the risk of major bleeding according to ISTH classification – 5.13% per year compared to 2.04% per year in the placebo group.

Use of thrombolytic agents for treatment of acute ischemic stroke.

Experience with thrombolytic agents for treatment of acute ischemic stroke in patients receiving apixaban is extremely limited (see section "Interaction with other medicinal products and other forms of interaction").

Patients with prosthetic heart valves.

The safety and efficacy of Eluxa® have not been studied in patients with prosthetic heart valves, with or without atrial fibrillation. Therefore, apixaban use is not recommended in these patients.

Patients with antiphospholipid syndrome.

Direct oral anticoagulants, including apixaban, are not recommended for patients with a history of thrombosis and diagnosed antiphospholipid syndrome. In particular, in patients positive for all three markers (lupus anticoagulant, anticardiolipin antibodies, and anti-beta-2-glycoprotein I antibodies), treatment with direct oral anticoagulants may be associated with an increased rate of recurrent thrombotic events compared to VKA therapy.

Surgical procedures and invasive interventions.

Treatment with Eluxa® should be discontinued at least 48 hours before elective surgery or invasive procedures associated with moderate or high bleeding risk. This applies to procedures where clinically significant bleeding cannot be excluded or where the bleeding risk is unacceptable.

Treatment with Eluxa® should be discontinued at least 24 hours before elective surgery or invasive procedures associated with low bleeding risk. This applies to interventions where any potential bleeding is expected to be minor in volume, non-critical for the site, or easily controllable.

If surgery or an invasive procedure cannot be postponed, appropriate precautionary measures should be taken, considering the increased bleeding risk. The bleeding risk and urgency of the intervention should be carefully weighed.

Treatment with Eluxa® should be resumed as soon as possible after surgery or invasive procedure, provided the clinical situation allows and adequate hemostasis measures have been taken (for cardioversion, see section "Method of administration and dosage").

Patients undergoing catheter ablation for treatment of atrial fibrillation do not need to interrupt treatment with Eluxa® (see sections "Method of administration and dosage", "Contraindications", and "Interaction with other medicinal products and other forms of interaction").

Temporary discontinuation of treatment.

Discontinuation of anticoagulant therapy (including apixaban) due to active bleeding, planned surgery, or invasive procedures increases the risk of thrombosis in patients. Treatment interruptions should be avoided, and if temporary discontinuation is necessary (for any reason), treatment should be resumed as soon as possible.

Spinal/epidural anaesthesia or puncture.

Patients receiving antithrombotic therapy for prevention of thromboembolic complications have an increased risk of developing epidural or spinal hematoma when undergoing neuraxial (spinal or epidural) anaesthesia or spinal/epidural puncture, which may lead to long-term or permanent paralysis. The risk of such events may be increased by the use of indwelling catheters in the postoperative period or concomitant use of medicinal products affecting blood coagulation. An indwelling epidural or subarachnoid catheter should be removed at least 5 hours before the first dose of Eluxa® is administered. The risk may also be increased by traumatic or repeated epidural or spinal puncture. Patients should be closely monitored for neurological symptoms (e.g., numbness or weakness in legs, bowel or bladder dysfunction). If neurological symptoms occur, immediate diagnosis and treatment are mandatory. Before neuraxial intervention, the physician should weigh the potential benefits and risks for patients receiving or scheduled to receive anticoagulants for thrombosis prevention.

There is no clinical experience with apixaban use in patients with indwelling subarachnoid or epidural catheters. If such use is required, based on pharmacokinetic data, an interval of 20–30 hours (i.e., twice the elimination half-life) should be maintained between the last dose of apixaban and catheter removal. Additionally, at least one dose of apixaban should be missed before catheter removal. The next dose may be administered no earlier than 5 hours after catheter removal. As with all new anticoagulants, experience with apixaban in patients undergoing neuraxial blockade is limited. Therefore, apixaban use in these patients requires special caution.

Patients with PE and unstable hemodynamics, or patients requiring thrombolysis or pulmonary embolectomy.

Eluxa® is not recommended as an alternative to unfractionated heparin in patients with PE and unstable hemodynamics or those who may undergo thrombolysis or pulmonary embolectomy, as the safety and efficacy of apixaban in these clinical situations have not been established.

Patients with active cancer.

The efficacy and safety of apixaban for treatment of DVT, treatment of PE, and prevention of recurrent DVT and PE (VTEt) in patients with active cancer have not been established.

Patients with renal impairment.

Some clinical data indicate that apixaban plasma concentrations are increased in patients with severe renal impairment (creatinine clearance 15–29 mL/min), which may increase bleeding risk. Apixaban should be used with caution in patients with severe renal impairment (creatinine clearance 15–29 mL/min) for prevention of VTE after elective hip or knee replacement surgery (VTEp), treatment of DVT, treatment of PE, and prevention of recurrent DVT and PE (VTEt) (see sections "Method of administration and dosage" and "Pharmacokinetics").

For prevention of stroke and systemic embolism in patients with NVAF who have renal impairment (creatinine clearance 15–29 mL/min) or serum creatinine ≥ 1.5 mg/dL (133 µmol/L) in combination with factors such as age over 80 years or body weight less than 60 kg, the apixaban dose should be 2.5 mg twice daily (see section "Method of administration").

There is no clinical experience with apixaban use in patients with creatinine clearance < 15 mL/min or in patients on dialysis; therefore, apixaban is not recommended for use in these patient populations (see sections "Method of administration and dosage" and "Pharmacokinetics").

Elderly patients.

The risk of bleeding may increase with age (see section "Pharmacokinetics").

Eluxa® in combination with ASA should also be used with caution in elderly patients due to increased bleeding risk.

Body weight.

Low body weight (< 60 kg) increases the risk of bleeding (see section "Pharmacokinetics").

Patients with hepatic impairment.

Eluxa® is contraindicated in patients with liver disease associated with coagulopathy and clinically relevant bleeding risk (see section "Contraindications").

The drug is not recommended for use in patients with severe hepatic impairment (see section "Pharmacokinetics").

Eluxa® should be used with caution in patients with mild to moderate hepatic impairment (Child–Pugh class A or B) (see sections "Method of administration and dosage" and "Pharmacokinetics").

Patients with elevated liver enzymes (alanine aminotransferase/aspartate aminotransferase [ALT/AST] more than twice the upper limit of normal [ULN]) or total bilirubin more than 1.5 times ULN were excluded from clinical trials. Therefore, Eluxa® should be used with caution in these patients (see section "Pharmacokinetics"). Liver function tests should be performed before initiating apixaban therapy.

Interactions with inhibitors of both cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp).

Eluxa® is not recommended for patients receiving systemic treatment with strong dual inhibitors of CYP3A4 and P-gp, such as azole antifungals (e.g., ketoconazole, itraconazole, voriconazole, posaconazole) or HIV protease inhibitors (e.g., ritonavir). These medicinal products may double apixaban exposure (see section "Interaction with other medicinal products and other forms of interaction") or even more in the presence of additional factors increasing apixaban exposure (such as severe renal impairment).

Interactions with medicinal products that are inducers of both CYP3A4 and P-gp.

Concomitant use of Eluxa® with strong inducers of CYP3A4 and P-gp (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital, or St. John’s wort) may reduce apixaban exposure by approximately 50%. In a clinical trial involving patients with atrial fibrillation, concomitant use of apixaban and strong inducers of CYP3A4 and P-gp reduced anticoagulant efficacy and increased bleeding risk compared to apixaban monotherapy.

For patients receiving concomitant treatment with strong inducers of CYP3A4 and P-gp, the following recommendations apply (see section "Interaction with other medicinal products and other forms of interaction"):

apixaban should be used with caution for prevention of VTE after elective hip or knee replacement surgery, prevention of stroke and systemic embolism in patients with NVAF, and prevention of recurrent DVT and PE;
apixaban should not be used for treatment of DVT and PE, as its efficacy may be compromised.

Surgical treatment of hip fracture.

Clinical trials on the efficacy and safety of apixaban in patients undergoing surgical treatment of hip fracture have not been conducted. Therefore, the use of the drug in these patients is not recommended.

laboratory parameters.

Coagulation test results (e.g., PT, INR, and aPTT) change as expected due to the mechanism of action of apixaban. Changes observed in these test results with therapeutic doses are minor and highly variable (see section "Pharmacodynamics").

Information on excipients.

Eluxa® contains lactose. If a patient has known intolerance to certain sugars, consultation with a physician is recommended before taking this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy. There are no data on apixaban use in pregnant women. Animal studies have not shown direct or indirect harmful effects on reproductive function. Apixaban is not recommended during pregnancy.

Breastfeeding. It is currently unknown whether apixaban or its metabolites are excreted in human breast milk. Animal studies indicate that apixaban is excreted in milk. A risk to newborns or breastfed infants cannot be excluded.

A decision should be made whether to discontinue breastfeeding or to discontinue/forego apixaban therapy.

Effect on fertility. Animal studies with direct administration of apixaban did not show any effect on fertility.

Ability to affect reaction speed when driving or operating machinery.

Eluxa® has no or negligible effect on the ability to drive or operate machinery.

Method of Administration and Dosage.

Method of Administration.

The medicinal product Eluxa® should be administered orally with water, with or without food.

For patients who cannot swallow whole tablets, Eluxa® tablets may be crushed and suspended in water, 5% aqueous dextrose solution, or apple juice, or mixed with apple puree, and administered orally immediately thereafter (see section "Pharmacokinetics"). Additionally, Eluxa® tablets may be crushed and suspended in 60 mL of water or 5% aqueous dextrose solution and administered immediately via a nasogastric tube (see section "Pharmacokinetics").

Eluxa® tablets, after crushing, remain stable in water, 5% aqueous dextrose solution, apple juice, or apple puree for up to 4 hours.

Dosage.

Prophylaxis of venous thromboembolism following elective knee or hip replacement surgery.

The recommended dose of Eluxa® is 2.5 mg orally twice daily. The first dose should be administered 12–24 hours after surgery.

When selecting the timing of the first dose within this window, physicians should balance the potential benefit of earlier initiation of anticoagulation for venous thromboembolism prophylaxis against the potential risk of postoperative bleeding.

For patients undergoing hip replacement surgery, the recommended duration of treatment is 32–38 days; for patients undergoing knee replacement surgery, the recommended duration is 10–14 days.

Stroke and systemic embolism prophylaxis in patients with non-valvular atrial fibrillation.

The recommended dose of Eluxa® is 5 mg orally twice daily.

Dose reduction.

For patients with non-valvular atrial fibrillation and at least two of the following characteristics: age ≥ 80 years, body weight ≤ 60 kg, or serum creatinine ≥ 1.5 mg/dL (133 µmol/L), the recommended dose of Eluxa® is 2.5 mg orally twice daily.

Treatment should be continued for a prolonged period.

Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of DVT and PE recurrence.

The recommended dose of Eluxa® for the treatment of DVT and PE is 10 mg orally twice daily for the first 7 days, with a maximum daily dose of 20 mg. Thereafter, the drug should be administered at a dose of 5 mg orally twice daily, with a maximum daily dose of 10 mg. According to current medical guidelines, short-term treatment (at least 3 months) should take into account transient risk factors (e.g., recent surgery, trauma, immobilization).

The recommended dose of Eluxa® for prevention of DVT and PE recurrence is 2.5 mg orally twice daily, with a maximum daily dose of 5 mg. If a patient requires prevention of DVT and PE recurrence, the 2.5 mg twice-daily dose should be initiated after completion of a 6-month course of Eluxa® 5 mg twice daily or a course of treatment with another anticoagulant (also see "Pharmacodynamics").

The total duration of treatment should be determined individually by the physician following careful assessment of the benefits of treatment versus bleeding risk (see section "Special Warnings and Precautions for Use").

Missed dose.

If a dose is missed, the patient should take Eluxa® immediately and continue treatment as usual, twice daily.

Switching medications.

Transition from parenteral anticoagulants to apixaban (and vice versa) can be performed at the time of the next scheduled dose (see section "Interaction with Other Medicinal Products and Other Forms of Interaction"). These medicinal products should not be used concomitantly.

Transition from vitamin K antagonist therapy to Eluxa®.

When switching patients from vitamin K antagonist therapy to Eluxa®, discontinue warfarin or other vitamin K antagonist and initiate Eluxa® when the international normalized ratio (INR) is < 2.0.

Transition from Eluxa® to vitamin K antagonist therapy.

When switching patients from Eluxa® to vitamin K antagonist therapy, continue Eluxa® for at least 2 days after initiating the vitamin K antagonist. After 2 days of concomitant apixaban and vitamin K antagonist administration, measure INR before the next Eluxa® dose. Combined therapy with Eluxa® and vitamin K antagonist should be continued until the INR reaches ≥ 2.0.

Renal impairment.

Recommendations for patients with mild or moderate renal impairment:

For prophylaxis of venous thromboembolism (VTE) during elective hip or knee replacement surgery (VTEp), treatment of DVT, treatment of PE, and prevention of DVT or PE recurrence (VTEt), no dose adjustment is required (see section "Pharmacokinetics").
For stroke and systemic embolism prophylaxis in patients with non-valvular atrial fibrillation (NVAF) and serum creatinine ≥ 1.5 mg/dL (133 µmol/L) in combination with either age > 80 years or body weight < 60 kg, a lower dose of apixaban should be used as described above. In the absence of other dose-reduction criteria (age, body weight), no dose adjustment is required (see section "Pharmacokinetics").

For patients with severe renal impairment (creatinine clearance 15–29 mL/min), the following recommendations apply (see sections "Special Warnings and Precautions for Use" and "Pharmacokinetics"):

For VTE prophylaxis during elective hip or knee replacement surgery (VTEp), treatment of DVT, treatment of PE, and prevention of DVT or PE recurrence (VTEt), apixaban should be used with caution.
For stroke and systemic embolism prophylaxis in patients with non-valvular atrial fibrillation (NVAF), a lower dose of apixaban – 2.5 mg twice daily – should be used.

There is no clinical experience with apixaban in patients with creatinine clearance < 15 mL/min or in patients on dialysis; therefore, apixaban is not recommended for use in these patient populations (see sections "Special Warnings and Precautions for Use" and "Pharmacokinetics").

Hepatic impairment.

Eluxa® is contraindicated in patients with liver disease associated with coagulopathy and clinically significant bleeding risk (see section "Contraindications").

The medicinal product is not recommended for use in patients with severe hepatic impairment (see sections "Special Warnings and Precautions for Use" and "Pharmacokinetics").

Eluxa® should be used with caution in patients with mild or moderate hepatic impairment (Child-Pugh class A or B); such patients do not require dose adjustment (see sections "Special Warnings and Precautions for Use" and "Pharmacokinetics").

Patients with elevated liver enzymes (ALT/AST > 2 times the upper limit of normal [ULN]) or elevated total bilirubin (≥ 1.5 times ULN) were excluded from clinical trials. Therefore, Eluxa® should be used with caution in this patient group (see section "Special Warnings and Precautions for Use" and "Pharmacokinetics"). Liver function tests should be performed before initiating apixaban therapy.

Body weight.

Prophylaxis of venous thromboembolism during elective hip or knee replacement surgery, treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of DVT and PE recurrence in adults: no dose adjustment is required (see section "Pharmacokinetics" and "Special Warnings and Precautions for Use").

Non-valvular atrial fibrillation: no dose adjustment is required, except in cases specified above (see "Dose Reduction" in section "Method of Administration and Dosage").

Gender.

No dose adjustment is required (see section "Pharmacokinetics").

Elderly patients.

Non-valvular atrial fibrillation: no dose adjustment is required, except in cases specified above (see "Dose Reduction" in section "Method of Administration and Dosage").

Patients undergoing catheter ablation

Patients may continue receiving apixaban during catheter ablation (see sections "Contraindications", "Special Warnings and Precautions for Use", and "Interaction with Other Medicinal Products and Other Forms of Interaction").

Patients undergoing cardioversion

Patients with NVAF undergoing cardioversion may initiate or continue apixaban.

In patients not previously receiving anticoagulants, the presence of left atrial thrombus should be excluded using imaging techniques (e.g., transesophageal echocardiography [TEE] or computed tomography [CT]) prior to cardioversion, in accordance with established medical guidelines.

For patients initiating apixaban therapy, 5 mg twice daily should be administered for at least 2.5 days (5 doses) prior to cardioversion to ensure adequate anticoagulation (see section "Pharmacodynamics"). If the patient meets criteria for dose reduction (see subsections "Dose Reduction" and "Renal Impairment" above), the dose should be reduced to 2.5 mg apixaban twice daily for at least 2.5 days (5 doses).

If urgent cardioversion is required, a loading dose of 10 mg should be administered before the fifth dose of apixaban, followed by 5 mg twice daily. The dosing regimen should be reduced to a loading dose of 5 mg, followed by 2.5 mg twice daily, if the patient meets criteria for dose reduction (see subsections "Dose Reduction" and "Renal Impairment" above). The loading dose should be taken at least 2 hours before cardioversion (see section "Pharmacodynamics").

For all patients undergoing cardioversion, it should be confirmed that the patient has received apixaban as prescribed. Decisions regarding initiation and duration of therapy should be made in accordance with established guidelines for anticoagulant use in patients undergoing cardioversion.

Patients with non-valvular atrial fibrillation (NVAF) and/or acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI)

There is limited experience with the use of apixaban at the recommended dose in patients with NVAF in combination with antiplatelet agents – patients with ACS and/or those undergoing PCI after achieving hemostasis (see sections "Special Warnings and Precautions for Use" and "Pharmacodynamics").

Pediatric population.

The efficacy and safety of Eluxa® in children (under 18 years of age) have not been established. Data are lacking.

Overdose.

Overdose of apixaban may increase the risk of bleeding. In case of hemorrhagic complications, treatment should be discontinued and the source of bleeding investigated. Appropriate management should be considered, such as surgical hemostasis, transfusion of fresh frozen plasma, or administration of a factor Xa inhibitor reversal agent.

In controlled clinical trials, oral administration of apixaban to healthy volunteers at doses up to 50 mg daily for 3–7 days (25 mg twice daily for 7 days or 50 mg once daily for 3 days) did not result in clinically significant adverse events.

In healthy volunteers, administration of activated charcoal 2 and 6 hours after a 20 mg dose of apixaban reduced the mean AUC of apixaban by 50% and 27%, respectively, without affecting Cmax. Administration of activated charcoal 2 or 6 hours after apixaban reduced the elimination half-life of apixaban, which was 13.4 hours with monotherapy, to 5.3 and 4.9 hours, respectively. Thus, activated charcoal may be beneficial in managing apixaban overdose or accidental ingestion.

For reversal of anticoagulation in cases of life-threatening or uncontrolled bleeding, a specific reversal agent for factor Xa inhibitors is available (see section "Special Warnings and Precautions for Use"). Administration of prothrombin complex concentrate (PCC) or recombinant factor VIIa may also be considered. The reversibility of the pharmacodynamic effects of Eluxa®, demonstrated by changes in thrombin generation assays, was evident at the end of infusion and returned to baseline within 4 hours after the start of a 30-minute infusion of four-factor PCC in healthy volunteers. However, there is no clinical experience with four-factor PCC for bleeding management in patients receiving Eluxa®. Experience with recombinant factor VIIa for treating patients on apixaban is currently lacking. Repeated administration of recombinant factor VIIa and dose titration based on bleeding control should be considered.

In cases of significant bleeding, consultation with a hematologist should be considered.

Single oral administration of 5 mg apixaban followed by hemodialysis reduced apixaban AUC by 14% in patients with end-stage renal disease. Therefore, hemodialysis is unlikely to be an effective method for treating apixaban overdose.

Adverse Reactions

The safety of apixaban has been evaluated in 7 Phase III clinical trials involving over 21,000 patients: over 5,000 patients in VTEp studies, over 11,000 patients in AF studies, and over 4,000 patients in VTEt studies. The average overall duration of treatment was 20 days, 1.7 years, and 221 days, respectively (see section "Pharmacodynamics").

Common adverse reactions included bleeding, contusion, epistaxis, and hematoma (the profile of adverse events and frequencies, classified by indication, are presented below).

In the VTEp studies, adverse reactions were observed in 11% of patients overall who received apixaban 2.5 mg twice daily. The overall frequency of bleeding-related adverse reactions in the comparative studies of apixaban versus enoxaparin was 10% in the apixaban group.

In the AF studies, the overall frequency of bleeding-related adverse reactions in the apixaban group was 24.3% in the apixaban versus warfarin comparison study and 9.6% in the apixaban versus aspirin comparison study. In the apixaban versus warfarin comparison study, the rate of major gastrointestinal bleeding according to ISTH classification (including upper gastrointestinal tract, lower gastrointestinal tract, and rectal bleeding) in patients receiving apixaban was 0.76%/year. The rate of major intraocular bleeding according to ISTH classification in patients receiving apixaban was 0.18%/year.

In the VTEt studies, the overall frequency of bleeding-related adverse reactions in the apixaban group was 15.6% in the apixaban versus enoxaparin/warfarin comparison study and 13.3% in the apixaban versus placebo comparison study (see section "Pharmacodynamics").

Below are the adverse reactions observed during administration of the medicinal product for the prevention of VTE, AF, treatment of DVT and PE, and prevention of recurrent DVT and PE in adults, categorized by system organ classes and frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), and not known (cannot be estimated from the available data).

Blood and lymphatic system disorders:
Anemia – common (VTEp, AF*, VTEt);
Thrombocytopenia – common (VTEt), uncommon (VTEp, AF*).

Immune system disorders:
Hypersensitivity, allergic edema, and anaphylaxis – uncommon (AF*, VTEt), rare (VTEp);
Pruritus – uncommon (VTEp, AF*, VTEt (in study CV185057 (long-term VTE prevention), cases of generalized pruritus were not observed));
Angioedema – not known (VTEp, AF*, VTEt).

Nervous system disorders:
Intracranial hemorrhage† – uncommon (AF*), rare (VTEt), not known (VTEp).

Eye disorders:
Ocular hemorrhage (including conjunctival hemorrhage) – common (AF*), uncommon (VTEt), rare (VTEp).

Vascular disorders:
Bleeding, hematoma – common (VTEp, AF*, VTEt);
Hypotension (including hypotension during procedures) – common (AF*), uncommon (VTEp, VTEt);
Intra-abdominal hemorrhage – uncommon (AF*), not known (VTEp, VTEt).

Respiratory, thoracic and mediastinal disorders:
Epistaxis – common (AF*, VTEt), uncommon (VTEp);
Hemoptysis – uncommon (AF*, VTEt), rare (VTEp);
Respiratory tract hemorrhage – rare (AF*, VTEt), not known (VTEp).

Gastrointestinal disorders:
Nausea – common (VTEp, AF*, VTEt);
Gastrointestinal hemorrhage – common (AF*, VTEt), uncommon (VTEp);
Hematochezia – uncommon (VTEp, AF*, VTEt);
Hemorrhoidal hemorrhage – uncommon (AF*, VTEt), not known (VTEp);
Oral cavity hemorrhage – common (VTEt), uncommon (AF*), not known (VTEp);
Rectal hemorrhage, gingival hemorrhage – common (AF*, VTEt), rare (VTEp);
Retroperitoneal hemorrhage – rare (AF*), not known (VTEp, VTEt).

Hepatobiliary disorders:
Abnormal liver function test results, increased AST levels, increased alkaline phosphatase activity in blood, increased bilirubin levels in blood – uncommon (VTEp, AF*, VTEt);
Increased gamma-glutamyltransferase levels – common (AF*, VTEt), uncommon (VTEp);
Increased ALT levels – common (VTEt), uncommon (VTEp, AF*).

Skin and subcutaneous tissue disorders:
Rash – common (VTEt), uncommon (AF*), not known (VTEp);
Alopecia – uncommon (AF*, VTEt), rare (VTEp);
Erythema multiforme – very rare (AF*), not known (VTEp, VTEt);
Cutaneous vasculitis – not known (VTEp, AF*, VTEt).

Musculoskeletal and connective tissue disorders:
Muscle hemorrhage – uncommon (VTEt), rare (VTEp, AF*).

Renal and urinary system disorders:
Hematuria – common (AF*, VTEt), uncommon (VTEp).

Reproductive system and breast disorders:
Pathological vaginal bleeding, urogenital tract bleeding – common (VTEt), uncommon (VTEp, AF*).

General disorders and administration site conditions:
Bleeding at the site of administration – uncommon (AF*, VTEt), not known (VTEp).

Investigations:
Positive occult blood test – uncommon (AF*, VTEt), not known (VTEp).

Injury, poisoning and procedural complications:
Bruising – common (VTEp, AF*, VTEt);
Bleeding from medical procedure site (including hematoma after medical procedure, postoperative wound hemorrhage, hematoma at vascular puncture site, bleeding from catheter insertion site), wound discharge, surgical incision site bleeding (including hematoma at surgical incision site), operative hemorrhage – uncommon (VTEp, AF*, VTEt);
Traumatic hemorrhage – uncommon (AF*, VTEt), not known (VTEp).

* AF with one or more risk factors;
† The term "Intracranial hemorrhage" includes all intracranial or intraspinal hemorrhages (e.g., hemorrhagic stroke, putaminal, cerebellar, intraventricular, or subdural hemorrhages).

The use of the medicinal product Eluxa® may be associated with an increased risk of occult or overt bleeding from any tissue or organ, which may lead to post-hemorrhagic anemia. Symptoms and their severity will vary depending on the location and extent or magnitude of bleeding (see sections "Special precautions for use" and "Pharmacodynamics").

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions after registration of the medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions.

Shelf life. 2 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions. No special storage conditions required. Keep out of the reach of children.

Packaging. 10 tablets in a blister. 6 blisters in a pack.

Prescription category. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address and place of business.
74 Kyrylivska Street, Kyiv, 04080, Ukraine