Trombapix

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TROMBAPIX (TROMBAPIX)

Composition:

Active ingredient: apixaban;

One film-coated tablet contains 2.5 mg of apixaban;

Excipients: sodium lauryl sulfate; povidone; lactose monohydrate; microcrystalline cellulose; crospovidone; sodium stearyl fumarate;

Film coating: Opadry II Yellow 32K220078: hypromellose; lactose monohydrate; titanium dioxide (E 171); triacetin; yellow iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: yellow, round, film-coated tablets.

Pharmacotherapeutic group. Antithrombotic medicinal products. Direct factor Xa inhibitors. ATC code B01A F02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Apixaban is a potent, reversible, direct, and highly selective inhibitor of the active site of factor Xa, intended for oral administration. It does not require antithrombin III for its antithrombotic effect. Apixaban inhibits both free and clot-bound factor Xa, as well as 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 effective antithrombotic activity for the prevention of arterial and venous thrombosis at doses that did not impair hemostatic processes.

Pharmacodynamic effects.

The pharmacodynamics of apixaban reflects its mechanism of action (inhibition of factor Xa). As a result of factor Xa inhibition, apixaban increases values of prothrombin time (PT), international normalized ratio (INR), and activated partial thromboplastin time (aPTT). Changes observed in coagulation parameters with therapeutic doses of apixaban are minimal and highly variable, and therefore 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 against factor Xa, as confirmed by reduced enzymatic activity of factor Xa measured using various commercial factor Xa activity inhibition assay kits, although specific results varied between different kits. Clinical study data are available only for the chromogenic assay Rotachrom® heparin (results provided below). Factor Xa inhibitory activity is related to apixaban plasma concentration. This relationship is approximately linear, with maximum factor Xa inhibition observed at peak apixaban plasma concentrations. The relationship between apixaban plasma concentration and factor Xa inhibitory activity is approximately linear over a wide range of apixaban doses.

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) following 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 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)
	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 non-valvular atrial fibrillation
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 (VTEt)
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 quantitative anti-Factor Xa assay method such as Rotachrom® may be used.

Clinical efficacy and safety.

Prevention of venous thromboembolism (VTE prophylaxis) 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. A total of 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 overall population included 1,262 patients aged 75 years or 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. b.i.d.) or subcutaneous enoxaparin 40 mg once daily (s.c. q.d.). The first dose of apixaban was administered 12–24 hours after surgery, whereas enoxaparin was initiated 9–15 hours before surgery. In the ADVANCE-3 study, apixaban and enoxaparin were administered for 32–38 days; in the ADVANCE-2 study, treatment duration was 10–14 days.

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 atherosclerosis.

Apixaban demonstrated statistically significant greater reduction in the rates of the primary efficacy endpoint (composite endpoint of all venous thromboembolism events and all-cause mortality) and the "Major venous thromboembolism" endpoint (composite endpoint of proximal deep vein thrombosis, non-fatal pulmonary embolism, and venous thromboembolism-related deaths) 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)
Study treatment Dose Treatment duration	Apixaban 2.5 mg orally twice daily 35 ± 3 days	Enoxaparin 40 mg subcutaneously once daily 35 ± 3 days	p value	Apixaban 2.5 mg orally twice daily 12 ± 2 days	Enoxaparin 40 mg subcutaneously once daily 12 ± 2 days	p value
Total number of venous thromboembolism events/all-cause 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)	- -		0.62 (0.51, 0.74)	-
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			0.50
95 % CI	(0.15; 0.80)			(0.26; 0.97)

In patients who received 2.5 mg apixaban or 40 mg enoxaparin, a similar frequency was observed for safety endpoints such as major bleeding, the composite endpoint of major and clinically relevant non-major bleeding (CRNMB), as well as 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 abnormalities in liver transaminase levels (e.g., alanine aminotransferase) was numerically lower in the apixaban treatment group compared to 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 incidence of pulmonary embolism cannot be explained.

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

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

• prior history of stroke or transient ischemic attack;
• 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 "Dosage and administration") or warfarin (target INR range 2–3). Patients received the active treatment for a mean 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 transient ischemic attack was present in 18.9% of patients.

In this study, apixaban treatment demonstrated a statistically significant advantage 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)	Risk 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 (0.1)	0.87 (0.44; 1.75)

In patients assigned to the warfarin treatment group, the median time (%) that the INR was within the range of 2–3 during therapeutic window was 66%.

Apixaban demonstrated a reduction in the rate of stroke and systemic embolism (compared to warfarin treatment) across various levels of 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 benefits were also observed for the key secondary endpoints of major bleeding and all-cause mortality (see Table 4). The advantages of apixaban over warfarin with respect to all-cause mortality diminished when INR control was more carefully managed.

Secondary endpoints in patients with atrial fibrillation in the ARISTOTLE study

Table 4

Parameter	Apixaban N = 9088 n (%/year)	Warfarin N = 9052 n (%/year)	Risk ratio (95 % CI)	p-value
Bleeding endpoints
Major*	327 (2.13)	462 (3.09)	0.69 (0.60; 0.8)	< 0.0001
Fatal	10 (0.06)	37 (0.24)
Intracranial	52 (0.33)	122 (0.8)
Major + clinically non-major	613 (4.07)	877 (6.01)	0.68 (0.61; 0.75)	< 0.0001
All cases	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)	0.0465
Myocardial infarction	90 (0.53)	102 (0.61)	0.88 (0.66; 1.17)

*Major bleeding, defined according to 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, history of stroke, transient ischemic attack, and diabetes) were consistent with the primary efficacy results in the overall study population.

The rate of ISTH-defined major gastrointestinal bleeding (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.

Rates of major bleeding in pre-specified subgroups (including subgroups based on CHADS2 score, age, body weight, sex, renal function, history of stroke, transient ischemic attack, and diabetes) were consistent with results in the overall population.

AVERROES study.

Overall, 5598 patients were randomized in the AVERROES study, in whom treatment with vitamin K antagonists was not feasible. Study participants were assigned to receive either apixaban 5 mg twice daily (or for some patients (6.4%) apixaban 2.5 mg twice daily (see section “Dosage and administration”)) or acetylsalicylic acid. Acetylsalicylic acid was administered once daily at a dose of 81 mg (64%), 162 mg (26.9%), 243 mg (2.1%), or 324 mg (6.6%). The dose was determined by the investigator. Patients received the study drug for a median duration of 14 months. The mean age of participants was 69.9 years, and the mean CHADS2 score was 2.0. 13.6% of patients had a prior history of stroke or transient ischemic attack. Common reasons for ineligibility for vitamin K antagonist therapy included: inability/low likelihood of achieving required international normalized ratio (INR) levels within the required timeframe (42.6%), patient refusal of vitamin K antagonist therapy (37.4%), CHADS2 score = 1 and physician recommendation against vitamin K antagonist therapy (21.3%), inability to ensure patient compliance with vitamin K antagonist dosing (15%), and difficulty/potential difficulty in contacting the patient for immediate dose adjustment if needed (11.7%).

The AVERROES study was terminated early on the recommendation of the independent Data Monitoring Committee due to compelling evidence of reduced risk of stroke and systemic embolism with a favorable safety profile of the investigational drug.

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

Key efficacy outcomes in patients with atrial fibrillation

who participated in the AVERROES study

Table 5

Parameter	Apixaban N = 2807 n (%/year)	Acetylsalicylic acid 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 unspecified 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 in the study.

† Secondary endpoint.

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

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

In the AUGUSTUS trial—a double-blind, randomized, controlled trial with a 2-by-2 factorial design—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; 4.2% received the lower dose) or a vitamin K antagonist (VKA), and acetylsalicylic acid (ASA) (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 and 12% above the TTR.

The primary objective of the AUGUSTUS trial was to assess safety, with the primary endpoint being major or clinically relevant non-major bleeding according to ISTH criteria. In the comparison between apixaban and VKA, 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 both non-inferiority and superiority). A supplementary analysis using TTR subgroups for VKA 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 subgroup with the highest TTR quartile.

In the comparison between ASA and 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 ASA and placebo groups, respectively (RR = 1.88, 95% CI: 1.58, 2.23; two-sided p < 0.0001).

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

Other treatment effects were evaluated as secondary trial objectives, using composite endpoints.

In the comparison of apixaban versus VKA, the composite endpoint of death or rehospitalization occurred in 541 (23.5%) and 632 (27.4%) patients in the apixaban and VKA groups, respectively. The composite endpoint of 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 ASA versus placebo, the composite endpoint of death or rehospitalization occurred in 604 (26.2%) and 569 (24.7%) patients in the ASA and placebo groups, respectively. The composite endpoint of death or ischemic event (stroke, myocardial infarction, stent thrombosis, or urgent revascularization) occurred in 163 (7.1%) and 189 (8.2%) patients in the ASA and placebo groups, respectively.

Patients undergoing cardioversion

EMANATE was an open-label, multicenter trial involving 1,500 patients with non-valvular atrial fibrillation (NVAF) who were not receiving anticoagulation or had received less than 48 hours of anticoagulation and were scheduled for cardioversion. Patients were randomized in a 1:1 ratio to receive either apixaban or heparin and/or vitamin K antagonists for the 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 10 mg, and 11 received 5 mg).

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

All-cause mortality occurred in 2 patients (0.27%) in the apixaban group and in 1 patient (0.13%) in the heparin and/or vitamin K antagonist group. No cases of systemic embolism were reported.

Major and clinically relevant non-major 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 vitamin K antagonist group. The trial demonstrated comparable efficacy and safety between the apixaban and heparin and/or vitamin K antagonist 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 utility of the drug in preventing VTE recurrence 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 assessed 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 (target INR range 2–3) receiving oral warfarin 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 group, the mean percentage of time in the therapeutic INR range (2–3) was 60.9%. Apixaban demonstrated a reduced rate of recurrent symptomatic VTE or VTE-related death across various levels of mean time in the therapeutic INR window. For the highest quartile, the relative 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 endpoint of confirmed recurrent symptomatic VTE (DVT or PE without fatal outcomes) or VTE-related death.

The efficacy of apixaban during initial VTE treatment was comparable in patients receiving apixaban for the treatment of PE [relative risk 0.9; 95% CI (0.5, 1.6)] and for 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 main 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).

Results of bleeding analysis in the AMPLIFY study

Table 6

Indicator	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. Clinically significant gastrointestinal bleeding, classified according to ISTH criteria, 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 course of anticoagulant therapy lasting 6–12 months. Among them, 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 benefits compared to placebo for the primary efficacy endpoint of symptomatic recurrent VTE (DVT or non-fatal PE) or death from any cause (see Table 7).

Efficacy results from the AMPLIFY-EXT study

Table 7

Parameter	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 (%)
Fatal outcome 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)¥
VTE*	6 (0.7)	7 (0.9)	53 (6.4)
PE*	7 (0.8)	4 (0.5)	13 (1.6)
Fatal outcome due to any cause	6 (0.7)	3 (0.4)	11 (1.3)
Fatal outcome associated with recurrent VTE or due to VTE	14 (1.7)	14 (1.7)	73 (8.8)	0.19 (0.11, 0.33)	0.20 (0.11; 0.34)
Fatal outcome associated with 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)
DVT† without fatal outcome	6 (0.7)	8 (1.0)	53 (6.4)	0.11 (0.05; 0.26)	0.15 (0.07; 0.32)
PE† without fatal outcome	8 (1.0)	4 (0.5)	15 (1.8)	0.51 (0.22; 1.21)	0.27 (0.09; 0.80)
Fatal outcome associated with VTE	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 of the composite endpoint, only the first event was reported (e.g., if a study participant experienced DVT first and then PE, only DVT was reported).

† More than one event could occur in individual subjects, and events could be included in both classifications.

The efficacy of apixaban 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 for 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.

Gastrointestinal bleeding classified as major by the ISTH criteria was observed in 1 (0.1%) patient receiving apixaban 5 mg twice daily, was not observed in any patient receiving apixaban 2.5 mg twice daily, and was reported in 1 (0.1%) patient receiving placebo.

Paediatric population.

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

Pharmacokinetics.

Absorption.

The absolute bioavailability of apixaban at doses up to and including 10 mg is approximately 50%. Apixaban is rapidly absorbed, with peak drug 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, the pharmacokinetics of apixaban 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-subject variability of approximately 20% coefficient of variation (CV) and inter-subject variability of approximately 30% CV.

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

This reduction in exposure is not considered clinically significant.

After administration of a crushed 5 mg apixaban tablet suspended in 60 mL of 5% aqueous glucose solution and administered via a 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 apixaban doses.

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 via multiple pathways. Approximately 25% of an 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. Minor roles in drug metabolism are played by CYP1A2, 2C8, 2C9, 2C19, and 2J2. Unchanged apixaban is the main circulating compound associated with apixaban in human plasma. There are no circulating active metabolites of the drug in plasma. Apixaban is a substrate of transporter proteins P-gp and breast cancer resistance protein (BCRP).

Elderly patients.

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

Renal impairment.

Renal function impairment did not affect the peak concentration of apixaban. Based on creatinine clearance assessment, increasing apixaban exposure correlated with decreasing 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 apixaban concentrations increased by 16%, 29%, and 44%, respectively, compared to individuals with normal creatinine clearance. Renal impairment had no pronounced effect on the relationship between apixaban plasma concentration and the degree of factor Xa inhibition.

Hepatic impairment.

In a study where 8 participants with mild hepatic impairment (Child–Pugh class A with scores of 5 (n=6) and 6 (n=2)) and 8 participants with moderate hepatic impairment (Child–Pugh class B with scores of 7 (n=6) and 8 (n=2)) were compared 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 international normalized ratio were comparable between healthy volunteers and patients with mild or moderate hepatic impairment.

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 across individuals with different body weights, exposure was approximately 30% lower in individuals weighing over 120 kg compared to those with 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, PT, aPTT, and anti-Xa activity) was evaluated after administration of various apixaban doses across a wide range of 0.5 to 50 mg. The relationship between apixaban plasma concentration and factor Xa inhibition activity was best described by a linear model. 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 DVT and PE recurrence in adults (information regarding patients with PE and hemodynamically unstable status 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 significant risk of major bleeding (e.g., active or recent gastrointestinal ulceration, presence of malignant neoplasms with high bleeding risk, recent trauma to brain or spinal cord, recent neurosurgical, spinal, or ophthalmologic procedures, recent intracranial hemorrhage, diagnosed or suspected esophageal varices, arteriovenous malformations, vascular aneurysms, or marked intraspinal or intracranial vascular anomalies). 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 cases of switching anticoagulant therapy (see section "Dosage and administration"): administration of unfractionated heparin at doses required to maintain patency of central venous or arterial catheters, 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.

CYP3A4 and P-gp inhibitors.

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

Apixaban is not recommended for use in 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) (see section "Special precautions").

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

CYP3A4 and P-gp inducers.

Concomitant administration of apixaban and rifampicin (a potent CYP3A4 and P-gp inducer) 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 used concomitantly 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 (NVAF), and prevention of recurrent DVT and PE, apixaban should be used with caution in patients receiving concomitant therapy with potent CYP3A4 and P-gp inducers.

Apixaban is not recommended for the treatment of DVT and PE in patients receiving concomitant systemic therapy 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 bleeding risk, 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 central venous or arterial catheters, 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 (325 mg once daily) did not result in significant pharmacokinetic or pharmacodynamic interactions. In Phase I studies, concomitant administration of apixaban with clopidogrel (75 mg once daily), or with a combination of 75 mg clopidogrel and 162 mg acetylsalicylic acid once daily, or with prasugrel (loading dose 60 mg, maintenance dose 10 mg once daily) did not show a significant increase in modeled bleeding time or additional inhibition of platelet aggregation compared to antiplatelet agents alone. Coagulation parameters (PT, INR, aPTT) were consistent with the effects of apixaban as monotherapy. Naproxen (500 mg), a P-gp inhibitor, increased mean AUC and Cmax of apixaban by 1.5-fold and 1.6-fold, respectively. Apixaban caused a corresponding increase 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 lead to clinically significant prolongation of bleeding time. Nevertheless, in some individuals, a more pronounced pharmacodynamic response may occur with concomitant use of antiplatelet agents and apixaban. Apixaban should be used with caution when administered concomitantly with SSRIs/SNRIs, NSAIDs, acetylsalicylic acid, 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 (e.g., GPIIb/IIIa receptor antagonists, dipyridamole, dextran, or sulfinpyrazone) or thrombolytic agents. Since these agents increase bleeding risk, their concomitant use with apixaban is not recommended (see section "Special precautions").

Other concomitant medicinal products.

No clinically relevant pharmacokinetic or pharmacodynamic interactions were observed with concomitant administration of apixaban and atenolol or famotidine. Concomitant administration of 10 mg apixaban and 100 mg atenolol had no clinically significant effect on apixaban pharmacokinetics. After co-administration of both drugs, mean AUC and Cmax of apixaban were 15% and 18% lower, respectively, compared to apixaban monotherapy. Concomitant administration of 10 mg apixaban and 40 mg famotidine had no effect on 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 substantially 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 conducted in 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 NSAID naproxen (500 mg) did not affect AUC or Cmax of naproxen.

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

Activated charcoal.

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

Special precautions for use.

Bleeding risk.

As with other anticoagulants, patients receiving apixaban require careful monitoring for signs of bleeding. Apixaban should be used with caution in conditions associated with an increased risk of bleeding. In the event of severe bleeding, apixaban should be discontinued (see section "Adverse reactions" and "Overdose").

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

There is an antidote available 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"). The use of apixaban together 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.

After surgical procedures, concomitant use of other platelet aggregation inhibitors with apixaban is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

For patients with atrial fibrillation and conditions requiring mono- 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 acetylsalicylic acid increased the risk of major bleeding associated with apixaban treatment from 1.8% per year to 3.4% per year, and the risk associated 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").

A clinical trial included patients with atrial fibrillation and/or those undergoing PCI with a planned treatment period of a P2Y12 inhibitor, with or without ASA, and an oral anticoagulant (apixaban or vitamin K antagonist (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 International Society on Thrombosis and Haemostasis (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 were receiving acetylsalicylic acid or a combination of acetylsalicylic acid 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 the treatment of acute ischemic stroke in patients taking 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 apixaban have not been studied in patients with prosthetic heart valves, with or without atrial fibrillation. Therefore, apixaban is not recommended in this case.

Patients with antiphospholipid syndrome.

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

Surgical procedures and invasive interventions.

Treatment with apixaban should be discontinued at least 48 hours before elective surgery or invasive procedures with moderate or high bleeding risk. This applies to procedures where clinically significant bleeding cannot be excluded, and to procedures where the bleeding risk is unacceptable. Apixaban treatment should be discontinued at least 24 hours before elective surgery or invasive procedures with low bleeding risk. This applies to interventions where any potential bleeding is expected to be minor in volume, non-critical to the site, or easily controllable.

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

Apixaban treatment should be resumed as soon as possible after surgery or an invasive procedure, provided that the clinical situation allows and adequate hemostasis has been achieved (for cardioversion, see section "Posology and method of administration").

Patients undergoing catheter ablation for the treatment of atrial fibrillation do not need to interrupt apixaban treatment (see sections "Posology and method of administration", "Contraindications", and "Interaction with other medicinal products and other forms of interaction"). Temporary discontinuation of apixaban 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 apixaban treatment must be temporarily discontinued (for any reason), the drug should be resumed as soon as possible.

Spinal/epidural anaesthesia or puncture.

Patients receiving antithrombotic therapy for the prevention of thromboembolic complications have an increased risk of developing epidural or spinal haematoma when undergoing neuraxial (spinal or epidural) anaesthesia or spinal/epidural puncture, which may lead to long-term or permanent paralysis. This risk 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 apixaban. The risk may also be increased by traumatic or repeated epidural or spinal puncture. Patients should be monitored continuously for signs of neurological impairment (e.g., numbness or weakness in the 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 about to receive anticoagulants for thrombosis prevention.

There is no clinical experience with the use of apixaban 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 omitted before catheter removal. The next dose of the drug may be administered no earlier than 5 hours after catheter removal. As with all new anticoagulant agents, experience with apixaban in patients undergoing neuraxial blockade is limited. Therefore, the use of apixaban in these patients requires special caution.

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

Apixaban is not recommended as an alternative to unfractionated heparin in patients with pulmonary embolism and unstable haemodynamics 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.

Patients with active cancer may have a high risk of both venous thromboembolism and bleeding. When considering apixaban for the treatment of DVT or PE in cancer patients, the benefits and risks should be carefully evaluated (see section "Contraindications").

Patients with renal impairment.

Some clinical data suggest that plasma concentrations of apixaban are increased in patients with severe renal impairment (creatinine clearance 15–29 mL/min), which may increase the risk of bleeding. For prevention of venous thromboembolism (VTE) during elective hip or knee replacement surgery (VTE prophylaxis), treatment of DVT, treatment of PE, and prevention of recurrent DVT and PE (VTE treatment), apixaban should be used with caution in patients with severe renal impairment (creatinine clearance 15–29 mL/min) (see sections "Posology and method of administration" and "Pharmacokinetics").

For prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) who have severe 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, a lower dose of apixaban – 2.5 mg twice daily – should be used (see section "Posology and method of administration").

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

Elderly patients.

The risk of bleeding may increase with age (see section "Pharmacokinetics"). Apixaban in combination with acetylsalicylic acid should also be used with caution in elderly patients due to the increased risk of bleeding.

Body weight.

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

Patients with hepatic impairment.

Apixaban is contraindicated in patients with liver disease associated with coagulopathy and clinically relevant bleeding risk (see section "Contraindications"). Apixaban is not recommended for use in patients with severe hepatic impairment (see section "Pharmacokinetics").

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

Patients with elevated liver enzymes (alanine aminotransferase/aspartate aminotransferase (ALT/AST) more than twice the upper limit of normal) or total bilirubin more than 1.5 times the upper limit of normal were excluded from clinical trials. Therefore, apixaban should be used with caution in this patient population (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). Apixaban 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, and 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 apixaban 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 with strong inducers of CYP3A4 and P-gp reduced the anticoagulant's efficacy and increased the risk of bleeding 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 VTE prophylaxis during 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 the 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 this medicinal product in such patients is not recommended.

Laboratory parameters.

Coagulation parameters (e.g., prothrombin time (PT), international normalized ratio (INR), and activated partial thromboplastin time (aPTT)) change as expected due to the mechanism of action of apixaban. Changes observed in these tests with therapeutic doses are minor and highly variable (see section "Pharmacodynamics").

Important information on excipients.

The medicinal product contains lactose and should not be taken by patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption. The medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., essentially sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy. There are no data on the use of apixaban in pregnant women. Animal studies have not shown direct or indirect harmful effects on reproductive function. As a precautionary measure, it is recommended to avoid using apixaban during pregnancy.

Breastfeeding. It is currently unknown whether apixaban or its metabolites pass into human breast milk. Animal studies indicate that apixaban is excreted in milk. Risk to the breastfed infant cannot be excluded.

A decision should be made whether to discontinue breastfeeding or to discontinue/abstain from apixaban therapy, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.

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

Ability to affect reaction speed when driving or operating machinery.

The medicinal product has no or negligible effect on the ability to drive or operate machinery.

Dosage and Administration

Administration.

The medicinal product should be administered orally. It should be taken with water, with or without food.

For patients who cannot swallow whole tablets, the tablets may be crushed and suspended in water, 5 % aqueous glucose solution, or apple juice, or mixed with apple puree, and administered orally immediately (see section "Pharmacokinetics"). The crushed tablets of the medicinal product may also be suspended in 60 mL of water or 5 % aqueous glucose solution and administered immediately via a nasogastric tube (see section "Pharmacokinetics"). The medicinal product in tablet form, after crushing, is stable in water, 5 % aqueous glucose solution, apple juice, or apple puree for up to 4 hours.

Dosage.

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

The recommended dose of the medicinal product 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 weigh the potential benefit of earlier initiation of anticoagulation for prevention of venous thromboembolism 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.

Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation.

The recommended dose of the medicinal product 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 the medicinal product is 2.5 mg orally twice daily.

Treatment should be continued long-term.

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

The recommended dose of the medicinal product for the treatment of DVT and PE is 10 mg orally twice daily for the first 7 days. After this, apixaban should be administered at a dose of 5 mg orally twice daily. According to current medical guidelines, the duration of treatment (at least 3 months) should take into account transient risk factors (e.g., recent surgery, trauma, immobilization). The recommended dose of the medicinal product for prevention of DVT and PE recurrence is 2.5 mg orally twice daily. 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 apixaban treatment at a dose of 5 mg twice daily or a course of treatment with another anticoagulant, as specified in Table 8 (see also "Pharmacodynamics").

Dosage recommendations (VTEp)

Table 8

Indications	Dosing regimen	Maximum daily dose
Treatment of DVT or PE	first 7 days – 10 mg twice daily	20 mg
	further administration of 5 mg twice daily	10 mg
Prevention of recurrence of DVT and/or PE after completion of a 6-month treatment course of DVT or PE	2.5 mg twice daily	5 mg

The duration of the overall treatment course should be determined individually after careful assessment of the benefits of therapy and the risk of bleeding (see section "Special Instructions"). Missed dose.

If a dose has been missed, the patient should take it immediately and continue treatment according to the usual regimen of twice daily.

Switching between medicinal products.

Switching from parenteral anticoagulants to apixaban therapy (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 simultaneously.

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

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

Elderly patients.

Prevention of venous thromboembolism (VTE) during elective hip or knee replacement surgery, treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as prevention of DVT and PE recurrence in adults: no dose adjustment is required (see sections "Pharmacokinetics" and "Special Instructions").

Non-valvular atrial fibrillation: dose adjustment is not required, except in cases specified above (see "Dose reduction" in section "Dosage and administration").

Renal impairment.

Recommendations for patients with mild or moderate renal impairment are as follows:

• For prevention 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 prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and serum creatinine level ≥ 1.5 mg/dL (133 µmol/L) in combination with either age over 80 years or body weight less than 60 kg, a lower dose of apixaban should be used as described above. If other criteria for dose reduction (age, body weight) are absent, no dose adjustment is required (see section "Pharmacokinetics").

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

• For prevention 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), apixaban should be used with caution;
• For prevention of stroke and systemic embolism 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 Instructions" and "Pharmacokinetics").

Hepatic impairment.

The medicinal product 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 Instructions" and "Pharmacokinetics").

The medicinal product 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 Instructions" and "Pharmacokinetics").

Patients with elevated liver enzymes (ALT/AST exceeding the upper limit of normal (ULN) by more than 2 times) or elevated total bilirubin (exceeding ULN by 1.5 times or more) were excluded from clinical trials. Therefore, the medicinal product should be used with caution in this patient group (see sections "Special Instructions" and "Pharmacokinetics"). Liver function tests should be performed before initiating apixaban therapy.

Body weight.

Prevention of venous thromboembolism during elective hip or knee replacement surgery, treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as prevention of DVT and PE recurrence in adults: no dose adjustment is required (see sections "Pharmacokinetics" and "Special Instructions").

Non-valvular atrial fibrillation: dose adjustment is not required, except in cases specified above (see "Dose reduction" in section "Dosage and administration").

Gender.

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

Patients undergoing catheter ablation.

Patients may continue receiving apixaban during catheter ablation (see sections "Contraindications", "Special Instructions", and "Interaction with other medicinal products and other forms of interaction").

Patients undergoing cardioversion.

Patients with NVAF who require cardioversion may initiate or continue apixaban.

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

Patients initiating apixaban therapy should receive 5 mg of the medicinal product twice daily for at least 2.5 days (5 doses) before cardioversion to ensure adequate anticoagulation (see section "Pharmacodynamics"). If the patient meets criteria for dose reduction (see above subsections "Dose reduction" and "Renal impairment"), 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 apixaban should be administered before the fifth dose, 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 above subsections "Dose reduction" and "Renal impairment"). The loading dose should be administered at least 2 hours before cardioversion (see section "Pharmacodynamics").

For all patients undergoing cardioversion, it is essential to confirm that the patient has been receiving 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 apixaban at the recommended dose in patients with NVAF when used in combination with antiplatelet agents – patients with ACS and/or those undergoing PCI after achieving hemostasis (see sections "Special Instructions" and "Pharmacodynamics").

Children.

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

Overdose.

Overdose of apixaban may lead to an increased risk of bleeding. In the event of hemorrhagic complications, treatment should be discontinued and the source of bleeding investigated. Appropriate treatment 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 reactions.

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, and had no effect on Cmax. Administration of activated charcoal 2 or 6 hours after apixaban intake reduced the elimination half-life of apixaban, which was 13.4 hours under monotherapy, to 5.3 and 4.9 hours, respectively. Thus, activated charcoal may be beneficial in treating apixaban overdose or accidental ingestion.

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

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

Single oral administration of 5 mg apixaban followed by hemodialysis reduced the AUC of apixaban 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 was evaluated in 7 phase III clinical trials involving over 21,000 patients: over 5,000 patients in VTE_p studies, over 11,000 patients in AF studies, and over 4,000 patients in VTE_t treatment studies; the mean overall duration of exposure was 20 days, 1.7 years, and 221 days, respectively (see section "Pharmacodynamics").

Common adverse reactions included bleeding, contusion, epistaxis, and hematoma (adverse event profiles and frequencies, classified by indication, are presented in Table 9). In the VTE_p studies, adverse reactions were observed overall in 11% of patients receiving 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 (International Society on Thrombosis and Haemostasis) 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 VTE_t 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").

Table 9 lists adverse reactions observed during administration of the medicinal product for the prevention of venous thromboembolism, non-valvular atrial fibrillation, treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as prevention of DVT and PE recurrence in adults, classified 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).

Table 9

Adverse reactions	VTEn	CVT with one or more risk factors	VTEl
Blood and lymphatic system disorders
Anaemia	Common	Common	Common
Thrombocytopenia	Uncommon	Uncommon	Common
Immune system disorders
Hypersensitivity, angioedema and anaphylaxis	Rare	Uncommon	Uncommon
Pruritus	Uncommon	Uncommon	Uncommon *
Angioedema	Unknown	Unknown	Unknown
Nervous system disorders
Intracranial haemorrhage†	Unknown	Uncommon	Rare
Eye disorders
Ocular haemorrhage (including conjunctival haemorrhage)	Rare	Common	Uncommon
Vascular disorders
Bleeding, haematoma	Common	Common	Common
Hypotension (including hypotension during procedures)	Uncommon	Common	Uncommon
Intra-abdominal haemorrhage	Unknown	Uncommon	Unknown
Respiratory, thoracic and mediastinal disorders
Nosebleeds	Uncommon	Common	Common
Haemoptysis	Rare	Uncommon	Uncommon
Respiratory tract haemorrhage	Unknown	Rare	Rare
Gastrointestinal disorders
Nausea	Common	Common	Common
Gastrointestinal haemorrhage	Uncommon	Common	Common
Haematochezia	Uncommon	Uncommon	Uncommon
Haemorrhoidal bleeding	Unknown	Uncommon	Uncommon
Oral cavity haemorrhage	Unknown	Uncommon	Common
Rectal bleeding, gingival bleeding	Rare	Common	Common
Retroperitoneal haemorrhage	Unknown	Rare	Unknown
Hepatobiliary disorders
Abnormal liver function tests, increased aspartate aminotransferase, increased alkaline phosphatase activity in blood, increased blood bilirubin level	Uncommon	Uncommon	Uncommon
Increased gamma-glutamyltransferase level	Uncommon	Common	Common
Increased alanine aminotransferase level	Uncommon	Uncommon	Common
Skin and subcutaneous tissue disorders
Skin rash	Unknown	Uncommon	Common
Alopecia	Rare	Uncommon	Uncommon
Multiform erythema	Unknown	Very rare	Unknown
Skin vasculitis	Unknown	Unknown	Unknown
Musculoskeletal and connective tissue disorders
Intramuscular haemorrhage	Rare	Rare	Uncommon
Renal and urinary disorders
Haematuria	Uncommon	Common	Common
Anticoagulant-related nephropathy	Unknown	Unknown	Unknown
Reproductive system and breast disorders
Abnormal vaginal bleeding, urogenital tract bleeding	Uncommon	Uncommon	Common
General disorders
Bleeding at site of drug administration	Unknown	Uncommon	Uncommon
Investigations
Positive occult blood test	Unknown	Uncommon	Uncommon
Injury, poisoning and procedural complications
Contusion	Common	Common	Common
Bleeding from medical procedure wound (including haematoma after medical procedure, postoperative wound bleeding, haematoma at vascular puncture site and bleeding from catheter site), wound discharge, bleeding from surgical incision (including haematoma at surgical incision site), surgical bleeding	Uncommon	Uncommon	Uncommon
Traumatic haemorrhage	Unknown	Uncommon	Uncommon

* Generalized pruritus cases were not observed in the CV185057 study (long-term VTE prophylaxis).

† The term "Intracranial hemorrhage" includes all intracranial or intraspinal hemorrhages (e.g., hemorrhagic stroke, putaminal, cerebellar, intraventricular, or subdural hemorrhages).

Use of apixaban 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 the bleeding (see sections "Dosage and Administration" and "Pharmacodynamics"). Reporting of suspected adverse reactions.

Reporting of adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

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

Packaging. 20 tablets in a blister; 1 blister per cardboard box.

Prescription status. Prescription only.

Manufacturer.

ADALVO LIMITED.

Pharmadox Healthcare Limited.

Manufacturer's address and location of business operations.

Malta Life Sciences Park, Building 1, Level 4, Sir Temi Zammit Buildings, San Gwann Industrial Estate, San Gwann, SGN 3000, Malta.

Kw20a Cordin Industrial Park, Paola, PLA 3000, Malta.