Eluxa

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

Composition:

Active substance: apixaban;

1 tablet contains 5 mg of apixaban;

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

Film coating: Opadry II Pink 85F240069 (polyvinyl alcohol, titanium dioxide (E 171), macrogol, talc, yellow iron oxide (E 172), red iron oxide (E 172)).

Medicinal form. Film-coated tablets.

Main physicochemical characteristics: round, biconvex, film-coated tablets ranging in color from pink to dark pink.

Pharmacotherapeutic group. Antithrombotic agents.

Direct factor Xa inhibitors. ATC code B01AF02.

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. For its antithrombotic effect, it does not require antithrombin III. Apixaban inhibits both free and clot-bound factor Xa, as well as suppresses prothrombinase activity. 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 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 minor 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 against factor Xa, as evidenced by reduced enzymatic activity of factor Xa in various commercial anti-Xa assays, although specific results varied among different assay systems. Clinical study data are available only for the chromogenic assay Rotachrom® heparin (results provided below). Anti-factor Xa activity is correlated with apixaban plasma concentration. This relationship is approximately linear, with maximum anti-factor Xa activity observed at peak apixaban plasma concentrations. The relationship between apixaban plasma concentration and anti-factor Xa activity is approximately linear over a wide dose range.

Table 1 (see below) shows the predicted steady-state concentrations and anti-Xa activity for each indication. In patients with atrial fibrillation receiving apixaban for stroke and systemic embolism prevention, observed results indicate less than a 1.7-fold fluctuation between peak and trough levels. In patients receiving apixaban for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), or for prevention of DVT and PE recurrence, less than a 2.2-fold fluctuation between peak and trough levels was observed.

Predicted steady-state concentration of apixaban and anti-Xa activity

Table 1

* Dose adjustment for the population was based on 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 situations when information on apixaban exposure levels may assist in making a clinical decision (e.g., in cases of overdose or emergency surgery), a quantitative method for measuring Factor Xa inhibition activity, Rotachrom®, can be used.

Clinical efficacy and safety.

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

In the clinical trial program (ARISTOTLE study: apixaban compared with warfarin; AVERROES study: apixaban compared with 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 NVAF who had one or more additional risk factors, namely:

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

ARISTOTLE study.

The ARISTOTLE study randomized a total of 18,201 patients; participants were assigned to double-blind treatment with either apixaban 5 mg twice daily (or 2.5 mg twice daily in certain patients (4.7%), see section "Method of administration and dosage"), 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 statistically significant superiority over warfarin for the primary efficacy endpoint of prevention of stroke (hemorrhagic or ischemic) and systemic embolism (see Table 2).

Efficacy in patients with atrial fibrillation enrolled in the ARISTOTLE study

Table 2

In patients assigned to the warfarin treatment group, the median time within the therapeutic range (INR 2.0–3.0) was 66%.

Apixaban demonstrated a reduction in the rate of stroke and systemic embolism (compared to warfarin therapy) across various levels of mean time in the therapeutic range. For the highest quartile relative to the mean, the 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 compared to warfarin for the key secondary endpoints of major bleeding and all-cause mortality (see Table 3). However, with more stringent INR control, the advantages of apixaban over warfarin with respect to all-cause mortality diminished.

Secondary endpoints in patients with atrial fibrillation in the ARISTOTLE study

Table 3

*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 study was 1.8% with apixaban and 2.6% with warfarin.

The efficacy results in pre-specified subgroups (including subgroups based on CHADS2 score, age, body weight, sex, renal function, prior history of stroke, 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 upper gastrointestinal, lower gastrointestinal, and rectal bleeding) was 0.76% per year with apixaban and 0.86% per year with warfarin.

The rates 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) were consistent with the results in the overall population.

AVERROES study.

A total of 5,598 patients were randomized in the AVERROES study, all of whom were unsuitable for treatment with vitamin K antagonists (VKAs). Study participants were assigned to receive either apixaban 5 mg twice daily (or 2.5 mg twice daily in some patients (6.4%) (see section "Posology and method of 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. Patients received study treatment for a median duration of 14 months. The mean age of participants was 69.9 years, and the mean CHADS2 score was 2.0. A prior history of 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 study was terminated prematurely upon recommendation of the independent Data Monitoring Committee due to compelling evidence of reduced stroke and systemic embolism rates with a favorable safety profile.

The cumulative incidence of treatment discontinuation due to adverse reactions in the AVERROES study was 1.5% with apixaban and 1.3% with ASA.

In this study, apixaban treatment demonstrated statistically significant superiority over ASA for the primary efficacy endpoint of prevention of stroke (hemorrhagic, ischemic, or undetermined) or systemic embolism (see Table 4).

Key efficacy results in patients with atrial fibrillation

who participated in the AVERROES study

Table 4

* Assessment using a sequential hypothesis 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)

The AUGUSTUS trial—a randomized, open-label, 2 × 2 factorial design study—enrolled 4,614 patients with NVAF who had ACS (43%) and/or underwent PCI (56%). 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), along with aspirin (81 mg once daily) or placebo. The mean patient age 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 proportion of time in the 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 assess safety, with the primary endpoint being major or clinically relevant non-major bleeding according to ISTH criteria. In the apixaban versus VKA comparison group, 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 (HR = 0.69, 95% CI: 0.58, 0.82; two-sided p<0.0001 for both non-inferiority and superiority). In a supplementary analysis of VKA using TTR subgroups, 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 aspirin versus placebo comparison, 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 (HR = 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 secondary study objectives using composite endpoints.

In the comparison of apixaban versus VKA, the composite endpoint of death or recurrent hospitalization occurred in 541 (23.5%) and 632 (27.4%) patients in the apixaban and VKA groups, respectively. The composite endpoint of death or ischemic events (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 versus placebo, the composite endpoint of death or recurrent hospitalization occurred in 604 (26.2%) and 569 (24.7%) patients in the aspirin and placebo groups, respectively. The composite endpoint of death or ischemic events (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—a multicenter, open-label study—included 1,500 patients with NVAF who were either not receiving anticoagulation or had been treated for less than 48 hours and for whom cardioversion was planned.

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 early 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 group (n = 747, RR 0.00, 95% CI 0.00, 0.64), 6 (0.80%) strokes were observed.

Fatal outcomes (without specification of 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.

Major bleeding 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 VKA group.

This exploratory study 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 potential of the drug for preventing 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 evaluated by an independent committee based on blinded data.

AMPLIFY study.

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

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

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

This study demonstrated that apixaban is 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 treated for 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 various subgroups, including those stratified by age, sex, body mass index (BMI), renal function, PE burden, location of DVT thrombus, and prior parenteral heparin use, was generally consistent.

The primary safety endpoint was bleeding. In this study, apixaban showed statistically significant advantages compared to enoxaparin/warfarin for the primary safety endpoint [relative risk 0.31, 95% confidence interval (0.17; 0.55), p <0.0001] (see Table 5).

Bleeding outcomes in the AMPLIFY study

Table 5

Significant bleeding and minor bleeding (clinically relevant non-major bleeding) at any anatomical site were generally lower in the apixaban group compared with the enoxaparin/warfarin group. ISTH-defined major 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 apixaban 2.5 mg orally twice daily, apixaban 5 mg orally twice daily, or placebo for 12 months after 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 the AMPLIFY-EXT study.

The mean age of patients was 56.7 years, and 91.7% of randomized patients had experienced unprovoked VTE events.

In this study, both doses of apixaban 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 6).

Efficacy results in the AMPLIFY-EXT study

Table 6

¥ p <0.0001.

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

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

The efficacy of apixaban in preventing recurrent VTE 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 was not statistically different from placebo. There was no statistically significant difference in the rates of major, non-major, clinically relevant bleeding, CRNM bleeding, or all bleeding between the apixaban 2.5 mg twice daily group and the placebo group.

Gastrointestinal bleeding classified as major according to 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.

Pediatric population.

The European Medicines Agency has deferred the obligation to submit the results of studies with apixaban involving pediatric patients for 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 at 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 can 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 within-subject variability of approximately 20% coefficient of variation (CV) and between-subject variability of approximately 30% CV.

Following oral administration of 10 mg apixaban as two 5 mg crushed tablets suspended in 30 mL of water, exposure was comparable to that following administration of two whole 5 mg tablets. Following oral administration of 10 mg apixaban as two 5 mg crushed tablets mixed with 30 g of apple puree, Cmax and AUC values were 20% and 16% lower, respectively, compared to administration of two 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% dextrose solution and delivered via nasogastric tube, exposure was similar to that observed in other clinical studies in healthy volunteers who received one 5 mg apixaban tablet orally.

Given the predictable 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 (Vs) is approximately 21 liters.

Biotransformation and elimination.

Apixaban is eliminated from the body via 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. Clinical and preclinical studies have demonstrated an additional role of biliary and direct intestinal excretion pathways.

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

The main metabolic pathways are O-demethylation and hydroxylation of the 3-oxopiperidinyl moiety. Apixaban metabolism is primarily mediated by CYP3A4/5. Minor contributions to metabolism are made by CYP1A2, 2C8, 2C9, 2C19, and 2J2. Unchanged apixaban is the main circulating compound in human plasma associated with this drug. 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 assessments, increased 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 did not have a pronounced effect on the relationship between apixaban plasma concentration and the degree of factor Xa inhibition.

Following a single 5 mg dose of apixaban administered immediately after hemodialysis in patients with end-stage chronic kidney disease, apixaban concentration increased by 36% compared to individuals with normal creatinine clearance.

Hepatic impairment.

In a study comparing 8 participants with mild hepatic impairment (Child-Pugh class A with score 5 (n=6) and 6 (n=2)) and 8 participants with moderate hepatic impairment (Child-Pugh class B with 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 anti-Xa activity were comparable between healthy volunteers and patients with mild or moderate hepatic impairment.

Elderly patients.

Higher plasma drug concentrations were observed in elderly patients (over 65 years) compared to younger patients; mean AUC values in elderly patients were approximately 32% higher.

Sex.

Apixaban exposure in women was approximately 18% higher than in men.

Ethnic origin and race.

Phase I study results indicate no notable differences in apixaban pharmacokinetic parameters among Caucasian, Mongoloid, and Negroid populations. Results from population pharmacokinetic analyses in 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 individuals weighing over 120 kg compared to those with normal body weight (65–85 kg), while exposure increased by approximately 30% in individuals weighing less than 50 kg.

Pharmacodynamic/pharmacokinetic relationship.

The pharmacokinetic/pharmacodynamic (PK/PD) relationship between apixaban plasma concentration and selected PD endpoints (factor Xa inhibition activity, anti-Xa, PT, aPTT) 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 observed in healthy volunteers.

Clinical characteristics.

Indications.

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 unstable hemodynamics is provided in the section "Special precautions").

Contraindications.

Hypersensitivity to the active substance or to any excipient.

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., current or recent gastrointestinal ulceration, presence of malignant neoplasms with high bleeding risk, recent head or spinal 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.), oral anticoagulants (warfarin, rivaroxaban, dabigatran, etc.), except in specific cases of switching anticoagulant therapy (see section "Dosage and administration"): or 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.

CYP3A4 and P-gp inhibitors.

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

Eluxa® is not recommended for 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 as potent inhibitors of CYP3A4 and/or 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 used concomitantly with substances 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 the mean AUC and Cmax of apixaban by 1.4- and 1.3-fold, respectively. Naproxen (single dose 500 mg) is a P-gp inhibitor but does not affect CYP3A4. This drug increased the mean AUC and Cmax of apixaban by 1.5- and 1.6-fold, respectively. Clarithromycin (500 mg twice daily), a P-gp inhibitor and strong CYP3A4 inhibitor, increased the mean AUC and Cmax of apixaban by 1.6- and 1.3-fold, respectively.

CYP3A4 and P-gp inducers.

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 products) may also lead to decreased plasma concentrations of apixaban. Dose adjustment of apixaban is not required when used concomitantly with such agents.

However, for stroke and systemic embolism prevention in patients with non-valvular atrial fibrillation and for 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 bleeding risk, concomitant use of any other anticoagulants is contraindicated, except under 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").

Following combined administration of enoxaparin (single dose 40 mg) and apixaban (single dose 5 mg), a cumulative effect on anti-Xa activity was observed.

No significant pharmacokinetic or pharmacodynamic interactions were observed when apixaban was administered concomitantly with acetylsalicylic acid (ASA) (325 mg once daily).

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 result in 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 monotherapy.

Naproxen (500 mg), which is a P-gp inhibitor, 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 lead to clinically significant prolongation of bleeding time. Nevertheless, in some individuals, a more pronounced pharmacodynamic response to concomitant administration of antiplatelet agents and apixaban may occur. Eluxa® should be used with caution in combination 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 bleeding risk, 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 administered concomitantly 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 subsequent co-administration of both drugs, mean AUC and Cmax values 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 values 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 considered unlikely 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 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 Eluxa® should be carefully monitored 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, Eluxa® should be discontinued (see sections "Adverse reactions" and "Overdose").

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

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

Interactions with other medicinal products affecting blood coagulation.

Due to increased bleeding risk, concomitant treatment with any other anticoagulants is contraindicated (see section "Contraindications").

Concomitant 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 ASA.

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

For patients with atrial fibrillation and conditions 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. Dual antiplatelet therapy was limited in this trial (2.1%) (see section "Pharmacodynamics").

A clinical trial included patients with atrial fibrillation and/or those undergoing PCI with a planned period of treatment with a P2Y12 inhibitor, with or without ASA, and an oral anticoagulant (apixaban or VKA) for 6 months. Concomitant use of ASA in patients receiving apixaban increased the risk of major or non-major clinically relevant bleeding according to International Society on Thrombosis and Haemostasis (ISTH) criteria from 16.4% to 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 cardiovascular and non-cardiovascular comorbidities and were receiving ASA or a combination of ASA and clopidogrel, apixaban use was associated with a significant increase in ISTH-defined major bleeding – 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 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, anti-cardiolipin antibodies, and anti-beta-2-glycoprotein I antibodies), treatment with direct oral anticoagulants may be associated with a higher rate of recurrent thrombotic events compared to VKA therapy.

Surgical procedures and invasive procedures.

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

Treatment with Eluxa® 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, non-critical, or easily controlled.

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

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

Patients undergoing catheter ablation for treatment of atrial fibrillation do not need to interrupt treatment with Eluxa® (see sections "Dosage and administration", "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 when temporary discontinuation of Eluxa® is necessary (for any reason), treatment should be resumed as soon as possible.

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

For stroke and systemic embolism prevention in patients with NVAF who have severe renal dysfunction (creatinine clearance 15–29 mL/min) or serum creatinine ≥ 1.5 mg/dL (133 µmol/L) in combination with 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 "Dosage and administration").

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 "Dosage and administration" 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) may increase the risk of bleeding (see section "Pharmacokinetics").

Hepatic impairment.

Eluxa® is contraindicated in patients with liver disease associated with coagulopathy and clinically significant 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 or moderate hepatic impairment (Child–Pugh class A or B) (see sections "Dosage and 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, Eluxa® 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).

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, and posaconazole) or HIV protease inhibitors (e.g., ritonavir). These drugs 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 dual inducers of CYP3A4 and P-gp.

Concomitant use of Eluxa® with strong dual 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 dual inducers of CYP3A4 and P-gp reduced anticoagulant efficacy and increased bleeding risk compared to apixaban monotherapy.

For patients receiving concomitant treatment with strong dual 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 stroke and systemic embolism prevention in patients with NVAF and for prevention of recurrent DVT and PE;
• apixaban should not be used for treatment of DVT and PE, as its efficacy may be compromised.

Laboratory parameters.

Coagulation tests (e.g., PT, INR, and 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").

Information on excipients.

Eluxa® contains lactose. If the patient has been diagnosed with an intolerance to certain sugars, they should consult their physician before taking this medicinal product.

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. 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 and breastfed infants cannot be excluded.

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

Effect on reproductive function. Animal studies with direct administration of apixaban did not reveal any effect of this drug on fertility.

Ability to influence reaction speed when driving or operating machinery.

Eluxa® has no or negligible influence 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 (see section "Pharmacokinetics"). Eluxa® tablets may also be crushed and suspended in 60 mL of water or 5% aqueous dextrose solution and administered immediately via a nasogastric tube (see section "Pharmacokinetics").

The Eluxa® tablet formulation, after crushing, is stable in water, 5% aqueous dextrose solution, apple juice, or apple puree for up to 4 hours.

Dosage.

Prevention of stroke and systemic embolism 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 (the 2.5 mg dosage form should be used). Treatment should be continued long-term.

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 acute deep vein thrombosis (DVT) and pulmonary embolism (PE) is 10 mg orally twice daily for the first 7 days, with a maximum daily dose of 20 mg. Thereafter, the drug is administered at a dose of 5 mg orally twice daily, with a maximum daily dose of 10 mg. According to current medical guidelines, the duration of 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 completing 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 after careful assessment of the benefits of treatment versus the risk of bleeding (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 treatment (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® treatment.

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

Transition from Eluxa® treatment 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 two days of concomitant apixaban and vitamin K antagonist therapy, measure the INR before administering the next Eluxa® dose. Combined treatment with Eluxa® and a vitamin K antagonist should continue until the INR reaches levels ≥ 2.0.

Renal Impairment.

Recommendations for patients with mild or moderate renal impairment:

• for treatment of DVT, treatment of PE, and prevention of DVT or PE recurrence (VTE), dose adjustment is not required (see section "Pharmacokinetics");
• for prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and serum creatinine ≥ 1.5 mg/dL (133 µmol/L) in combination with 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), dose adjustment is not required (see section "Pharmacokinetics").

Recommendations for patients with severe renal impairment (creatinine clearance 15–29 mL/min) (see sections "Special Warnings and Precautions for Use" and "Pharmacokinetics"):

• for treatment of DVT, treatment of PE, and prevention of DVT or PE recurrence (VTE), 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 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 drug 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 sections "Special Warnings and Precautions for Use" and "Pharmacokinetics"). Liver function tests should be performed before initiating apixaban therapy.

Body Weight.

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 sections "Pharmacokinetics" and "Special Warnings and Precautions for Use").

Non-valvular atrial fibrillation: dose adjustment is not required, except in cases specified above (see "Dose Reduction" in the section "Method of Administration and Dosage").

Gender.

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

Elderly Patients.

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 sections "Special Warnings and Precautions for Use" and "Pharmacokinetics").

Non-valvular atrial fibrillation: dose adjustment is not required, except in cases specified above (see "Dose Reduction" in the section "Method of Administration and Dosage").

Patients Undergoing Catheter Ablation.

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

Cardioversion (non-valvular atrial fibrillation).

Apixaban treatment may be initiated or continued in patients with NVAF who may require cardioversion.

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

For patients initiating apixaban treatment, 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 apixaban dose, followed by 5 mg twice daily. The dosing regimen should be reduced to a 5 mg loading dose, then 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, confirmation should be obtained that the patient has been receiving apixaban as prescribed. The decision on initiation and duration of treatment 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, in combination with antiplatelet agents, and in patients with ACS and/or those undergoing PCI after achieving hemostasis (see sections "Special Warnings and Precautions for Use" and "Pharmacodynamics").

Children.

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. Initiation of 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 studies, 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 subjects, 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 did not affect Cmax. Administration of activated charcoal 2 or 6 hours after apixaban intake 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 in cases of life-threatening or uncontrolled bleeding, a specific factor Xa inhibitor reversal agent is available (see section "Special Warnings and Precautions for Use"). Administration of prothrombin complex concentrate (PCC) or recombinant factor VIIa may also be considered. Reversal of the pharmacodynamic effects of Eluxa®, as confirmed by thrombin generation assay, was evident at the end of infusion and returned to baseline levels within 4 hours after the start of a 30-minute infusion of 4-factor PCC in healthy volunteers. However, there is no clinical experience with 4-factor PCC for bleeding management in patients receiving Eluxa®. Experience with recombinant factor VIIa for treating patients on apixaban is currently lacking. Repeated administration and dose titration of recombinant factor VIIa based on bleeding control should be considered.

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

With single oral administration of 5 mg apixaban, 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 four phase III clinical trials involving over 15,000 patients: over 11,000 patients in NVAF studies and over 4,000 patients in VTEt studies; the average overall duration of exposure was 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 frequency, classified by indication, are presented below).

In the NVAF studies, the overall frequency of bleeding-related adverse reactions in the apixaban group was 24.3% in the apixaban versus warfarin study and 9.6% in the apixaban versus aspirin study. In the apixaban versus warfaran study, the rate of major gastrointestinal bleeding according to ISTH criteria (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 criteria in patients receiving apixaban was 0.18% per year.

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

The adverse reactions listed below are classified by system organ class 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 available data) for NVAF and VTEt, respectively.

Blood and lymphatic system disorders:
Anemia – common (NVAF*, VTEt); thrombocytopenia – common (VTEt), uncommon (NVAF*).

Immune system disorders:
Hypersensitivity, allergic edema, and anaphylaxis – uncommon (NVAF*, VTEt); pruritus – uncommon (NVAF*), uncommon** (VTEt); angioedema – not known (NVAF*, VTEt).

Nervous system disorders:
Intracranial hemorrhage – uncommon (NVAF*), rare (VTEt).

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

Vascular system disorders:
Bleeding, hematoma – common (NVAF*, VTEt); hypotension (including procedural hypotension) – common (NVAF*), uncommon (VTEt); intra-abdominal hemorrhage – uncommon (NVAF*), not known (VTEt).

Respiratory, thoracic and mediastinal disorders:
Epistaxis – common (NVAF*, VTEt); hemoptysis – uncommon (NVAF*, VTEt); respiratory tract hemorrhage – rare (NVAF*, VTEt).

Gastrointestinal disorders:
Nausea – common (NVAF*, VTEt); gastrointestinal hemorrhage – common (NVAF*, VTEt); hemorrhoidal hemorrhage – uncommon (NVAF*, VTEt); oral cavity hemorrhage – uncommon (NVAF*), common (VTEt); hematochezia – uncommon (NVAF*, VTEt); rectal hemorrhage, gingival hemorrhage – common (NVAF*, VTEt); retroperitoneal hemorrhage – rare (NVAF*), not known (VTEt).

Hepatobiliary disorders:
Abnormal liver function tests, increased aspartate aminotransferase, increased alkaline phosphatase, increased blood bilirubin – uncommon (NVAF*, VTEt); increased gamma-glutamyltransferase – common (NVAF*, VTEt); increased alanine aminotransferase – common (VTEt), uncommon (NVAF*).

Skin and subcutaneous tissue disorders:
Rash – common (VTEt), uncommon (NVAF*); alopecia – uncommon (NVAF*, VTEt); erythema multiforme – very rare (NVAF*), not known (VTEt); cutaneous vasculitis – not known (NVAF*, VTEt).

Musculoskeletal and connective tissue disorders:
Muscle hematoma – rare (NVAF*), uncommon (VTEt).

Renal and urinary disorders:
Hematuria – common (NVAF*, VTEt).

Reproductive system and breast disorders:
Pathological vaginal bleeding, genitourinary tract hemorrhage – common (VTEt), uncommon (NVAF*).

General disorders and administration site conditions:
Bleeding at the site of administration – uncommon (NVAF*, VTEt).

Investigations:
Positive occult blood test – uncommon (NVAF*, VTEt).

Injury, poisoning and procedural complications:
Bruising – common (NVAF*, VTEt); bloody drainage from surgical wound (including post-procedural hematoma, postoperative wound hemorrhage, hematoma at vascular puncture site, and catheter site hemorrhage), wound drainage, surgical wound hemorrhage (including hematoma at surgical incision site), operative hemorrhage – uncommon (NVAF*, VTEt); traumatic hemorrhage – uncommon (NVAF*, VTEt).

* NVAF with one or more risk factors
** In study CV185057 (long-term VTE prevention), cases of generalized pruritus were not observed.
† The term "Intracranial hemorrhage" includes all intracranial or intraspinal hemorrhages (e.g., hemorrhagic stroke, putaminal, cerebellar, intraventricular, or subdural hemorrhages).

The use of 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, degree, and duration of bleeding (see sections "Special precautions for use" and "Pharmacodynamics").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. 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 reach of children.

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

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address and location of its business activity.
74 Kyrylivska Street, Kyiv, 04080, Ukraine.