Eliquis

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ELIQUIS® (ELIQUIS®)

Composition:

Active substance: apixaban;

One film-coated tablet contains 2.5 mg of apixaban;

Excipients: anhydrous lactose, microcrystalline cellulose, sodium croscarmellose, sodium lauryl sulfate, magnesium stearate, Opadry® II Yellow (hypromellose 15 cP; lactose monohydrate; titanium dioxide (E 171); triacetin; yellow iron oxide (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: yellow, round, biconvex film-coated tablets, with "893" engraved on one side and "2\ 1/2" on the other.

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 oral inhibitor of the active site of factor Xa. It does not require antithrombin III for antithrombotic activity. Apixaban inhibits both free and clot-bound factor Xa and also suppresses the activity of prothrombinase. Apixaban does not directly affect platelet aggregation but indirectly inhibits thrombin-induced platelet aggregation. By inhibiting factor Xa, apixaban prevents thrombin generation and thrombus formation. Preclinical studies of apixaban in animals demonstrated effective antithrombotic activity in 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 (factor Xa inhibition). 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 in blood coagulation parameters observed with therapeutic doses of apixaban are minimal and highly variable, and therefore are not recommended for assessing the pharmacodynamic effects of apixaban. In thrombin generation assays, apixaban reduced endogenous thrombin potential — a quantitative measure of thrombin formation 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 assay kits, although specific results varied among different kits. Clinical study data are available only for the chromogenic assay Rotachrom® heparin (results provided below). Factor Xa inhibitory activity is correlated with apixaban plasma concentration. This relationship is approximately linear, with maximum factor Xa inhibition occurring 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 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 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 2.2-fold fluctuation was observed between peak and trough levels.

Table 1

Predicted steady-state apixaban concentrations and factor Xa inhibitory activity

* 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 chromogenic assay (Rotachrom®) can be used.

Clinical efficacy and safety.

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

The clinical development program for apixaban was designed to demonstrate the efficacy and safety of apixaban for the prevention of venous thromboembolism in various populations of adult patients undergoing elective hip or knee replacement surgery. Overall, 8,464 patients were randomized in two pivotal, double-blind, multinational studies comparing oral apixaban 2.5 mg twice daily (4,236 patients) with subcutaneous enoxaparin 40 mg once daily (4,228 patients). The total population included 1,262 patients aged 75 years and older (of whom 618 were in the apixaban treatment group), 1,004 patients with low body weight (≤ 60 kg) (of whom 499 were in the apixaban treatment group), 1,495 patients with 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. Apixaban and enoxaparin were administered for 32–38 days in the ADVANCE-3 study and for 10–14 days in the ADVANCE-2 study.

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

Apixaban demonstrated 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 Thrombosis" endpoint (composite endpoint of proximal deep vein thrombosis, non-fatal pulmonary embolism, and fatal events related to venous thromboembolism) compared to enoxaparin in both patient groups undergoing elective hip and knee replacement surgery (see Table 2).

Table 2

Efficacy results from the pivotal Phase III studies

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

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

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

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

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

• prior history of stroke or transient ischemic attack;
• age ≥ 75 years;
• 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 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 2.0–3.0). Patients received the active substance 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 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).

Table 3

Efficacy in patients with atrial fibrillation enrolled in the ARISTOTLE study

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

Apixaban demonstrated a reduction in the rate of stroke and systemic embolism (compared to warfarin therapy) across various levels of time in the therapeutic range. For the highest quartile of time in the therapeutic range, 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 benefit of apixaban over warfarin with regard to all-cause mortality diminished with more stringent INR control.

Table 4

Secondary endpoints in patients with atrial fibrillation in the ARISTOTLE study

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

† Clinically relevant non-major bleeding.

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 predefined subgroups (including subgroups based on such factors as 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 predefined subgroups (including subgroups based on such factors as CHADS2 score, age, body weight, sex, renal function, history of stroke, transient ischemic attack, and diabetes) were consistent with results in the overall population.

Study AVERROES.

Overall, 5598 patients were randomized in the AVERROES study, in whom vitamin K antagonist therapy was not feasible. Study participants were assigned to treatment with apixaban 5 mg twice daily (or in some patients (6.4%) 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 active substance 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 infeasibility of 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 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 incidence of stroke and systemic embolism combined with a favorable safety profile of the 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 statistically significant superiority over acetylsalicylic acid for the primary efficacy endpoint of prevention of stroke (hemorrhagic, ischemic, or undetermined) or systemic embolism (see Table 5).

Table 5

Key efficacy outcomes in patients with atrial fibrillation participating in the AVERROES study

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

† Secondary endpoint.

There was no statistically significant difference in the rate of major bleeding between apixaban and 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 randomized, open-label, 2x2 factorial-designed, controlled study—4,614 patients with NVAF who had ACS (43%) and/or underwent PCI (56%) were enrolled. All patients received background therapy with a P2Y12 inhibitor (clopidogrel: 90.3%), administered according to local treatment standards.

Patients within 14 days after ACS and/or PCI were randomized to receive apixaban 5 mg twice daily (2.5 mg twice daily if patients met two or more dose-reduction criteria; 4.2% received the lower dose) or a vitamin K antagonist (VKA), and either 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 apixaban versus VKA comparison, the primary endpoint—major or clinically relevant non-major bleeding according to ISTH criteria at 6 months—occurred in 241 (10.5%) and 332 (14.7%) patients in the apixaban and VKA groups, respectively (RR = 0.69, 95% CI: 0.58, 0.82; two-sided p<0.0001 for non-inferiority and p<0.0001 for superiority). 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 subgroup with the highest TTR quartile.

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

Specifically, in patients receiving apixaban treatment, major or clinically relevant non-major bleeding occurred in 157 (13.7%) and 84 (7.4%) patients in the ASA 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 ASA and placebo groups, respectively.

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

In the apixaban versus VKA comparison, 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 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 ASA versus placebo comparison, the composite endpoint of death or recurrent hospitalization 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—a multicenter, open-label study—enrolled 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 a 10 mg dose and 11 received a 5 mg dose).

No strokes (0%) were observed in the apixaban group (n = 753), compared to 6 (0.80%) in the heparin and/or vitamin K antagonist group (n = 747, RR 0.00, 95% CI 0.00, 0.64).

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 exploratory study demonstrated comparable efficacy and safety between the apixaban and heparin and/or vitamin K antagonist 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 to evaluate its extended use for the prevention of recurrent DVT and/or PE after 6–12 months of anticoagulant therapy for DVT and/or PE (AMPLIFY-EXT). Both studies were randomized, double-blind, international, parallel-group trials involving patients with symptomatic proximal DVT or symptomatic PE. All major safety and efficacy endpoints were adjudicated by an independent committee based on blinded data.

AMPLIFY study.

In the AMPLIFY study, 5,395 patients were randomized to: the apixaban treatment group receiving oral apixaban 10 mg twice daily for 7 days, followed by 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); and the warfarin treatment group receiving oral warfarin (target INR range 2.0–3.0) for 6 months.

The mean age of patients 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 (2.0–3.0) was 60.9%. Apixaban demonstrated reduced rates 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 adjudicated recurrent symptomatic VTE (DVT or non-fatal PE) 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 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, PE burden, DVT thrombus location, and prior parenteral heparin use, was generally consistent.

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

Table 6

Bleeding outcomes in the AMPLIFY study

Significant bleeding and MHE (major hemorrhagic events) at any anatomical site were generally lower in the apixaban group compared to 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 either apixaban 2.5 mg orally twice daily, apixaban 5 mg orally twice daily, or placebo for 12 months following completion of an initial 6–12 month anticoagulant treatment course. 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 outcome of symptomatic recurrent VTE (DVT or non-fatal PE) or death from any cause (see Table 7).

Table 7

Efficacy results in the AMPLIFY-EXT study

¥ p <0.0001.

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

† Individual patients may have experienced more than one event, and events may have been counted in both categories.

The efficacy of apixaban for prevention of 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 did not differ statistically from placebo. There was no statistically significant difference in the incidence of major, clinically relevant non-major bleeding, CRNM, or all bleeding between the group receiving apixaban 2.5 mg twice daily and the placebo group.

ISTH-defined major gastrointestinal bleeding 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 occurred in 1 (0.1%) patient receiving placebo.

Use in pediatric patients

Currently, there are no approved pediatric indications (see section "Paediatric population").

Prevention of VTE in pediatric patients with acute lymphoblastic leukemia or lymphoblastic lymphoma (ALL, LL)

In the PREVAPIX-ALL study, 512 patients aged ≥1 to <18 years with newly diagnosed ALL or LL who were receiving induction chemotherapy, including intravenous asparaginase via a central venous catheter, were randomized 1:1 to receive either open-label thromboprophylaxis with apixaban or standard care (no systemic anticoagulation). Apixaban was administered at a fixed dose based on patient body weight, designed to achieve exposures comparable to those in adults receiving 2.5 mg of the drug twice daily (see Table 8). Apixaban was administered as 2.5 mg and 0.5 mg tablets or as an oral solution 0.4 mg/mL. The mean duration of exposure in the apixaban group was 25 days.

Table 8

Apixaban dosing in the PREVAPIX-ALL study

The primary efficacy endpoint was a composite of confirmed symptomatic and asymptomatic non-fatal deep vein thrombosis, pulmonary embolism, cerebral venous sinus thrombosis, and death related to venous thromboembolism. The incidence of the primary efficacy endpoint was 31 (12.1%) in the apixaban group versus 45 (17.6%) in the standard therapy group. The relative risk reduction did not reach statistical significance.

Safety endpoints were assessed according to ISTH (International Society on Thrombosis and Haemostasis) criteria. The major safety endpoint—major bleeding—occurred in 0.8% of patients in both treatment groups. Clinically relevant non-major bleeding (CRNMB) occurred in 11 patients (4.3%) in the apixaban group and in 3 patients (1.2%) in the standard therapy group. The most common CRNMB events contributing to the treatment difference were mild to moderate epistaxis. Minor bleeding occurred in 37 patients (14.5%) in the apixaban group and in 20 patients (7.8%) in the standard therapy group.

Prevention of thromboembolism (TE) in children with congenital or acquired heart defects

SAXOPHONE is a randomized, open-label, multicenter comparative study with a 2:1 allocation involving patients aged from 28 days to 18 years with congenital or acquired heart defects requiring anticoagulation. Patients received either apixaban or standard thromboprophylaxis with a vitamin K antagonist or low-molecular-weight heparin. Apixaban was administered as a fixed dose based on body weight, designed to achieve exposure comparable to that observed in adults receiving 5 mg of the drug twice daily (see Table 9). Apixaban was administered as 5 mg tablets, 0.5 mg tablets, or oral solution 0.4 mg/mL. The mean duration of exposure in the apixaban group was 331 days.

Table 9

Apixaban dosing in the SAXOPHONE study

The primary safety endpoint, a composite of ISTH-defined major and clinically relevant non-major (CRNM) bleeding, occurred in 1 (0.8%) of 126 patients in the apixaban group and in 3 (4.8%) of 62 patients in the standard therapy group. Secondary safety endpoints—defined major bleeding, CRNM bleeding, and all bleeding events—were similar in frequency between both treatment groups. The secondary safety endpoint of discontinuation of study drug due to an adverse reaction, intolerance, or bleeding was recorded in 7 (5.6%) patients in the apixaban group and in 1 (1.6%) patient in the standard therapy group. No patient in either treatment group experienced thromboembolic events. There were no deaths in either treatment group.

This study was prospectively designed to describe efficacy and safety due to the anticipated low frequency of thromboembolic (TE) events and bleeding in this population. Due to the observed low incidence of TE events in this study, a definitive assessment of the benefit-risk balance was not possible.

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

Pharmacokinetics

Absorption

The absolute bioavailability of apixaban following doses up to and including 10 mg is approximately 50%. Apixaban is rapidly absorbed, with peak drug concentration (C_max) reached within 3–4 hours after tablet intake. Food intake does not affect the AUC or C_max of apixaban when a 10 mg dose is administered. 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-participant variability of approximately 20% coefficient of variation (CV) and inter-participant variability of approximately 30% CV.

Following oral administration of 10 mg apixaban as 2 crushed 5 mg tablets suspended in 30 mL of water, exposure was comparable to that following oral administration of 2 intact 5 mg tablets. Following oral administration of 10 mg apixaban as 2 crushed 5 mg tablets mixed with 30 g of apple puree, C_max 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.

Following administration of a crushed 5 mg apixaban tablet suspended in 60 mL of 5% aqueous glucose solution and delivered via nasogastric tube, exposure was similar to that observed in other clinical studies in healthy volunteers who received a single 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 is approximately 21 litres.

Biotransformation and elimination

Apixaban is eliminated from the body via multiple pathways. Approximately 25% of an administered dose of apixaban in humans is excreted as metabolites, with the majority of metabolites excreted in faeces. Renal clearance of apixaban accounts for approximately 27% of total clearance. Clinical and preclinical studies have shown 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 biotransformation 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 medicinal product. There are no circulating active metabolites in plasma. Apixaban is a substrate of the transporter proteins P-gp and breast cancer resistance protein (BCRP).

Elderly patients

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

Renal impairment

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

Hepatic impairment

In a study comparing 8 participants with mild hepatic impairment (Child-Pugh class A, score 5 (n=6) and 6 (n=2)) and 8 participants with moderate hepatic impairment (Child-Pugh class B, score 7 (n=6) and 8 (n=2)) to 16 healthy control volunteers, 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 (INR) 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 in patients receiving apixaban after elective hip or knee replacement surgery was consistent with Phase I study results.

Body weight

When comparing apixaban exposure across different body weights, exposure was approximately 30% lower in individuals weighing over 120 kg compared to those with normal body 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 plasma apixaban concentration and several PD endpoints (factor Xa inhibition activity, PT, aPTT, and TT) was evaluated after administration of various apixaban doses across a wide range (0.5 to 50 mg). The linear model best describes the relationship between plasma apixaban concentration and factor Xa inhibition activity. 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 recurrence of 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 of the excipients.

Clinically significant active bleeding.

Liver disease associated with coagulopathy and clinically relevant bleeding risk.

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 head or spinal trauma, recent surgery on the brain or spinal cord or ophthalmologic procedures, recent intracranial hemorrhage, diagnosed or suspected esophageal varices, arteriovenous malformations, vascular aneurysms, pronounced 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.), 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 CYP3A4 and P-gp, resulted in a 2-fold increase in mean AUC and a 1.6-fold increase in mean Cmax of apixaban.

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) (see section "Special precautions").

Active substances 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 co-administered 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 decreased 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 treatment 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 CYP3A4 and P-gp inducers, 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.

No significant pharmacokinetic or pharmacodynamic interactions were observed when apixaban was administered concomitantly with acetylsalicylic acid (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 acetylsalicylic acid once daily, or with prasugrel (loading dose 60 mg, maintenance 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. Coagulation parameters (PT, INR, and 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 corresponding increases in coagulation parameters. Concomitant administration of naproxen and apixaban did not alter naproxen’s effect on arachidonic acid-induced platelet aggregation and did not lead to clinically significant prolongation of bleeding time. Nevertheless, in individual patients, a more pronounced pharmacodynamic response to concomitant administration of antiplatelet agents and apixaban may occur. Apixaban should be used with caution in combination 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 (such as 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 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 relevant effect on apixaban pharmacokinetics. After repeated co-administration of both drugs, mean AUC and Cmax of apixaban were 15% and 18% lower, respectively, compared to monotherapy. Concomitant administration of 10 mg apixaban and 40 mg famotidine 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 involving healthy volunteers, apixaban did not cause significant changes in the pharmacokinetics of digoxin, naproxen, or atenolol.

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

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

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

Activated charcoal.

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

Special precautions for use.

Risk of bleeding.

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

Although treatment with apixaban does not require routine monitoring of exposure levels, in exceptional circumstances when information about 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® (see section "Pharmacodynamics") may be used.

There is an antidote available for Factor Xa inhibitor activity.

A patient information leaflet for the use of Eliquis can be found at www.pfizer.ua/node/2196.

Interactions with other medicinal products affecting blood coagulation.

Due to the increased risk of bleeding, concomitant treatment with any other anticoagulants is contraindicated (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 types of interactions").

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

After surgical procedures, it is not recommended to administer other platelet aggregation inhibitors concomitantly with apixaban (see section "Interaction with other medicinal products and other types of interactions").

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 study 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 with warfarin from 2.7% per year to 4.6% per year. In this clinical study, concomitant use of dual antiplatelet therapy was limited (2.1%) (see section "Pharmacodynamics").

A clinical study included patients with atrial fibrillation and/or those undergoing percutaneous coronary intervention (PCI) with a planned treatment period with 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 the criteria of the International Society on Thrombosis and Haemostasis (ISTH) from 16.4% to 33.1% per year (see section "Pharmacodynamics").

In a clinical study involving high-risk patients after acute coronary syndrome without atrial fibrillation, who had multiple concurrent cardiovascular and non-cardiovascular conditions and were receiving acetylsalicylic acid or a combination of acetylsalicylic acid and clopidogrel, apixaban treatment 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 the 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 types of interactions").

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, the use of apixaban is not recommended in such cases.

Patients with antiphospholipid syndrome.

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

Surgical procedures and invasive procedures.

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 or where the risk of bleeding is unacceptable.

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

If surgery or an invasive procedure cannot be postponed, appropriate precautions should be taken, considering the increased risk of bleeding. The risk of bleeding and the urgency of the procedure 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 hemostatic measures have been taken (for cardioversion, see section "Dosage and administration").

Patients undergoing catheter ablation for the treatment of atrial fibrillation do not need to interrupt apixaban treatment (see sections "Dosage and administration", "Contraindications", and "Interaction with other medicinal products and other types of interactions").

Temporary discontinuation of treatment.

Discontinuation of anticoagulant therapy (including apixaban) due to active bleeding, planned surgery, or invasive procedures increases the risk of thrombosis in patients. Treatment interruptions should be avoided, and if 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 who undergo neuraxial (spinal or epidural) anaesthesia or spinal/epidural puncture have an increased risk of developing epidural or spinal hematoma, which may result in long-term or permanent paralysis. The risk of such events may be increased by the use of indwelling catheters in the postoperative period or concomitant use of medicinal products affecting blood coagulation. An indwelling epidural or subdural catheter must 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 punctures. Patients should be closely monitored for signs of neurological impairment (e.g., numbness or weakness in the legs, bowel or bladder dysfunction). If signs of neurological impairment occur, immediate diagnosis and treatment are mandatory. Before neuraxial procedures, the physician should carefully weigh the potential benefits and risks for patients receiving or planned to receive anticoagulants for thrombosis prevention.

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

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

Apixaban is not recommended as an alternative to unfractionated heparin in patients with pulmonary embolism and unstable hemodynamics or those who may require 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 "Dosage and administration" and "Pharmacokinetics").

For stroke and systemic embolism prevention 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 "Dosage and administration").

There is no clinical experience with apixaban in patients with creatinine clearance < 15 mL/min or 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").

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").

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

The drug should be used with caution in patients with mild to 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, apixaban should be used with caution in this patient population (see section "Pharmacokinetics"). Liver function tests should be performed before initiating apixaban treatment.

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 inhibitors of both 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 types of interactions") 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 both 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 study involving patients with atrial fibrillation, concomitant use of apixaban with strong inducers of CYP3A4 and P-gp reduced anticoagulant efficacy and increased bleeding risk compared to apixaban monotherapy.

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

• apixaban should be used with caution for VTE prophylaxis during elective hip or knee replacement surgery, stroke and systemic embolism prevention 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 studies on the efficacy and safety of apixaban in patients undergoing surgical treatment of hip fracture have not been conducted. Therefore, the use of the drug in such patients is not recommended.

Laboratory parameters.

Coagulation test results (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 test results during therapeutic dosing are minor and highly variable (see section "Pharmacodynamics").

Information on excipients.

Eliquis contains lactose. This medicine should not be taken by patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption syndrome.

This 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 did not reveal any 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 are excreted in human breast milk. Animal studies indicate excretion of apixaban into milk. The risk to the breastfed infant cannot be excluded.

A decision should be made whether to discontinue breastfeeding or discontinue/abandon apixaban treatment, 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 reveal any effect of this drug on fertility.

Ability to affect reaction speed when driving or operating machinery.

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

Administration and Dosage

Route of Administration

The medication is administered orally. ELIQUIS should be taken with water, with or without food.

For patients unable to swallow whole tablets, ELIQUIS tablets may be crushed and suspended in water, 5% aqueous glucose solution, or apple juice, or mixed with applesauce, and administered orally immediately (see section "Pharmacokinetics"). Additionally, crushed ELIQUIS tablets may be suspended in 60 mL of water or 5% aqueous glucose solution and administered immediately via a nasogastric tube (see section "Pharmacokinetics").

Crushed ELIQUIS tablets are stable in water, 5% aqueous glucose solution, apple juice, or applesauce for up to 4 hours.

Dosage

Prevention of venous thromboembolism following elective knee or hip replacement surgery

The recommended dose of ELIQUIS 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 consider the potential benefit of earlier initiation of anticoagulation for prevention of venous thromboembolism and 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 ELIQUIS 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 ELIQUIS is 2.5 mg orally twice daily.

Long-term treatment is recommended.

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

The recommended dose of ELIQUIS for the treatment of DVT and PE is 10 mg orally twice daily for the first 7 days, followed by 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 ELIQUIS for the prevention of recurrent DVT and PE is 2.5 mg orally twice daily. If a patient requires prevention of recurrent DVT and PE, the 2.5 mg twice-daily dose should be initiated after completing a 6-month course of ELIQUIS 5 mg twice daily or after completing treatment with another anticoagulant, as specified in Table 10 (see also "Pharmacodynamics").

Table 10
Dosing Recommendations (VTEl)

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

Missed dose.

If a dose has been missed, the patient should take Eliquis immediately and continue treatment as usual, twice daily.

Switching between medicinal products.

Switching from parenteral anticoagulants to treatment with apixaban (and vice versa) can be performed at the time of the next scheduled dose (see section "Interaction with other medicinal products and other forms of interaction"). These medicinal products should not be used concomitantly.

Switching from vitamin K antagonist therapy to Eliquis.

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

Switching from Eliquis to vitamin K antagonist therapy.

When switching patients from Eliquis to vitamin K antagonist therapy, continue Eliquis for at least 2 days after initiating the vitamin K antagonist. After two days of concomitant administration of apixaban and vitamin K antagonist, measure the INR before administering the next dose of Eliquis. Combined treatment with Eliquis and vitamin K antagonist should continue 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 for 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), for treatment of DVT, 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 no other criteria for dose reduction (age, body weight) are present, no dose adjustment is required (see section "Pharmacokinetics").

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

• for prevention of VTE during elective hip or knee replacement surgery (VTEp), for treatment of DVT, 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.

Eliquis is contraindicated in patients with liver disease associated with coagulopathy and clinically relevant 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").

Eliquis 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 more than twice the upper limit of normal (ULN)) or elevated total bilirubin (≥ 1.5 times ULN) were excluded from clinical trials. Therefore, Eliquis 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 for cases specified above (see "Dose reduction" in section "Dosage and administration").

Sex.

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

Patients undergoing catheter ablation.

Patients may continue to receive 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)) prior to cardioversion, in accordance with established medical guidelines.

Patients initiating apixaban therapy should receive 5 mg twice daily 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 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 should be administered before the fifth dose of apixaban, followed by 5 mg twice daily. The dosing regimen should be reduced to a loading dose of 5 mg, followed by 2.5 mg twice daily, if the patient meets criteria for dose reduction (see 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, confirmation should be obtained that the patient has been receiving apixaban as prescribed. Decisions regarding 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 when used in combination with antiplatelet agents in patients with ACS and/or those undergoing PCI after achieving hemostasis (see sections "Special Instructions" and "Pharmacodynamics").

Children.

The efficacy and safety of Eliquis in children (under 18 years of age) have not been established. Available data on thromboembolism prevention are described in the "Pharmacodynamics" section, but dosing recommendations are not provided.

Overdose.

Overdose of apixaban may increase the risk of bleeding. In the event of hemorrhagic complications, treatment should be discontinued and the source of bleeding investigated. Consider initiating appropriate treatment, 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 ingestion of 20 mg apixaban reduced the mean AUC of apixaban by 50% and 27%, respectively, without affecting Cmax. Administration of activated charcoal 2 or 6 hours after apixaban 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 the management of apixaban overdose or accidental ingestion.

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

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

Hemodialysis reduced the AUC of apixaban by 14% after a single 5 mg oral dose 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 treatment was 20 days, 1.7 years, and 221 days, respectively (see section "Pharmacodynamics").

Common adverse reactions included bleeding, contusion, epistaxis, and hematoma (the profile of adverse events and frequencies, classified by indication, are presented in Table 11).

In the VTE_p studies, adverse reactions were observed in 11% of patients overall who received apixaban 2.5 mg twice daily. The overall frequency of bleeding-related adverse reactions in the studies comparing apixaban with 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 ocular 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 11 lists the adverse reactions observed during administration of the drug 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 recurrent DVT and PE 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 11

* In study CV185057 (long-term VTE prophylaxis), cases of generalized pruritus were not observed.

† The term "Intracranial hemorrhage" encompasses 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 site and extent or magnitude of bleeding (see sections "Special precautions" and "Pharmacodynamics").

Reporting of suspected adverse reactions.

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

Shelf life. 3 years.

Storage conditions. No special storage conditions required.

Packaging. 2.5 mg tablets, 10 tablets in a blister. 2 blisters in a cardboard box.

2.5 mg tablets, 20 tablets in a blister. 1 blister in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Catalent Anagni S.r.l. / Catalent Anagni S.r.l.

Manufacturer's location and address of the place of business.

Localita Fontana del Ceraso SNC, Strada Provinciale Casilina, 41, Anagni (FR), 03012, Italy / Localita’ Fontana del Ceraso SNC, Strada Provinciale Casilina, 41, Anagni (FR), 03012, Italy.

or ٭

Manufacturer.

Pfizer Manufacturing Deutschland GmbH / Pfizer Manufacturing Deutschland GmbH.

Manufacturer's location and address of the place of business.

Mooswaldallee 1, 79108 Freiburg Im Breisgau, Germany / Mooswaldallee 1, 79108 Freiburg Im Breisgau, Germany.

or ٭

Manufacturer.

Swords Laboratories Unlimited Company / Swords Laboratories Unlimited Company.

Manufacturer's location and address of the place of business.

Blanchardstown Corporate Park 2 Plaza 254, Dublin 15, D15 T867, Ireland / Blanchardstown Corporate Park 2 Plaza 254, Dublin 15, D15 T867, Ireland.

or ٭

Manufacturer.

Pfizer Ireland Pharmaceuticals / Pfizer Ireland Pharmaceuticals.

Manufacturer's location and address of the place of business.

Little Connell, Newbridge, Ireland / Little Connell, Newbridge, Ireland.

٭ The package leaflet inserted into the cardboard packaging will indicate only one manufacturer (the one involved in the production of the batch).