ELIQUIS

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

Composition:

Active substance: apixaban;

One film-coated tablet contains 5 mg of apixaban;

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

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: pink, oval, biconvex film-coated tablets, engraved with «894» on one side and «5» 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 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 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 formation and thrombus development. Preclinical studies of apixaban in animals demonstrated effective antithrombotic activity in preventing both 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 values of prothrombin time (PT), international normalized ratio (INR), and activated partial thromboplastin time (aPTT). Changes in blood coagulation parameters observed 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 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 inhibition 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 related to 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 anti-factor Xa activity is approximately linear over a wide range of apixaban doses.

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, peak-to-trough fluctuations were less than 1.7-fold. In patients receiving apixaban for treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), or for prevention of recurrent DVT and PE, peak-to-trough fluctuations were less than 2.2-fold.

Table 1

Predicted steady-state apixaban concentrations and anti-factor Xa 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 activity assay such as Rotachrom® may be used.

Clinical efficacy and safety.

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

In the clinical trial program (the ARISTOTLE study: apixaban compared with warfarin, and the 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 non-valvular atrial fibrillation and at least one additional risk factor, namely:

• prior history of stroke or transient ischemic attack;
• age ≥ 75 years;
• arterial 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 some patients (4.7%), see section "Posology and method of administration"), or warfarin (target INR range 2.0–3.0). Patients received study treatment 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 prior history of stroke or transient ischemic attack was reported 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).

Table 2

Efficacy in patients with atrial fibrillation enrolled in the ARISTOTLE study

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

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

The key secondary endpoints of major bleeding and all-cause mortality were evaluated using a pre-specified hierarchical hypothesis-testing strategy to control the overall type I error rate in the study. Statistically significant advantages were also observed for apixaban over warfarin for the key secondary endpoints of major bleeding and all-cause mortality (see Table 3). However, with tighter INR control, the advantages of apixaban over warfarin with respect to all-cause mortality diminished.

Table 3

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

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

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

AVERROES trial.

Overall, 5598 patients were randomized in the AVERROES trial, in whom vitamin K antagonist therapy was considered unsuitable. Study participants were assigned to treatment with apixaban 5 mg twice daily (or in some patients (6.4%) apixaban 2.5 mg twice daily (see section "Dosage and administration")) or acetylsalicylic acid. Acetylsalicylic acid was administered once daily at a dose of 81 mg (64%), 162 mg (26.9%), 243 mg (2.1%), or 324 mg (6.6%). The dose was determined by the investigator. Patients received study medication 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 history of stroke or transient ischemic attack.

Common reasons for unsuitability of vitamin K antagonist therapy included: inability/low likelihood of achieving required international normalized ratio (INR) levels within a 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/potential difficulty in contacting the patient promptly when immediate dose adjustment was needed (11.7%).

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

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

In this trial, apixaban treatment demonstrated a statistically significant benefit over acetylsalicylic acid for the primary efficacy outcome of prevention of stroke (hemorrhagic, ischemic, or unspecified) or systemic embolism (see Table 4).

Table 4

Key efficacy outcomes in patients with atrial fibrillation enrolled in the AVERROES trial

* 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)

The AUGUSTUS trial was an open-label, randomized, controlled 2 × 2 factorial design study that included 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; 4.2% received the lower dose) or a vitamin K antagonist (VKA), along with 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 the therapeutic range (TTR) (INR 2–3) was 56%, with 32% 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). A subgroup analysis of VKA using TTR quartiles showed that the highest bleeding rate was associated with the lowest TTR quartile. The bleeding rate was similar when comparing apixaban with VKA in the highest TTR quartile subgroup. In the 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, among patients receiving apixaban, major or clinically relevant non-major bleeding occurred in 157 (13.7%) and 84 (7.4%) patients in the ASA and placebo groups, respectively. Among patients receiving VKA, major or clinically relevant non-major bleeding occurred in 208 (18.5%) and 122 (10.8%) patients in the ASA and placebo groups, respectively.

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

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

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

Patients undergoing cardioversion

EMANATE was an open-label, multicenter study involving 1,500 patients with non-valvular atrial fibrillation (NVAF) who were not receiving anticoagulants or had been treated for less than 48 hours and were scheduled for cardioversion.

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

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

In the apixaban group (n = 753), there were no strokes (0%), compared to 6 (0.80%) strokes 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.

Cases of major and clinically relevant non-major bleeding were observed in 3 (0.41%) and 11 (1.50%) patients, respectively, in the apixaban group, compared to 6 (0.83%) and 13 (1.80%) patients in the heparin and/or vitamin K antagonist group.

A prespecified analysis 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 the extended potential of the drug in preventing recurrence of 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 assessed by an independent committee based on blinded data.

AMPLIFY study.

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

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

In patients assigned to the warfarin group, the mean percentage of time within the therapeutic INR range (2.0–3.0) was 60.9%. Apixaban demonstrated a reduced rate of recurrent symptomatic VTE or VTE-related death across various levels of mean time in the therapeutic INR range. 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 was non-inferior to enoxaparin/warfarin for the primary composite endpoint of confirmed 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 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).

Table 5

Bleeding outcomes in the AMPLIFY study

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

AMPLIFY-EXT study.

In the AMPLIFY-EXT study, 2482 patients were randomized to receive either apixaban 2.5 mg orally twice daily, apixaban 5 mg orally twice daily, or placebo for 12 months following completion of an initial 6–12 month course of anticoagulant therapy. 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 6).

Table 6

Efficacy outcomes in the AMPLIFY-EXT study

¥ p-value <0.0001.

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

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

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

ISTH-defined major gastrointestinal bleeding occurred 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.

Use in pediatric patients

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

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, who had recently been diagnosed with ALL or LL and were receiving induction chemotherapy including asparaginase administered via a venous catheter, were randomized 1:1 to receive open-label thromboprophylaxis with apixaban or standard therapy (without systemic anticoagulation). Apixaban was administered at a fixed dose based on patient body weight, designed to achieve exposures comparable to those observed 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 main 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 in the apixaban group (14.5%) and in 20 patients (7.8%) in the standard therapy group.

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

SAXOPHONE is a randomized, open-label, multicenter, comparative study (2:1) involving patients aged 28 days to 18 years with congenital or acquired heart disease requiring anticoagulation. Patients received either apixaban or standard thromboprophylaxis with a vitamin K antagonist or low-molecular-weight heparin. Apixaban was administered using a fixed-dose regimen based on body weight, designed to achieve exposure comparable to that observed in adults receiving 5 mg twice daily (see Table 9). Apixaban was administered as 5 mg tablets, 0.5 mg tablets, or as an 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 as confirmed major bleeding, CRNM bleeding, and all bleeding events—were similar in frequency between the two 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, a definitive assessment of the benefit-risk balance could not be established in this study.

The European Medicines Agency has deferred the obligation to submit the results of studies with the medicinal product Eliquis for the treatment of venous thromboembolism involving one or more paediatric subgroups (for information on paediatric use, see 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 (Cmax) reached within 3–4 hours after tablet intake. Food intake does not affect the AUC or Cmax of apixaban when administered at a dose of 10 mg. Apixaban may be taken with or without food.

Following oral administration at doses not exceeding 10 mg, the pharmacokinetics of apixaban demonstrate a linear, dose-proportional increase 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 two 5 mg crushed tablets suspended in 30 mL of water, exposure was comparable to that following administration of two intact 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 were 20% and 16% lower, respectively, compared to administration of two 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 receiving a single 5 mg apixaban tablet orally.

Given the predictable, dose-proportional pharmacokinetic profile of apixaban, the results of 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 litres.

Biotransformation and elimination

Apixaban is eliminated from the body via multiple pathways. Approximately 25% of the administered dose of apixaban in humans is excreted as metabolites, with the majority of metabolites eliminated in faeces. 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 biotransformation pathways are O-demethylation and hydroxylation of the 3-oxopiperidinyl moiety. Apixaban metabolism is primarily mediated by CYP3A4/5. CYP1A2, 2C8, 2C9, 2C19, and 2J2 play minor roles in the metabolism of the drug. In human plasma, unchanged apixaban is the predominant circulating compound associated with this medicinal product. There are no circulating active metabolites of the drug in plasma. Apixaban is a substrate of the transport proteins P-glycoprotein (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 Cmax.

Renal impairment

Renal function impairment did not affect the peak concentration of apixaban. Based on creatinine clearance assessment, 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, apixaban plasma 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 extent of factor Xa inhibition.

Following a single 5 mg dose of apixaban administered immediately after haemodialysis in patients with end-stage chronic renal failure, apixaban concentrations 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, score 5 (n = 6) and 6 (n = 2)) and 8 participants with moderate hepatic impairment (Child-Pugh class B, score 7 (n = 6) and 8 (n = 2)) to 16 healthy volunteers in the control group, the pharmacokinetics and pharmacodynamics of a single 5 mg dose of apixaban were not altered by hepatic impairment. Changes in factor Xa inhibition activity and international normalized ratio (INR) were comparable between healthy volunteers and patients with mild or moderate hepatic impairment.

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 a population pharmacokinetic analysis conducted 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 with body weight above 120 kg compared to those with normal weight (65–85 kg), while body weight below 50 kg was associated with an approximately 30% increase in exposure.

Pharmacodynamic/pharmacokinetic relationship

The pharmacokinetic/pharmacodynamic (PK/PD) relationship between apixaban plasma concentration and selected PD endpoints (factor Xa inhibition activity, PT, aPTT, and anti-Xa activity) was evaluated following administration of various apixaban doses across a wide range (0.5 to 50 mg). The linear model best described the concentration-dependent relationship between apixaban plasma 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 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 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., current or recent gastrointestinal ulceration, presence of malignancies 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, or marked 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 for specific situations 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 the 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 strong 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/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 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 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 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 strong 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 strong inducers of CYP3A4 and P-gp (e.g., phenytoin, carbamazepine, phenobarbital, or St. John's wort products) may also lead to reduced 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 (NVAF) and for prevention of recurrent DVT and PE, apixaban should be used with caution in patients receiving concomitant therapy with strong inducers of CYP3A4 and P-gp.

Apixaban is not recommended for the treatment of DVT and PE in patients receiving concomitant systemic therapy with strong 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 other anticoagulants is contraindicated, except in specific circumstances of switching anticoagulant therapy, when unfractionated heparin is administered at doses required to maintain patency of a central venous or arterial catheter, or unfractionated heparin is administered during catheter ablation for treatment of atrial fibrillation (see section "Contraindications").

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

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. Changes in coagulation parameters (PT, INR, and aPTT) were consistent with the effects of apixaban monotherapy.

Naproxen (500 mg), a P-gp inhibitor, increased 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 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 relevant 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 apixaban pharmacokinetics. After subsequent co-administration of both drugs, mean AUC and Cmax of apixaban were 15% and 18% lower, respectively, compared to monotherapy. Concomitant administration of 10 mg apixaban and 40 mg famotidine did not affect AUC or Cmax of apixaban.

Effect of apixaban on other medicinal products.

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

Bleeding risk.

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 the event of severe bleeding, apixaban administration should be discontinued (see section "Adverse reactions" and "Overdose").

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 quantitative assay measuring factor Xa inhibition activity, such as Rotachrom®, may be used (see section "Pharmacodynamics").

There is an antidote available to reverse the activity of factor Xa inhibitors.

The patient information leaflet for Eliquis can be found at the following link: www.pfizer.ua/node/2196.

Interactions with other medicinal products affecting blood coagulation.

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

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

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

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

For patients with atrial fibrillation and conditions requiring 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 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 trial, concomitant dual antiplatelet therapy was limited (2.1%) (see section "Pharmacodynamics").

The clinical trial included patients with atrial fibrillation and/or those undergoing percutaneous coronary intervention (PCI) with a planned treatment period of a P2Y12 inhibitor, with or without ASA, and an oral anticoagulant (apixaban or vitamin K antagonist (VKA)) for 6 months. Concomitant use of ASA in subjects receiving apixaban increased the risk of major or non-major clinically relevant bleeding according to International Society on Thrombosis and Haemostasis (ISTH) criteria 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 concomitant cardiovascular and non-cardiovascular conditions and were receiving acetylsalicylic acid or a combination of acetylsalicylic acid and clopidogrel, apixaban use was associated with a significant increase in the risk of major bleeding according to ISTH classification – 5.13% per year compared to 2.04% per year in the placebo group.

Use of thrombolytic agents for the treatment of acute ischaemic stroke.

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

Patients with prosthetic heart valves.

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

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 an increased rate of recurrent thrombotic events compared to vitamin K antagonist therapy.

Surgical procedures and invasive procedures.

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

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

If surgery or an invasive procedure cannot be delayed, appropriate precautions should be taken, considering the increased bleeding risk. 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 the clinical situation allows and adequate measures to ensure haemostasis 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 forms of interaction").

Temporary interruption 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 apixaban treatment must be temporarily discontinued (for any reason), the drug should be resumed as soon as possible.

Patients with pulmonary embolism (PE) and haemodynamic instability, or patients requiring thrombolysis or pulmonary embolectomy.

Apixaban is not recommended as an alternative to unfractionated heparin in patients with pulmonary embolism and haemodynamic instability or those who may undergo thrombolysis or pulmonary embolectomy, as the safety and efficacy of apixaban in these clinical situations have not been established.

Patients with active cancer.

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

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 the risk of bleeding. For the prevention of venous thromboembolism (VTE) during elective hip or knee replacement surgery (VTEk), for the treatment of DVT, PE, and prevention of recurrent DVT and PE (VTEk), 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 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").

Apixaban in combination with acetylsalicylic acid should also be used with caution in elderly patients due to an increased risk of bleeding.

Body weight.

Low body weight (<60 kg) may increase 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 such patients (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 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 that may increase apixaban exposure (such as severe renal impairment).

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

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

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

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

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 tests with therapeutic doses are minor and highly variable (see section "Pharmacodynamics").

Information on excipients.

Eliquis contains lactose. This medicinal product should not be used in 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 have not shown any direct or indirect harmful effects on reproductive performance. As a precautionary measure, apixaban use during pregnancy is not recommended.

Breastfeeding period. It is currently unknown whether apixaban or its metabolites are excreted in human breast milk. Animal studies indicate excretion of apixaban into milk. A risk to the breastfed infant cannot be excluded.

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

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

Ability to affect reaction speed when driving or operating machinery.

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

Dosage and Administration

Administration.

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

For patients who are unable to swallow whole tablets, ELIQUIS tablets may be crushed and suspended in water, 5% aqueous glucose solution, or apple juice, or mixed with apple puree, and administered orally immediately (see section "Pharmacokinetics"). Additionally, ELIQUIS tablets may be crushed and 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 apple puree for up to 4 hours.

Dosage.

Prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

The recommended dose of ELIQUIS is 5 mg orally twice daily.

Dose reduction.

For patients with nonvalvular 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.

Treatment should be continued long-term.

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

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

Table 10
Dosing recommendations (VTEp)

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 precautions").

Missed dose.

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

Switching medications.

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

Transition from vitamin K antagonist therapy to Eliquis.

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

Transition from Eliquis to vitamin K antagonist therapy.

When switching patients from Eliquis to vitamin K antagonist therapy, Eliquis should be continued for at least 2 days after initiation of the vitamin K antagonist. After two days of concomitant administration of apixaban and vitamin K antagonist, the international normalized ratio (INR) should be determined before the next dose of Eliquis. Combined treatment with Eliquis and vitamin K antagonist should be continued until the INR reaches levels ≥ 2.0.

Elderly patients.

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 "Special precautions" and "Pharmacokinetics").

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 treatment of DVT, treatment of PE, and prevention of DVT or PE recurrence (VTEp), 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 such factors as age over 80 years or body weight less than 60 kg, a lower dose of apixaban should be used as described above. If other criteria for dose reduction (age, body weight) are absent, dose adjustment is not required (see section "Pharmacokinetics").

Recommendations for patients with severe renal impairment (creatinine clearance 15–29 mL/min) are as follows (see sections "Special precautions" and "Pharmacokinetics"):

• for treatment of DVT, treatment of PE, and prevention of DVT or PE recurrence (VTEp), 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 groups (see sections "Special precautions" and "Pharmacokinetics").

Hepatic impairment.

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

The drug is not recommended for use in patients with severe hepatic impairment (see sections "Special precautions" 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 precautions" and "Pharmacokinetics").

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

Body weight.

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 precautions").

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

Gender.

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

Patients undergoing catheter ablation.

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

Cardioversion (non-valvular atrial fibrillation).

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

In 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)) 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 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 5 mg loading dose, then 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 taking apixaban as prescribed. Decisions regarding initiation and duration of therapy should be made in accordance with established guidelines for anticoagulant use in patients undergoing cardioversion.

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

There is limited experience with apixaban at the recommended dose in patients with NVAF in combination with antiplatelet agents – patients with ACS and/or those undergoing PCI after achieving hemostasis (see sections "Special precautions" 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 section "Pharmacodynamics", but dosing recommendations are not provided.

Overdose.

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

In controlled clinical 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 reactions.

In healthy subjects, administration of activated charcoal 2 and 6 hours after intake of 20 mg apixaban resulted in a 50% and 27% reduction in mean apixaban AUC, respectively, without affecting Cmax. Administration of activated charcoal 2 or 6 hours after apixaban intake reduced the elimination half-life of apixaban from 13.4 hours (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 bleeding or uncontrolled bleeding, a factor Xa inhibitor reversal agent is available (see section "Special precautions"). Administration of prothrombin complex concentrate (PCC) 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 within 4 hours after the start of a 30-minute infusion of four-factor prothrombin complex concentrate in healthy volunteers. However, there is no clinical experience with four-factor prothrombin complex concentrate for bleeding management in individuals receiving apixaban. Experience with recombinant factor VIIa for treating individuals 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.

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

Adverse reactions

The safety of apixaban was evaluated in four phase III clinical trials involving over 15,000 patients: over 11,000 patients in atrial fibrillation (AF) studies and over 4,000 patients in venous thromboembolism treatment (VTE_t) studies; the mean overall duration of exposure was 1.7 years and 221 days, respectively (see section "Pharmacodynamics").

Common adverse reactions were bleeding, contusion, epistaxis, and hematoma (the adverse event profile and frequency, classified by indication, are presented in Table 11).

In the AF studies, the overall incidence 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% per year. The rate of major intraocular bleeding according to ISTH classification in patients receiving apixaban was 0.18% per year.

In the VTE_t studies, the overall incidence of adverse reactions related to bleeding 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 adverse reactions 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 the available data) for AF and VTE_t, respectively.

Table 11

* In study CV185057 (long-term VTE prophylaxis), 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).

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, extent, 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 continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals are requested to report any suspected adverse reactions.

Shelf life. 3 years.

Storage conditions. No special storage conditions required.

Packaging. 5 mg tablets, 10 tablets in a blister. 3, 6, or 10 blisters in a cardboard box. 5 mg tablets, 14 tablets in a blister. 2 blisters 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 manufacturing site.

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 manufacturing site.

Betriebsstatte Freiburg, Mooswaldallee 1, 79090 Freiburg, Germany / Betriebsstatte Freiburg, Mooswaldallee 1, 79090 Freiburg, Germany.

or ٭

Manufacturer.

Swords Laboratories Unlimited Company / Swords Laboratories Unlimited Company.

Manufacturer's location and address of manufacturing site.

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 manufacturing site.

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

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