Trombapix

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

Composition:

Active substance: apixaban;

One film-coated tablet contains 5 mg of apixaban;

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

Film coating: Opadry II Pink 32K240066: hypromellose; lactose monohydrate; titanium dioxide (E 171); triacetin; iron oxide red (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: pink oval film-coated tablets.

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. It exerts its antithrombotic effect without requiring antithrombin III. Apixaban inhibits both free and clot-bound factor Xa, as well as the activity of prothrombinase. Apixiban 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 animal studies with apixaban demonstrated effective antithrombotic activity for the prevention of both 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 observed in coagulation parameters during therapeutic dosing are minor and highly variable, and are not recommended for assessing the pharmacodynamic effects of apixaban. In thrombin generation assays, apixaban reduced endogenous thrombin potential — a quantitative measure of thrombin generation in human plasma.

Apixaban also demonstrates activity against factor Xa, as confirmed by reduced enzymatic activity of factor Xa measured using various commercial factor Xa activity assay kits, although specific results varied between different kits. Clinical study data are available only for the chromogenic assay Rotachrom® heparin (results provided below). Factor Xa inhibitory activity is related to the plasma concentration of apixaban. This relationship is approximately linear, with maximum factor Xa inhibition observed at peak plasma concentrations of apixaban. The relationship between apixaban plasma concentration and factor Xa inhibitory 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, observed results showed less than a 1.7-fold fluctuation between peak and trough levels. In patients receiving apixaban for treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), or for prevention of recurrent DVT and PE, less than a 2.2-fold fluctuation between peak and trough levels was observed.

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

Table 1

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

2 r.d. – twice daily.

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

Clinical efficacy and safety.

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

In the clinical trial 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 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.

In the ARISTOTLE study, a total of 18,201 patients were randomized; participants were assigned to double-blind treatment with either apixaban 5 mg twice daily (or 2.5 mg twice daily in certain patients (4.7%), see section "Dosage and administration"), or warfarin (target INR range 2.0–3.0). Patients received study medication for a mean duration of 20 months. The mean age of participants was 69.1 years, and the mean CHADS2 score was 2.1. A prior history of stroke or transient ischemic attack was reported in 18.9% of patients.

In this study, apixaban treatment demonstrated a statistically significant benefit over warfarin for the primary efficacy outcome of prevention of stroke (hemorrhagic or ischemic) and systemic embolism (see Table 2).

Efficacy in patients with atrial fibrillation included in the

ARISTOTLE

Table 2

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 apixaban 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 relative to the mean value, the risk ratio for apixaban versus warfarin was 0.73 (95% CI 0.38, 1.40). The key secondary endpoints of major bleeding and all-cause mortality were evaluated using a pre-specified hierarchical hypothesis testing strategy to control the overall type I error rate in the study. Statistically significant advantages were also observed for the key secondary endpoints of major bleeding and all-cause mortality (see Table 3). With more careful INR control, the advantages of apixaban over warfarin with respect to all-cause mortality diminished.

Secondary endpoints in patients with atrial fibrillation in the ARISTOTLE study

Table 3

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

The cumulative incidence of 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 ischaemic 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, lower gastrointestinal tract and rectal bleeding) was 0.76% per year with apixaban and 0.86% per year with warfarin.

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

AVERROES study.

Overall, 5,598 patients were randomized in the AVERROES study, in whom treatment with vitamin K antagonists was not feasible. Study participants were assigned to receive either apixaban 5 mg twice daily (or 2.5 mg twice daily in some patients (6.4%) (see section "Posology and method of 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 treatment for a median duration of 14 months. The mean age of participants was 69.9 years, and the mean CHADS2 score was 2.0. 13.6% of patients had a history of stroke or transient ischaemic attack. Common reasons for ineligibility for vitamin K antagonist therapy included: inability/unlikelihood 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 on the recommendation of the independent Data Monitoring Committee due to compelling evidence of reduced stroke and systemic embolism rates with a favourable safety profile for apixaban.

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

In this study, apixaban treatment demonstrated a statistically significant benefit over acetylsalicylic acid for the primary efficacy endpoint of prevention of stroke (haemorrhagic, ischaemic, or unspecified) or systemic embolism (see Table 4).

Key efficacy results in patients with atrial fibrillation enrolled in the AVERROES study

Table 4

* 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 study with a 2x2 factorial design, which 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 were randomized within 14 days after ACS and/or PCI to receive either apixaban 5 mg twice daily (2.5 mg twice daily if the patient met two or more dose-reduction criteria; 4.2% received the lower dose) or a vitamin K antagonist (VKA), and 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 the 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 evaluate safety, and the primary endpoint was major or clinically relevant non-major bleeding according to ISTH criteria. In the apixaban versus VKA comparison group, the primary endpoint—major or clinically relevant non-major bleeding according to ISTH criteria at 6 months—occurred in 241 (10.5%) and 332 (14.7%) patients in the apixaban and VKA groups, respectively (HR = 0.69, 95% CI: 0.58, 0.82; two-sided p<0.0001 for both non-inferiority and superiority). In a supplementary analysis for VKA using TTR subgroups, the highest bleeding rate was associated with the lowest TTR quartile. The bleeding rate was similar when comparing apixaban with VKA in the highest TTR quartile subgroup. In the 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 (HR = 1.88, 95% CI: 1.58, 2.23; two-sided p<0.0001).

Specifically, in 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. In 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 a secondary study objective using composite endpoints.

In the comparison of apixaban versus VKA, the composite endpoint of death or recurrent hospitalization occurred in 541 (23.5%) and 632 (27.4%) patients in the apixaban and VKA groups, respectively. The composite endpoint of death or ischemic 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 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 was an open-label, multicenter study involving 1,500 patients with non-valvular atrial fibrillation (NVAF) who were not taking 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 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).

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

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

Major and clinically relevant non-major bleeding events occurred in 3 (0.41%) and 11 (1.50%) patients, respectively, in the apixaban group compared to 6 (0.83%) and 13 (1.80%) patients in the heparin and/or vitamin K antagonist group. 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 use of apixaban for the prevention of recurrent DVT and/or PE after 6–12 months of anticoagulant treatment for DVT and/or PE (AMPLIFY-EXT). Both studies were randomized, double-blind, international, parallel-group trials conducted in patients with symptomatic proximal DVT or symptomatic PE. All major 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 an 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 in 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 mean time-in-therapeutic-range values. 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 PE without fatal outcomes) or VTE-related death.

The efficacy of apixaban during initial VTE treatment was comparable in patients receiving apixaban for the treatment of PE [relative risk 0.9; 95% CI (0.5; 1.6)] and for DVT [relative risk 0.8; 95% CI (0.5; 1.3)]. Efficacy across various subgroups, including those classified by age, sex, body mass index (BMI), renal function, size of PE, location of DVT thrombus, and prior parenteral heparin use, was generally consistent. The main primary safety endpoint was bleeding. In this study, apixaban demonstrated statistically significant advantages compared to enoxaparin/warfarin for the primary safety endpoint [relative risk 0.31, 95% confidence interval (0.17; 0.55), p<0.0001] (see Table 5).

Bleeding outcomes in the AMPLIFY study

Table 5

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

AMPLIFY-EXT study.

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

836 patients (33.7%) had participated in the AMPLIFY study prior to enrollment in the AMPLIFY-EXT study.

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

In this study, both apixaban doses demonstrated statistically significant benefits compared to placebo for the primary efficacy endpoint of symptomatic recurrent VTE (DVT or non-fatal PE) or death from any cause (see Table 6).

Efficacy outcome results from the AMPLIFY-EXT study

Table 6

¥ p-value <0.0001.

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

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

The efficacy of apixaban in preventing VTE recurrence remained consistent across various subgroups, including those classified by age, sex, body mass index, and renal function.

The primary safety endpoint was major bleeding during the treatment period. In this study, the rate of major bleeding for both apixaban doses was not statistically different from placebo. There was no statistically significant difference in the incidence of major, minor, clinically relevant non-major (CRNM), or all bleeding events between the group receiving apixaban 2.5 mg twice daily and the placebo group. ISTH-classified 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.

Paediatric population.

The European Medicines Agency has deferred the obligation to submit the results of studies with apixaban involving one or more paediatric subgroups of patients with venous or arterial thromboembolism (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 concentration (Cmax) reached within 3–4 hours after tablet intake. Food intake does not affect the AUC or Cmax of apixaban when a 10 mg dose is administered. Apixaban can be taken with or without food.

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

After oral administration of 10 mg apixaban as two 5 mg crushed tablets suspended in 30 mL of water, exposure was comparable to that after oral administration of two intact 5 mg tablets. After 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.

After administration of a crushed 5 mg apixaban tablet suspended in 60 mL of 5% 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 the bioavailability studies are applicable to lower doses of apixaban.

Distribution.

Plasma protein binding in humans is approximately 87%. The volume of distribution (Vs) is approximately 21 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 eliminated in faeces. Renal clearance accounts for approximately 27% of total clearance. Additional roles of biliary and direct intestinal elimination pathways for apixaban were observed in clinical and preclinical studies.

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

The main biotransformation pathways are O-demethylation and hydroxylation of the 3-oxopiperidinyl moiety. Apixaban metabolism is primarily mediated by CYP3A4/5. Minor contributions to apixaban metabolism are made by CYP1A2, 2C8, 2C9, 2C19, and 2J2. In human plasma, unchanged apixaban is the predominant circulating compound associated with this medicinal product. There are no circulating active metabolites of apixaban in plasma. Apixaban is a substrate of the transport 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 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, plasma concentrations of apixaban increased by 16%, 29%, and 44%, respectively, compared to individuals with normal creatinine clearance. Renal impairment did not have a pronounced effect on the relationship between apixaban plasma concentration and the degree of factor Xa inhibition. After administration of a single 5 mg dose of apixaban immediately following haemodialysis in patients with end-stage chronic renal failure, apixaban concentration increased by 36% compared to individuals with normal creatinine clearance.

Hepatic impairment.

In a study comparing 8 participants with mild hepatic impairment (Child–Pugh class A, 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 racial groups. Population pharmacokinetic analysis results from patients receiving apixaban after elective hip or knee replacement surgery were consistent with Phase I study findings.

Body weight.

When comparing apixaban exposure across individuals with different body weights, exposure decreased by approximately 30% in individuals with body weight over 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 certain PD endpoints (factor Xa inhibition activity, PT, aPTT, and anti-Xa activity) was evaluated after administration of various apixaban doses across a wide range from 0.5 to 50 mg. The concentration of apixaban in plasma and factor Xa inhibition activity were best described by a linear model. PK/PD relationships observed in patients receiving apixaban after elective hip or knee replacement surgery were consistent with those observed in healthy volunteers.

Clinical characteristics.

Indications.

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

Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as prevention of recurrent DVT and PE in adults (information regarding patients with PE and hemodynamically unstable condition 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 conditions or states associated with a significant risk of major bleeding (e.g., current or recent peptic ulcer disease of the gastrointestinal tract, presence of malignant neoplasms with high bleeding risk, recent trauma to the brain or spinal cord, recent surgery on the brain, spinal cord or eye, recent intracranial hemorrhage, diagnosed or suspected esophageal varices, arteriovenous malformations, vascular aneurysms, or severe intraspinal or intracranial vascular abnormalities). Concomitant use of any other anticoagulants, such as unfractionated heparin, low-molecular-weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), or oral anticoagulants (warfarin, rivaroxaban, dabigatran, etc.), except in specific circumstances of switching anticoagulant therapy (see section "Dosage and administration"): or administration of unfractionated heparin at doses required to maintain patency of a central venous or arterial catheter, or administration of unfractionated heparin during catheter ablation for treatment of atrial fibrillation (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Inhibitors of CYP3A4 and P-gp.

Concomitant administration of apixaban and ketoconazole (400 mg once daily), a potent inhibitor of CYP3A4 and P-gp, resulted in a two-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 potent inhibitors of CYP3A4 and P-gp, such as azole antifungals (e.g., ketoconazole, itraconazole, voriconazole, posaconazole) or HIV protease inhibitors (e.g., ritonavir) (see section "Special precautions").

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

Inducers of CYP3A4 and P-gp.

Concomitant administration of apixaban and rifampicin (a potent inducer of CYP3A4 and P-gp) resulted in approximately a 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 coadministered with such medicinal products.

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 who are concomitantly receiving treatment with potent inducers of CYP3A4 and P-gp.

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

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

Due to increased bleeding risk, concomitant use of any other anticoagulants is contraindicated, except 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 coadministered 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 (initial dose 60 mg, subsequent dose 10 mg once daily) in Phase I studies did not result in a significant increase in modeled bleeding time or additional inhibition of platelet aggregation compared to antiplatelet agents without apixaban. Changes in coagulation parameters (PT, INR, aPTT) were consistent with the effects of apixaban in monotherapy.

Naproxen (500 mg), an inhibitor of P-gp, increased the mean AUC and Cmax of apixaban by 1.5- and 1.6-fold, respectively. Apixaban caused corresponding increases in coagulation parameters. Concomitant administration of naproxen and apixaban did not alter the effect of naproxen on arachidonic acid-induced platelet aggregation and did not lead to clinically significant prolongation of bleeding time. Nevertheless, in some individuals, a more pronounced pharmacodynamic response to concomitant administration of antiplatelet agents and apixaban may occur. 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 medicinal products.

No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when apixaban was coadministered with atenolol or famotidine. Coadministration of 10 mg apixaban and 100 mg atenolol had no clinically relevant effect on the pharmacokinetics of apixaban. After repeated coadministration of both drugs, mean AUC and Cmax of apixaban were 15% and 18% lower, respectively, compared to monotherapy. Coadministration 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 significantly higher than peak plasma concentrations of apixaban in patients. Apixaban at concentrations up to 20 µmol/L does not induce the activity of CYP1A2, CYP2B6, or CYP3A4/5. Therefore, apixaban is considered unlikely to alter the metabolic clearance of concomitant drugs metabolized by these enzymes. Apixaban does not significantly inhibit P-gp activity.

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

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

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

Atenolol. Coadministration 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 medicinal product should be used with caution in conditions associated with an increased risk of bleeding. In the event of severe bleeding, apixaban should be discontinued (see sections "Adverse reactions" and "Overdose").

Although treatment with apixaban does not require routine monitoring of exposure levels, in exceptional circumstances when information on apixaban exposure levels may assist in making a clinical decision (e.g., in cases of overdose or emergency surgery), a quantitative assay measuring factor Xa inhibition activity, Rotachrom®, may be used (see section "Pharmacodynamics"). A medicinal product is available to neutralize the activity of factor Xa inhibitors.

Interactions with other medicinal products affecting blood coagulation.

Concomitant treatment with any other anticoagulants is contraindicated due to increased bleeding risk (see section "Contraindications"). Concurrent use of 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 use of dual antiplatelet therapy was limited (2.1%) (see section "Pharmacodynamics").

The clinical trial included patients with atrial fibrillation and either HAS-BLED score ≥3 or undergoing percutaneous coronary intervention (PCI) with planned treatment with a P2Y12 inhibitor, with or without acetylsalicylic acid (ASA), and an oral anticoagulant (apixaban or vitamin K antagonist (VKA)) for 6 months. Concomitant use of ASA in subjects receiving apixaban increased the risk of major or non-major clinically relevant bleeding according to International Society on Thrombosis and Haemostasis (ISTH) criteria by 16.4–33.1% per year (see section "Pharmacodynamics").

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

Use of thrombolytic agents for treatment of acute ischaemic stroke. Experience with thrombolytic agents for 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 use is not recommended in these patients.

Patients with antiphospholipid syndrome.

Direct oral anticoagulants, including apixaban, are not recommended for patients with a history of thrombosis and diagnosed antiphospholipid syndrome. In particular, in patients positive for all three markers (lupus anticoagulant, 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 interventions.

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

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 intervention should be carefully considered.

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

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

Temporary discontinuation of apixaban treatment.

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

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

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

Patients with active cancer.

Patients with active cancer may have a high risk of both venous thromboembolism and bleeding. When considering apixaban for 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 bleeding risk. For prevention of venous thromboembolism (VTE) following elective hip or knee replacement surgery (VTEp), treatment of DVT, treatment of PE, and prevention of recurrent DVT and PE (VTEt), apixaban should be used with caution in patients with severe renal impairment (creatinine clearance 15–29 mL/min) (see sections "Dosage and administration" and "Pharmacokinetics").

For stroke and systemic embolism prevention in patients with 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").

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 "Dosage and administration" and "Pharmacokinetics").

Geriatric patients.

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

Body weight.

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

Patients with hepatic impairment.

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

Apixaban should be used with caution in patients with mild to moderate hepatic impairment (Child-Pugh class A or B) (see sections "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 dual inhibitors of CYP3A4 and P-gp, such as azole antifungals (e.g., ketoconazole, itraconazole, voriconazole, and posaconazole) or HIV protease inhibitors (e.g., ritonavir). These medicinal products may double apixaban exposure (see section "Interaction with other medicinal products and other forms of interaction") or even more in the presence of additional factors that may increase apixaban exposure (such as severe renal impairment).

Interactions with agents 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 and strong CYP3A4 and P-gp inducers reduced anticoagulant efficacy and increased bleeding risk compared to apixaban monotherapy.

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

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

Laboratory parameters.

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

Important information on excipients.

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

Use during pregnancy or breastfeeding.

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

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

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

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

Ability to affect reaction speed when driving or operating machinery.

The medicinal product has no or negligible effect on reaction speed when driving or operating machinery.

Dosage and Administration.

Administration method.

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

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

Dosage.

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

The recommended dose of apixaban 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 apixaban is 2.5 mg orally twice daily.

Treatment should be continued long-term.

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

The recommended dose of apixaban for treatment of acute deep vein thrombosis (DVT) and pulmonary embolism (PE) is 10 mg orally twice daily for the first 7 days. After this, apixaban should be administered at a dose of 5 mg orally twice daily. According to current medical guidelines, the duration of treatment (at least 3 months) should take into account transient risk factors (e.g., recent surgery, trauma, immobilization).

The recommended dose of apixaban for 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 treatment with apixaban 5 mg twice daily or a course of treatment with another anticoagulant, as specified in Table 7 (also see "Pharmacodynamics").

Dosage recommendations (VTEp)

Table 7

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

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

Switching between medicinal products.

Transition from parenteral administration of 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.

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

Transition from apixaban therapy to vitamin K antagonist therapy. When switching patients from apixaban therapy to vitamin K antagonist therapy, apixaban 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 apixaban dose. Combined treatment with apixaban 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 necessary, except for cases specified above (see "Dose reduction" in section "Dosage and administration").

Renal impairment.

Recommendations for patients with mild or moderate renal impairment:

• for treatment of DVT, treatment of PE, and prevention of DVT or PE recurrence (VTEt), no dose adjustment is required (see section "Pharmacokin游戏副本

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 (VTEt) 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 8). 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% per year.

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

Table 8 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 available data) for AF and VTEt, respectively.

Table 8

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

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

Use of apixaban may be associated with an increased risk of occult or overt bleeding from any tissue or organ, which may lead to post-hemorrhagic anemia. Symptoms and their severity will vary depending on the location, extent, and duration of bleeding (see sections "Special precautions for use" and "Pharmacodynamics"). Reporting suspected adverse reactions.

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

Shelf life. 3 years.

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

Packaging. 20 tablets in a blister; 3 blisters in a cardboard pack.

Prescription status. Prescription only.

Manufacturer.

ADALVO LIMITED.

Pharmadox Health Care Limited.

Manufacturer's address and location of its operations.

Malta Life Sciences Park, Building 1, Level 4, Sir Temi Zammit Buildings, San Gwann SGN3000, Malta.

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