Eliquis film-coated tablets 5 mg blister No. 60

Instructions Eliquis film-coated tablets 5 mg blister No. 60

Composition

active ingredient: apixaban;

1 film-coated tablet contains 5 mg of apixaban;

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

Dosage 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 drugs. Direct inhibitors of factor Xa. ATX code B01 AF02.

Pharmacological properties

Pharmacodynamics

Mechanism of action.

Apixaban is a potent, reversible, direct, and highly selective inhibitor of the active site of factor Xa, intended for oral administration. It does not require antithrombin III for its antithrombotic effect. Apixaban inhibits free and clot-bound factor Xa, and also inhibits prothrombinase activity. Apixaban does not directly affect platelet aggregation, but indirectly inhibits the thrombin-induced platelet aggregation process. By inhibiting factor Xa, apixaban prevents the formation of thrombin and the formation of a thrombus. Preclinical studies of apixaban in animals have shown the effectiveness of the antithrombotic effect of the drug for the prevention of arterial and venous thrombosis when administered in doses that do not disrupt hemostasis.

Pharmacodynamic effects.

The pharmacodynamics of apixaban reflect its mechanism of action (inhibition of factor Xa). As a result of inhibition of factor Xa, apixaban increases the values of such parameters as prothrombin time (PT), international normalized ratio (INR), and activated partial thromboplastin time (aPTT). Changes observed in blood coagulation parameters at therapeutic doses are insignificant and highly variable, and are not recommended for use in assessing the pharmacodynamic properties of apixaban. In the thrombin generation assay, apixaban reduced endogenous thrombin potential, a quantitative indicator of thrombin generation in human plasma.

Apixaban also exhibits factor Xa inhibitory activity, as demonstrated by a decrease in factor Xa enzymatic activity as assessed using various commercial factor Xa inhibition assay kits, although specific results varied between kits. Clinical study results are available only for the Rotachrom® heparin chromogenic assay (results are provided below). Factor Xa inhibitory activity is related to apixaban plasma concentration. This relationship is approximately linear, with maximal factor Xa inhibitory activity occurring at peak apixaban plasma concentrations. The relationship between apixaban plasma concentration and factor Xa inhibitory activity is approximately linear over a wide range of apixaban doses.

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

Table 1

Predicted steady-state apixaban concentration and factor Xa inhibition activity

Although apixaban treatment does not require routine monitoring of exposure levels, in exceptional situations where information on apixaban exposure levels may assist clinical decision-making (e.g. in overdose and emergency surgery), the Rotachrom® factor Xa inhibition activity assay may be used.

Clinical efficacy and safety.

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

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

history of stroke or transient ischemic attack; age ≥ 75 years; arterial hypertension; diabetes mellitus; symptomatic heart failure (class ≥ II according to the NYHA classification).

ARISTOTLE research.

In the ARISTOTLE study, a total of 18,201 patients were randomized; participants were assigned to double-blind treatment with apixaban 5 mg twice daily (or for some patients (4.7%) 2.5 mg twice daily, see section 4.2) or warfarin (target MNC level between 2.0 and 3.0). Patients received study drug for a median of 20 months. The median age of participants was 69.1 years, and the median CHADS2 score was 2.1. 18.9% of patients had a history of stroke or transient ischemic attack.

In this study, apixaban treatment provided a statistically significant advantage in the primary endpoint of stroke prevention (hemorrhagic or ischemic) and systemic embolism (see Table 2) compared to warfarin.

Table 2

Efficacy in patients with atrial fibrillation who participated in the ARISTOTLE study

In patients assigned to the warfarin treatment group, the median percentage of time within the therapeutic interval (MNR 2.0–3.0) was 66%.

Apixaban demonstrated a reduction in the incidence of stroke and systemic embolism (compared to warfarin treatment) at different values of the median therapeutic window time. For the highest quartile, the hazard ratio for apixaban versus warfarin was 0.73 (95% CI 0.38, 1.40).

The primary secondary endpoints of major bleeding and all-cause mortality were examined using a pre-selected hierarchical hypothesis testing strategy to control for the overall type I error in the study. A statistically significant advantage was also obtained for the primary secondary endpoints of major bleeding and all-cause mortality (see Table 3). With closer control of the MEC, the advantage of apixaban over warfarin in all-cause mortality was reduced.

Table 3

Secondary endpoints in patients with atrial fibrillation in the ARISTOTLE study

*Major bleeding defined according to the International Society for the Study of Thrombosis and Hemostasis (ISTH) criteria.

The overall rate of discontinuation due to adverse reactions in the ARISTOTLE study was 1.8% for apixaban and 2.6% for warfarin.

The incidence of major gastrointestinal bleeding according to the ISTH classification (including upper, lower gastrointestinal bleeding and rectal bleeding) was 0.76% per year with apixaban and 0.86% per year with warfarin.

The rates of major bleeding in pre-selected subgroups (including subgroups based on CHADS2 score, age, weight, gender, renal function status, history of stroke, transient ischemic attack, and diabetes) were consistent with the results in the general population.

AVERROES research.

A total of 5,598 patients ineligible for vitamin K antagonist therapy were randomized in the AVERROES study. Patients were randomized to receive apixaban 5 mg twice daily (or 2.5 mg twice daily for some patients (6.4%) (see 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 drug for a median of 14 months. The median age of the participants was 69.9 years, and the median CHADS2 score was 2.0. 13.6% of patients had a history of stroke or transient ischemic attack.

Common reasons for not being able to use vitamin K antagonists included: inability/low probability of achieving the required levels of international normalized ratio within the required time frame (42.6%), patient refusal of vitamin K antagonist treatment (37.4%), CHADS2 index = 1 and physician recommendation not to use vitamin K antagonists (21.3%), inability to ensure patient compliance with vitamin K antagonist instructions (15%), and difficulty/anticipated difficulty in contacting the patient in cases where an immediate dosage change is necessary (11.7%).

The AVERROES study was terminated early on the recommendation of the independent Data Monitoring Committee due to the receipt of convincing evidence of a reduction in the incidence of stroke and systemic embolism combined with a favorable safety profile of the drug.

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

In this study, apixaban treatment provided a statistically significant advantage in the primary endpoint of prevention of stroke (hemorrhagic, ischemic, or unspecified) or systemic embolism (see Table 4) compared to acetylsalicylic acid.

Table 4

Key efficacy results for patients with atrial fibrillation participating in the AVERROES study

*Estimated using a sequential hypothesis testing strategy designed to control the total type I error in the study.

† Secondary endpoint.

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

Patients with nonvalvular atrial fibrillation (NAF) with acute coronary syndrome (ACS) and/or undergoing percutaneous coronary intervention (PCI)

The AUGUSTUS study, an open-label, randomized, controlled trial with a 2-by-2 factorial design, enrolled 4614 patients with NPF who had had ACS (43%) and/or undergone PCI (56%). All patients received background treatment with a P2Y12 inhibitor (clopidogrel: 90.3%), administered according to local standards of care.

The primary objective of the AUGUSTUS trial was to assess safety, and the primary endpoint was ISTH major or minor bleeding. In the apixaban versus VKA arm, the primary endpoint of ISTH major or minor bleeding at 6 months was reported in 241 (10.5%) and 332 (14.7%) patients in the apixaban and VKA arms, respectively (HR = 0.69, 95% CI: 0.58, 0.82, 2-sided p < 0.0001 for non-inferiority and p < 0.0001 for superiority). For VKA, additional analysis using subgroups of CTD showed that the highest bleeding rate was associated with the lowest quartile of CTD. Bleeding rates were similar when comparing apixaban with VKA in the subgroup with the highest quartile of CTD. When comparing ASA with placebo, the primary endpoint – major or non-major clinically significant bleeding according to ISTH criteria at 6 months – was observed 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 treated with apixaban, major or minor clinically significant bleeding occurred in 157 (13.7%) and 84 (7.4%) patients in the ASA and placebo groups, respectively. In patients treated with VKA, major or minor clinically significant bleeding occurred in 208 (18.5%) and 122 (10.8%) patients in the ASA and placebo groups, respectively.

Other treatment effects were assessed as a secondary objective of the study with combined endpoints.

When comparing apixaban with VKA, the combined composite endpoint of death or rehospitalization occurred in 541 (23.5%) and 632 (27.4%) patients in the apixaban and VKA groups, respectively. The combined 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.

When comparing ASA with placebo, the composite endpoint of death or rehospitalization was observed 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) was observed in 163 (7.1%) and 189 (8.2%) patients in the ASA and placebo groups, respectively.

Patients undergoing cardioversion

EMANATE is an open-label, multicenter study involving 1,500 patients with nonvalvular atrial fibrillation (NAF) who were not taking anticoagulants or had been on treatment for less than 48 hours and who were scheduled for cardioversion.

Patients were randomized 1:1 to receive 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 cardioversion was required earlier (*see 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).

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

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

Major and clinically important minor bleeding events were observed in 3 (0.41%) and 11 (1.50%) patients, respectively, in the apixaban treatment group compared to 6 (0.83%) and 13 (1.80%) patients in the heparin and/or vitamin K antagonist treatment group.

The conducted exploratory study showed comparable efficacy and safety between the treatment groups of apixaban and heparin and/or vitamin K antagonists during cardioversion.

Treatment of DVT, treatment of PE and prevention of recurrence of DVT and PE (VTE).

The clinical program (AMPLIFY: apixaban versus enoxaparin/warfarin, AMPLIFY-EXT: apixaban versus 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 the prevention of recurrent DVT and/or PE after 6 to 12 months of treatment of DVT and/or PE with anticoagulants (AMPLIFY-EXT). Both studies were randomized, double-blind, parallel-group, international trials conducted in patients with symptomatic proximal DVT or symptomatic PE. All primary safety and efficacy endpoints were assessed by an independent committee on a blinded basis.

AMPLIFY study.

In the AMPLIFY study, 5,395 patients were randomized to receive apixaban 10 mg orally twice daily for 7 days followed by apixaban 5 mg orally twice daily for 6 months, enoxaparin 1 mg/kg orally twice daily for at least 5 days (until an INR (international normalized ratio) ≥ 2) and warfarin (target INR range 2.0-3.0) orally for 6 months.

For patients in the warfarin group, the mean percentage of time in the therapeutic window of the MVC score (2.0–3.0) was 60.9. Apixaban demonstrated a reduction in the rate of recurrent symptomatic VTE or VTE-related deaths at different values of the mean therapeutic window time of the MVC. For the highest quartile relative to the median, the hazard ratio for apixaban and enoxaparin/warfarin was 0.79 (95% CI 0.39, 1.61).

This study showed that apixaban was non-inferior to enoxaparin/warfarin in the combined primary endpoint of graded recurrent symptomatic VTE (non-fatal DVT or PE) or VTE-related death.

The efficacy of apixaban in the initial treatment of VTE was comparable for patients receiving the drug 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 was generally similar across subgroups, including those stratified by age, sex, body mass index (BMI), renal function, PE score, DVT thrombus location, and prior parenteral heparin use.

The primary endpoint for the safety analysis was bleeding. In this study, apixaban demonstrated a statistically significant advantage over enoxaparin/warfarin for the primary safety endpoint [relative risk 0.31, 95% confidence interval (0.17; 0.55), P value <0.0001] (see Table 5).

Table 5

Bleeding analysis results in the AMPLIFY study

Major bleeding and clinically significant minor bleeding (CMB) at any site were generally lower in the apixaban group compared with the enoxaparin/warfarin group. ISTH-classified major gastrointestinal bleeding occurred in 6 patients (0.2%) on apixaban and 17 patients (0.6%) on enoxaparin/warfarin.

AMPLIFY-EXT study.

In the AMPLIFY-EXT study, 2482 patients were randomized to receive apixaban 2.5 mg orally twice daily, apixaban 5 mg orally twice daily, or placebo for 12 months after completing an initial 6-12 month course of anticoagulant therapy. Of these, 836 patients (33.7%) were enrolled in the AMPLIFY study prior to enrollment in the AMPLIFY-EXT study.

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

In this study, both doses of apixaban demonstrated statistically significant benefits over placebo for the primary endpoint of symptomatic recurrent VTE (nonfatal DVT or PE) or all-cause mortality (see Table 6).

Table 6

Efficacy results from the AMPLIFY-EXT study

¥ p-value <0.0001.

* For patients who experienced more than one event that was part of the composite endpoint, only the first event was reported (e.g., if a subject experienced a DVT event first and then a PE, only the DVT event was reported).

The efficacy of apixaban in preventing recurrent VTE remained consistent across subgroups, including those stratified by age, gender, body mass index, and renal function.

The primary safety endpoint was major bleeding during the treatment period. In this study, the incidence of major bleeding for both doses of apixaban was not statistically different from placebo. There was no statistically significant difference in the incidence of major, minor, CVID, or all bleeding between the apixaban 2.5 mg twice daily and placebo groups.

ISTH-classified major gastrointestinal bleeding was observed in 1 (0.1%) patient receiving apixaban 5 mg twice daily, in none of the patients receiving apixaban 2.5 mg twice daily, and in 1 (0.1%) patient receiving placebo.

Children.

The European Medicines Agency has deferred the obligation to submit the results of studies with Eliquis in one or more subsets of the paediatric population with venous or arterial thromboembolism (see section 4.2 for information on paediatric use).

Pharmacokinetics

Absorption.

The absolute bioavailability of apixaban at doses up to and including 10 mg is approximately 50%. Apixaban is rapidly absorbed, with peak plasma concentrations (Cmax) occurring 3 to 4 hours after tablet administration. Food does not affect the AUC or Cmax of apixaban at a dose of 10 mg. Apixaban can be taken with or without food.

When administered orally at doses up to 10 mg, the pharmacokinetics of apixaban demonstrate linearity with dose-proportional increase in exposure. At doses ≥ 25 mg, apixaban exhibits solubility-limited absorption and reduced bioavailability. Apixaban exposure parameters exhibit low to moderate variability, as reflected by intra-subject variability within 20% of the coefficient of variation (CV) and inter-subject variability within 30% of the CV.

Following oral administration of 10 mg apixaban as 2 crushed 5 mg tablets suspended in 30 mL of water, exposure was comparable to that following oral administration of 2 whole 5 mg tablets. Following oral administration of 10 mg apixaban as 2 crushed 5 mg tablets with 30 g of applesauce, Cmax and AUC were 20% and 16% lower, respectively, compared to 2 whole 5 mg tablets.

The reduction in exposure is not considered clinically significant.

Following administration of a crushed 5 mg apixaban tablet suspended in 60 mL of 5% aqueous dextrose and administered via nasogastric tube, exposure was similar to that observed in other clinical studies in healthy volunteers administered a single 5 mg apixaban tablet orally.

Given the predicted dose-proportional pharmacokinetic profile of apixaban, the results of the bioavailability studies are applicable to lower doses of apixaban.

Distribution.

Plasma protein binding in humans is approximately 87%. The volume of distribution (Vs) is approximately 21 liters.

Biotransformation and excretion.

Apixaban is eliminated from the body by several routes. Approximately 25% of an administered dose of apixaban was excreted as metabolites, with the majority of the metabolites excreted in the feces. Renal clearance of apixaban accounts for approximately 27% of total clearance. In clinical and preclinical studies, additional roles for the biliary and enteric routes of drug elimination have been observed.

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

The main mechanisms of biotransformation are O-demethylation and hydroxylation of the 3-oxopiperidinyl ring. Apixaban is metabolized primarily by CYP3A4/5. CYP1A2, 2C8, 2C9, 2C19, and 2J2 play minor roles in drug metabolism. In human plasma, unchanged apixaban is the major circulating compound associated with this drug. There are no circulating active metabolites of the drug in plasma. Apixaban is a substrate for the transport proteins, P-gp, and breast cancer resistance protein.

Kidney dysfunction.

Renal impairment did not affect peak apixaban concentrations. As assessed by creatinine clearance, increased apixaban exposure correlated with decreased renal function. In subjects with mild (creatinine clearance 51–80 mL/min), moderate (creatinine clearance 30–50 mL/min), and severe (creatinine clearance 15–29 mL/min), apixaban plasma concentrations increased by 16%, 29%, and 44%, respectively, compared with subjects with normal creatinine clearance. Renal impairment did not significantly affect the relationship between apixaban plasma concentrations and the extent of factor Xa inhibition.

When a single dose of apixaban (5 mg) was administered immediately after hemodialysis to patients with end-stage chronic renal failure, apixaban concentrations increased by 36% compared to subjects with normal creatinine clearance.

In a study in which 8 subjects with mild hepatic impairment (Child-Pugh A with scores of 5 (n = 6) and 6 (n = 2)) and 8 subjects with moderate hepatic impairment (Child-Pugh B with scores of 7 (n = 6) and 8 (n = 2)) were compared with 16 healthy control subjects, the pharmacokinetics and pharmacodynamics of a single dose of apixaban (5 mg) were not altered in the presence of hepatic impairment. Changes in factor Xa inhibition activity and changes in international normalized ratio were comparable in healthy subjects and subjects with mild to moderate hepatic impairment.

Elderly patients.

Elderly patients (over 65 years of age) had higher plasma concentrations of the drug compared to younger patients; mean AUC values in elderly patients were approximately 32% higher.

Sex.

Apixaban exposure levels in women were approximately 18% higher than in men.

Ethnicity and race.

Results from phase I studies indicate that there is no significant difference in the pharmacokinetics of apixaban between Caucasians, Mongoloids, and Negroids. The results of a population pharmacokinetic analysis conducted in patients receiving apixaban after elective hip or knee replacement surgery were consistent with the results from phase I studies.

Body weight.

When comparing apixaban exposure in individuals with different body weights, exposure was reduced by approximately 30% in individuals with a body weight of over 120 kg compared to that of normal weight (65–85 kg), while exposure was increased by approximately 30% in individuals with a body weight of less than 50 kg.

Pharmacodynamic/pharmacokinetic relationship.

The pharmacokinetic/pharmacodynamic (PK/PD) relationship between apixaban plasma concentrations and several PD endpoints (factor Xa inhibitory activity, MHC, PC, aPTT) was evaluated after administration of apixaban over a wide dose range of 0.5 to 50 mg. The relationship between apixaban plasma concentrations and factor Xa inhibitory activity was best described by a linear model. The pharmacokinetic/pharmacodynamic relationships observed in patients receiving apixaban after elective hip or knee replacement surgery were consistent with those observed in healthy volunteers.

Indication

Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation who have one or more risk factors, such as a history of stroke or transient ischemic attack, age 75 years or older, hypertension, diabetes mellitus, symptomatic heart failure (at least class II according to the New York Heart Association classification).

Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as prevention of recurrent DVT and PE in adults (information regarding patients suffering from PE and unstable hemodynamics is provided in the section "Special instructions for use").

Contraindication

Hypersensitivity to the active substance or to any of the excipients. Clinically significant active bleeding. Liver disease with coagulopathy and a clinically significant risk of bleeding. Pathology or condition with a significant risk of severe bleeding (e.g. current or recent history of gastrointestinal ulcer, presence of malignant neoplasms with a high risk of bleeding, recent head or spinal cord injury, recent brain, spinal cord or ophthalmological surgery, recent intracranial bleeding, diagnosed or suspected esophageal varices, arterial