Xarelto film-coated tablets 2.5 mg blister No. 56

Instructions for Xarelto film-coated tablets 2.5 mg blister No. 56

Composition

active ingredient: rivaroxaban;

1 film-coated tablet contains 2.5 mg of rivaroxaban;

Excipients: microcrystalline cellulose, croscarmellose sodium, hydroxypropylcellulose, lactose monohydrate, magnesium stearate, sodium lauryl sulfate, yellow iron oxide (E 172), polyethylene glycol, titanium dioxide (E 171).

Dosage form

Film-coated tablets.

Main physicochemical properties: round, biconvex, light yellow tablets with a triangle and the number 2.5 on one side and a cross-shaped Bayer logo on the other.

Pharmacotherapeutic group

Antithrombotic agents. ATX code B01A F01.

Pharmacological properties

Pharmacodynamics

Mechanism of action

Rivaroxaban is a highly selective direct inhibitor of factor Xa with high oral bioavailability. Blocking factor Xa activity interrupts the intrinsic and extrinsic pathways of the coagulation cascade, resulting in inhibition of thrombin generation and thrombus formation. Rivaroxaban does not directly inhibit thrombin (activated factor II) activity and does not affect platelets.

Pharmacodynamic effects

When administered to humans, a dose-dependent inhibition of factor Xa activity is observed. Rivaroxaban exhibits a dose-dependent effect on prothrombin time, which is significantly correlated with plasma concentration (r=0.98) when the Neoplastin kit is used for analysis. The results will be different when other reagents are used. Prothrombin time readings should be evaluated in seconds, since the INR (international normalized ratio) is calibrated and validated only for coumarins and cannot be used for other anticoagulants.

A clinical pharmacology study of rivaroxaban inhibition in healthy adult volunteers (n=22) evaluated the effects of single doses (50 IU/kg) of two different types of prothrombin complex concentrates (PCC): 3-factor PCC (factors II, IX, and X) and 4-factor PCC (factors II, VII, IX, and X). The 3-factor PCC resulted in a decrease in mean PCC (Neoplastin) values of approximately 1.0 seconds over 30 minutes, while the 4-factor PCC resulted in a decrease of approximately 3.5 seconds. However, the 3-factor PCC had a more potent and rapid overall effect on inhibiting changes in endogenous thrombin generation than the 4-factor PCC (see section 4.4).

Rivaroxaban also dose-dependently increases activated partial thromboplastin time (APTT) and HepTest results; however, these parameters are not recommended for use in assessing the pharmacodynamic effects of rivaroxaban. Monitoring of coagulation parameters is not required during treatment with rivaroxaban as part of standard clinical practice. However, if clinically indicated, rivaroxaban levels can be measured using calibrated quantitative anti-factor Xa assays (see section 5.2).

Clinical efficacy and safety

Acute coronary syndrome (ACS)

Clinical trials of rivaroxaban were conducted to determine the efficacy of Xarelto® in preventing cardiovascular death, myocardial infarction, or stroke in patients who had recently had an ACS (ST-segment elevation myocardial infarction [STEMI], non-ST-segment elevation myocardial infarction [NSTEMI], or unstable angina [UA]). In the pivotal double-blind ATLAS ACS 2 TIMI 51 study, 15,526 patients were randomized in a 1:1:1 ratio to receive one of three treatment groups: Xarelto® 2.5 mg orally twice daily, Xarelto® 5 mg orally twice daily, or placebo twice daily, either with acetylsalicylic acid (ASA) alone, or with ASA and a thienopyridine (clopidogrel or ticlopidine). Patients with ACS aged <55 years had either diabetes mellitus or a history of myocardial infarction. The median duration of therapy was 13 months and the total duration of therapy was almost 3 years. 93.2% of patients received ASA as concomitant therapy plus a thienopyridine and 6.8% received ASA alone. Among patients receiving dual antiplatelet therapy, 98.8% received clopidogrel, 0.9% ticlopidine and 0.3% prasugrel. Patients received the first dose of Xarelto® within 24 hours to 7 days (mean 4.7 days) after hospitalization, but as soon as possible after ACS stabilization, including revascularization procedures and when parenteral anticoagulant therapy could be discontinued.

Compared with placebo, Xarelto® significantly reduced the incidence of fatal cardiovascular events, myocardial infarction, or stroke (primary composite endpoint). The benefit was due to a reduction in the number of fatal cardiovascular events, myocardial infarction, and was evident early, with a consistent treatment effect throughout the treatment period (see Table 1). The incidence of major bleeding not related to coronary artery bypass grafting, as defined by TIMI (the primary safety endpoint), was higher in patients treated with Xarelto® than in patients treated with placebo (see Table 1). However, the difference in the incidence of fatal bleeding, hypotension requiring intravenous inotropic therapy, and surgical intervention to control bleeding was not statistically significant between the Xarelto® and placebo groups.

Table 1. Efficacy indicators according to the phase III study ATLAS ACS 2 TIMI 51

a modified analysis of the population of all randomized patients

b compared to placebo; p-value for log-rank test

* statistical advantage

** nominal significance

Table 2. Safety indicators according to the ATLAS ACS 2 TIMI 51 Phase III study

a patient population in which safety is being assessed and who is receiving treatment

b compared to placebo; p-value for log-rank test

* statistically significant indicator

Coronary heart disease (CHD)/peripheral artery disease (PAD)

The COMPASS phase III study (27,395 patients) demonstrated the efficacy and safety of Xarelto® for the prevention of cardiovascular death, myocardial infarction, and stroke in patients with coronary artery disease or symptomatic peripheral arterial disease (PAD) at high risk of ischemic events. Patients were followed for a median of 23 months and a maximum of 3.9 years.

Patients not requiring long-term proton pump inhibitor treatment were randomised to receive pantoprazole or placebo. All patients (78.0% male, 22.0% female) were randomised in a 1:1:1 ratio to receive one of three treatment groups: Xarelto® 2.5 mg twice daily in combination with ASA 100 mg once daily, Xarelto® 5 mg twice daily or ASA 100 mg once daily alone and their respective placebos.

Patients with CAD had multivessel CAD and/or previous myocardial infarction. For patients under 65 years of age, the required inclusion criteria for the study were atherosclerosis involving at least two vascular basins or at least two additional risk factors.

Patients with peripheral arterial disease had either undergone surgical interventions such as coronary artery bypass grafting or percutaneous transluminal angioplasty, or amputation of a foot due to arterial vascular disease, or intermittent claudication with a lower-extremity to upper-extremity blood pressure ratio < 0.90, or significant peripheral artery stenosis, or undergone carotid revascularization, or asymptomatic carotid artery stenosis ≥ 50%.

Xarelto® 2.5 mg twice daily in combination with ASA 100 mg once daily was superior to ASA 100 mg in reducing the risk of the composite of cardiovascular death, myocardial infarction, and stroke (see Table 3).

In patients treated with Xarelto® 2.5 mg twice daily in combination with ASA
100 mg once daily compared to ASA 100 mg, there was a significantly higher incidence of the primary safety endpoint (massive bleeding according to the modified ISTH definition) (see Table 4).

The advantage of Xarelto® 2.5 mg twice daily in combination with ASA 100 mg once daily compared to ASA 100 mg was observed for the primary efficacy endpoint HR=0.89 (95% CI 0.7-1.1) in patients ≥75 years (event rate 6.3% vs. 7.0%) and HR=0.70 (95% CI 0.6-0.8) in patients <75 years (3.6% vs. 5.0%). The increased risk of major bleeding events according to the modified ISTH definition was HR=2.12 (95% CI 1.5-3.0) in patients ≥75 years (5.2% vs. 2.5%) and HR=1.53 (95% CI 1.2-1.9) in patients <75 years (2.6% vs. 1.7%).

The use of pantoprazole 40 mg once daily in addition to an antithrombotic medicinal product in patients who did not have a clinical need for proton pump inhibitors did not show any benefit in preventing upper gastrointestinal events (i.e. the composite of upper gastrointestinal bleeding, upper gastrointestinal ulceration, or upper gastrointestinal obstruction or perforation); the rate of upper gastrointestinal events was 0.39 per 100 patient-years in the pantoprazole 40 mg once daily group and 0.44 per 100 patient-years in the placebo once daily group.

Table 3. Efficacy indicators according to the COMPASS Phase III study

a Statistical analysis of all randomized patients, primary analysis

b compared to ASA 100 mg; p-value for log-rank test

* statistically superior reduction in event rate of primary efficacy endpoint

CI – confidence interval

KM % – cumulative risk estimate calculated at day 900 according to Kaplan–Meier

Table 4. Safety indicators according to the COMPASS phase III study

a Statistical analysis of all randomized patients, primary analysis

b compared to ASA 100 mg; p-value for log-rank test

CI – confidence interval

Cumulative risk – Kaplan–Meier estimate at 30 months

ISTH – International Society for the Study of Thrombosis and Hemostasis

The COMMANDER HF trial enrolled 5022 patients with heart failure and significant coronary artery disease after hospitalization for decompensated heart failure (HF) who were randomized to receive rivaroxaban 2.5 mg twice daily (N = 2507) or placebo (N = 2515). The overall median duration of treatment was 504 days.

Patients had to have symptomatic HF for at least 3 months with a left ventricular ejection fraction (LVEF) ≤ 40% documented within the year prior to study entry. At baseline, the median ejection fraction was 34% (IQR: 28–38%); 53% of patients had New York Heart Association (NYHA) functional class III or IV HF.

The primary efficacy analysis (i.e., composite of all-cause death, MI, or stroke) showed no statistically significant difference between the rivaroxaban 2.5 mg group and the placebo group with HR = 0.94 (95% CI 0.84–1.05), p = 0.270. All-cause mortality did not differ between the rivaroxaban and placebo groups in terms of the number of events (event rate per 100 patient-years; 11.41 vs. 11.63, HR: 0.98; 95% CI: 0.87 to 1.10; p = 0.743). The incidence of MI events per 100 patient-years in the rivaroxaban and placebo groups was 2.08 and 2.52 (HR 0.83; 95% CI: 0.63 to 1.08; p = 0.165), and the incidence of stroke events per 100 patient-years was 1.08 and 1.62 (HR: 0.66; 95% CI: 0.47 to 0.95; p = 0.023), respectively. The primary safety endpoint (i.e. the composite of fatal or critical organ bleeding events that could lead to permanent disability) occurred in 18 (0.7%) patients in the rivaroxaban 2.5 mg twice daily group and in 23 (0.9%) patients in the placebo group (HR = 0.80; 95% CI 0.43–1.49; p = 0.484). There was a statistically significant increase in the incidence of major bleeding events as defined by ISTH in the rivaroxaban group compared to placebo (event rates per 100 patient-years: 2.04 and 1.21 (HR 1.68; 95% CI 1.18–2.39; p = 0.003), respectively).

In the subgroup of patients with mild to moderate heart failure, the effects of rivaroxaban treatment in the COMPASS study were similar to those observed in the overall study population (see CHD/PAD section).

Patients with positive test results for three antiphospholipid antibodies

Rivaroxaban was compared with warfarin in patients with a history of thrombosis and diagnosed antiphospholipid syndrome (APS) at high risk of thromboembolic events (positive results for all three antiphospholipid antibodies: lupus anticoagulant, anticardiolipin antibodies, anti-beta-2-glycoprotein I antibodies) in a randomized, open-label, multicenter, investigator-sponsored clinical trial with a blinded endpoint assessment. The study was stopped early after 120 patients were enrolled due to an increased incidence of thromboembolic events in patients taking rivaroxaban. The median follow-up period was 569 days, 59 patients were randomized to rivaroxaban 20 mg (15 mg for patients with creatinine clearance < 50 mL/min) and 61 to warfarin (INR 2.0–3.0). Thrombotic events occurred in 12% of patients randomized to rivaroxaban (4 ischemic strokes and 3 myocardial infarctions). No thromboembolic events were reported in patients randomized to warfarin. Major bleeding occurred in 4 patients (7%) in the rivaroxaban group and 2 patients (3%) in the warfarin group.

Use in children

The European Medicines Agency has deferred the obligation to submit the results of studies on the use of Xarelto® in one or more subsets of children for the treatment of thromboembolic complications.

The European Medicines Agency has waived the obligation to submit the results of studies with Xarelto® in all subsets of the paediatric population for the prevention of thromboembolic complications (see also section “Method of administration and dosage”).

Pharmacokinetics

Absorption

Rivaroxaban is rapidly absorbed; maximum concentration (Cmax) is reached 2-4 hours after taking the tablet.

When administered orally, rivaroxaban is almost completely absorbed and its bioavailability after taking doses of 2.5 mg and 10 mg is high and is 80-100% regardless of food intake. The use of rivaroxaban tablets 2.5 mg, 10 mg during food intake does not affect the AUC and Cmax of rivaroxaban. The drug Xarelto®, tablets 2.5 mg and 10 mg, can be taken regardless of food intake.

The pharmacokinetics of rivaroxaban are close to linear when administered in doses up to
15 mg once daily. The pharmacokinetics of rivaroxaban are characterized by moderate variability; the interindividual variability (coefficient of variation) is 30 to 40%.

The bioavailability (AUC and Cmax) of rivaroxaban 20 mg administered orally as a crushed tablet mixed with applesauce or water and administered via a gastric tube immediately before a liquid meal is similar to that of rivaroxaban taken as a whole tablet. Given the expected dose-proportional pharmacokinetic profile of rivaroxaban, the bioavailability data obtained in this study are likely to apply to lower doses of rivaroxaban.

Distribution

In humans, rivaroxaban is largely bound to plasma proteins (92-95%), with serum albumin being the major binding component. The volume of distribution is medium, with Vss approximately 50 l.

Metabolism and excretion

Rivaroxaban is excreted mainly in the form of metabolites (approximately ⅔ of the administered dose), with half of them excreted by the kidneys and the other half in the feces. ⅓ of the dose is subject to direct renal excretion in the urine as unchanged active substance, mainly by active renal secretion.

Rivaroxaban is metabolized by CYP 3A4, CYP 2J2 isoenzymes, as well as enzymes independent of the cytochrome P system. The main sites of biotransformation are the morpholine group, which is subject to oxidative decomposition, and the amide groups, which are subject to hydrolysis.

According to in vitro data, rivaroxaban is a substrate for transport proteins
P-gp (P-glycoprotein) and Bcrp (breast cancer resistance protein).

Unchanged rivaroxaban plays the most important role in human plasma, no significant or active circulating metabolites have been detected in plasma. Rivaroxaban, with a systemic clearance of approximately 10 l/h, can be classified as a drug with a low clearance rate. After intravenous administration of a 1 mg dose, the elimination half-life is approximately 4.5 hours. After oral administration, elimination is limited by the rate of absorption. The terminal half-life of rivaroxaban from blood plasma is from
5 to 9 hours in young patients and 11 to 13 hours in elderly patients.

Special categories

Sex

No clinically significant differences in pharmacokinetics and pharmacodynamics were found between men and women.

Elderly patients

In elderly patients, rivaroxaban plasma concentrations are higher than in young patients; the mean AUC is approximately 1.5 times higher than in young patients, mainly due to reduced (apparent) total renal clearance. No dose adjustment is required.

Patient body weight

Too low or too high body weight (less than 50 kg or more than 120 kg) has only a minor effect on the plasma concentration of rivaroxaban (the difference is less than 25%). No dose adjustment is required.

Interethnic features

No clinically significant differences in the pharmacokinetics (PK) and pharmacodynamics (PD) of rivaroxaban were observed in patients of European, African-American, Hispanic, Japanese, or Chinese ethnicity.

Liver failure

In patients with cirrhosis of the liver with mild hepatic insufficiency (class A according to the Child-Pugh classification), only minor differences in the pharmacokinetics of rivaroxaban were observed (an average 1.2-fold increase in AUC), which almost coincided with the parameters observed in the control group of healthy volunteers.

In patients with cirrhosis and moderate hepatic impairment (Child-Pugh class B), the mean AUC of rivaroxaban was significantly increased (2.3-fold) compared to healthy volunteers. The AUC of unbound substance was increased in
2.6-fold. These patients also showed reduced urinary excretion of rivaroxaban, typical of patients with moderate renal impairment. There are no data in patients with severe hepatic impairment.

In patients with moderate hepatic impairment, inhibition of factor Xa activity was more pronounced (2.6-fold difference) than in healthy volunteers. The PK was also (2.1-fold) higher than in healthy volunteers. Patients with moderate hepatic impairment were more sensitive to rivaroxaban, resulting in a steeper PK/PD curve between concentration and PK.

Xarelto® is contraindicated in patients with liver disease associated with coagulopathy and a clinically significant risk of bleeding, including patients with class B and C cirrhosis (see section “Contraindications”).

Kidney failure

There was an increase in rivaroxaban exposure, which correlated with a decrease in renal function, as measured by creatinine clearance.

In individuals with mild (creatinine clearance 50-80 ml/min), moderate (creatinine clearance
In subjects with mild (creatinine clearance 30-49 ml/min) or severe (creatinine clearance 15-29 ml/min) renal impairment, rivaroxaban plasma concentrations (AUC) were 1.4, 1.5 and 1.6 times higher than in healthy volunteers. Accordingly, an increase in pharmacodynamic effects was observed.

Due to its high plasma protein binding, dialysis is unlikely to remove rivaroxaban from the body. It is not recommended to use the drug in patients with creatinine clearance < 15 ml/min. Rivaroxaban should be used with caution in patients with severe renal impairment with creatinine clearance 15-29 ml/min (see section "Special warnings and precautions for use").

Pharmacokinetic data observed in patients

In patients with ACS receiving rivaroxaban at a dose of 2.5 mg twice daily for the prevention of atherothrombotic events, the geometric mean concentration (90% predictive interval) 2–4 hours and about 12 hours after taking the drug (the time approximately reflecting the achievement of maximum and minimum concentrations in the intervals between doses) was 47 (13–123) and 9.2 (4.4–18) μg/l, respectively.

Pharmacokinetic/pharmacodynamic relationships

The pharmacokinetic/pharmacodynamic (PK/PD) relationship between rivaroxaban plasma concentrations and several pharmacodynamic endpoints (factor Xa inhibition, HR, APTT, Heptest) was assessed over a wide dose range (5 to 30 mg twice daily). The relationship between rivaroxaban concentration and factor Xa activity is best described using the Emax model. For HR, a linear intercept model usually provides the most robust data. The slope may vary significantly between different HR reagents. When using Neoplastin for HR, the initial HR was approximately 13 seconds and the slope was 3-4 seconds/(100 μg/L). The PK/PD relationship analyses in the Phase II and Phase III studies were consistent with those in healthy volunteers.

Use in children

The efficacy and safety of the drug in children have not been studied.

Preclinical safety data

Existing non-clinical data obtained during conventional studies of safety pharmacology, single-dose toxicity, phototoxicity, genotoxicity, carcinogenic potential and reproductive toxicity indicate the absence of any specific risks for humans.

The reactions observed in multiple dose toxicity studies were mainly due to the excessive pharmacological activity of rivaroxaban.

No effects on male or female fertility were observed. In animal studies, reproductive toxicity related to the pharmacological mechanism of action of rivaroxaban (including haemorrhagic lesions) was observed. At clinically relevant plasma concentrations, embryo-fetal toxicity (post-implantation loss, delayed/progressive ossification, diffuse vitreous spots) and an increased incidence of general malformations and placental changes were observed. In prenatal and postnatal studies in rats, reduced viability of offspring was observed at maternally toxic doses.

Indication

Xarelto® is indicated in combination with acetylsalicylic acid (ASA) or in combination with ASA and clopidogrel or ticlopidine for the prevention of atherothrombotic events in adult patients after acute coronary syndrome (ACS) with elevated cardiac biomarkers (see sections “Contraindications”, “Special instructions for use”, “Pharmacodynamics”).

Xarelto® is indicated in combination with acetylsalicylic acid (ASA) for the prevention of atherothrombotic events in adult patients with coronary artery disease (CAD) or symptomatic peripheral arterial disease (PAD) at high risk of ischemic events.

Contraindication

Hypersensitivity to rivaroxaban or to any of the excipients. Clinically significant active bleeding. Injuries or conditions associated with a significant risk of bleeding. These may include current or recent gastrointestinal ulcers, malignancies with a high risk of bleeding, recent head or spinal cord injury, recent brain, spinal cord or eye surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or significant intraspinal or intracerebral vascular anomalies.

Concomitant use with any other anticoagulants, e.g. unfractionated heparin, low molecular weight heparins (enoxaparin, dalteparin), heparin derivatives (fondaparinux), oral anticoagulants (warfarin, dabigatran etexilate, apixaban), except in specific circumstances of switching to anticoagulant therapy (see section "Method of administration and dosage") or when unfractionated heparin is prescribed in doses necessary to ensure the functioning of a central venous or arterial catheter (see section "Interaction with other medicinal products and other types of interactions").

Concomitant therapy with corticosteroids and antiplatelet agents in patients with a history of stroke or transient ischemic attack (TIA) (see section "Special warnings and precautions for use").

Liver diseases associated with coagulopathy and clinically significant risk of bleeding, including Child-Pugh class B and C cirrhosis (see section "Pharmacokinetics"). Pregnancy or lactation (see section "Use during pregnancy and lactation").

Interaction with other medicinal products and other types of interactions

CYP3A4 and P-gp inhibitors

Concomitant use of rivaroxaban with ketoconazole (400 mg once daily) or ritonavir (600 mg twice daily) resulted in a 2.6-fold/2.5-fold increase in the mean steady-state AUC of rivaroxaban and a 1.7-fold/1.6-fold increase in the mean Cmax of rivaroxaban, which was accompanied by a significant increase in the pharmacodynamic effects of the drug, which may lead to an increased risk of bleeding. Therefore, the use of Xarelto® is not recommended in patients receiving concomitant systemic treatment with azole antifungals such as ketoconazole, itraconazole, voriconazole and posaconazole, or HIV protease inhibitors. These drugs are potent inhibitors of CYP3A4 and P-gp (see section "Special instructions").

Substances that actively inhibit only one of the rivaroxaban clearance pathways, CYP3A4 or P-gp, are expected to increase rivaroxaban plasma concentrations to a lesser extent. For example, clarithromycin (500 mg twice daily), a potent CYP3A4 inhibitor and a moderate P-gp inhibitor, caused a 1.5-fold increase in mean AUC and a 1.4-fold increase in Cmax of rivaroxaban. The interaction with clarithromycin is unlikely to be clinically significant in most patients, but may be potentially significant in high-risk patients (for use in patients with renal impairment, see section 4.4).

Erythromycin (500 mg 3 times a day), a moderate inhibitor of CYP3A4 and P-gp, caused a 1.3-fold increase in the mean steady-state AUC and Cmax of rivaroxaban. The interaction with erythromycin is unlikely to be clinically significant in most patients, but may be potentially significant in high-risk patients.

In patients with mild renal impairment, in contrast to patients with normal renal function, when using erythromycin (500 mg 3 times a day), a 1.8-fold increase in the mean AUC and a 1.6-fold increase in Cmax of rivaroxaban was observed. In patients with moderate renal impairment, a 2-fold increase in the mean AUC of rivaroxaban and a 1.6-fold increase in Cmax of rivaroxaban were observed against the background of erythromycin compared with patients with normal renal function. The effect of erythromycin is additive to the phenomena of renal failure (see section "Special instructions").

Fluconazole (400 mg once daily) is considered a moderate CYP3A4 inhibitor and its use caused a 1.4-fold increase in mean AUC and a 1.3-fold increase in Cmax of rivaroxaban. The interaction with fluconazole is probably not clinically significant in most patients, but may be potentially significant in high-risk patients (for use in patients with renal impairment, see section 4.4).

Given the limited clinical data on dronedarone, its concomitant use with rivaroxaban should be avoided.

Anticoagulants

After combined administration of enoxaparin (single dose 40 mg) and rivaroxaban (single dose 10 mg), an additive effect was observed on anti-factor Xa activity, which was not accompanied by additional changes in the results of blood coagulation tests (PT (prothrombin time), APTT (activated partial thromboplastin time)). Enoxaparin did not