INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KSARELTO® (XARELTO®)

Composition:

Active substance: rivaroxaban;

One film-coated tablet contains 2.5 mg of rivaroxaban;

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

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: light yellow, round, biconvex 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. Direct factor Xa inhibitors. Rivaroxaban. ATC code B01AF01.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Rivaroxaban is a highly selective direct inhibitor of factor Xa with high oral bioavailability. By blocking factor Xa activity, it interrupts both the intrinsic and extrinsic pathways of the coagulation cascade, thereby inhibiting thrombin formation and thrombus development. Rivaroxaban does not directly inhibit thrombin (activated factor II) activity and does not affect platelets.

Pharmacodynamic effects

In humans, a dose-dependent inhibition of factor Xa activity is observed. Rivaroxaban exerts a dose-dependent effect on prothrombin time, which correlates strongly with plasma concentration (r = 0.98) when the Neoplastin reagent is used for analysis. Results may vary when other reagents are used. Prothrombin time (PT) values should be reported in seconds, as the INR (International Normalized Ratio) is calibrated and validated only for coumarin derivatives and cannot be applied to other anticoagulants.

In a clinical pharmacology study assessing the reversal of rivaroxaban's pharmacodynamic effects in healthy adult volunteers (n = 22), the impact of single doses (50 IU/kg) of two types of prothrombin complex concentrates (PCC) was evaluated: 3-factor PCC (factors II, IX, and X) and 4-factor PCC (factors II, VII, IX, and X). Administration of 3-factor PCC resulted in a reduction of mean PT (Neoplastin) by approximately 1.0 second at 30 minutes, whereas 4-factor PCC reduced PT by approximately 3.5 seconds. However, 3-factor PCC demonstrated a more potent and faster overall effect on reversing endogenous thrombin generation compared to 4-factor PCC (see section "Overdose").

Rivaroxaban also dose-dependently increases activated partial thromboplastin time (aPTT) and HepTest results; however, these parameters are not recommended for assessing the pharmacodynamic effects of rivaroxaban. Routine monitoring of coagulation parameters is not required during rivaroxaban therapy under standard clinical practice. However, if clinically necessary, rivaroxaban levels can be measured using calibrated quantitative anti-factor Xa assays (see section "Pharmacokinetics").

Clinical efficacy and safety

Acute Coronary Syndrome (ACS)

Clinical trials of rivaroxaban were conducted to evaluate its efficacy in preventing cardiovascular death, myocardial infarction, or stroke in patients who recently experienced ACS (ST-segment elevation myocardial infarction [STEMI], non-ST-segment elevation myocardial infarction [NSTEMI], or unstable angina [UA]). In the double-blind ATLAS ACS 2 TIMI 51 trial, 15,526 patients were randomized in a 1:1:1 ratio to receive one of three treatments: rivaroxaban 2.5 mg orally twice daily, rivaroxaban 5 mg orally twice daily, or placebo twice daily, administered either with aspirin (ASA) alone or with ASA plus a thienopyridine (clopidogrel or ticlopidine). Patients with ACS were aged 55 years or younger and had either diabetes mellitus or a history of myocardial infarction. The mean duration of therapy was 13 months, with a total treatment period of nearly 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% received ticlopidine, and 0.3% received prasugrel. The first dose of rivaroxaban was administered within 24 hours to 7 days (mean 4.7 days) after hospitalization, as soon as possible after stabilization of ACS, including after revascularization procedures and when parenteral anticoagulant therapy could be discontinued.

Both rivaroxaban regimens (2.5 mg twice daily and 5 mg twice daily on a background of standard antiplatelet therapy) were effective in further reducing the incidence of cardiovascular complications. Since the 2.5 mg twice-daily regimen reduced mortality and demonstrated a lower risk of bleeding compared to the higher dose, rivaroxaban should be administered at a dose of 2.5 mg twice daily in combination with ASA or with ASA plus clopidogrel/ticlopidine for the prevention of atherothrombotic events in adult patients after ACS with elevated cardiac biomarkers.

Compared to placebo, rivaroxaban significantly reduced the rate of cardiovascular death, myocardial infarction, or stroke (primary composite endpoint). The benefit was driven by reductions in cardiovascular mortality and myocardial infarction and emerged early, with a sustained treatment effect throughout the entire treatment period (see Table 1). The rate of major bleeding not related to coronary artery bypass grafting, as defined by TIMI (primary safety endpoint), was higher in patients receiving rivaroxaban than in those receiving placebo (see Table 1). However, the difference in the rates of fatal bleeding, hypotension requiring intravenous inotropic support, or surgical intervention to control bleeding between the rivaroxaban and placebo groups was not statistically significant.

Table 1. Efficacy outcomes from the Phase III ATLAS ACS 2 TIMI 51 study

Study objective	Patients with recent acute coronary syndrome (ACS)
Treatment dose	Rivaroxaban 2.5 mg twice daily, N = 5114, n (%) Relative risk (95 % CI [confidence interval]) pb value	Placebo N = 5113 n (%)
Cardiovascular death, myocardial infarction, or stroke	313 (6.1 %) 0.84 (0.72; 0.97) p = 0.020*	376 (7.4 %)
Death from any cause, myocardial infarction, or stroke	320 (6.3 %) 0.83 (0.72; 0.97) p = 0.016*	386 (7.5 %)
Cardiovascular death	94 (1.8 %) 0.66 (0.51; 0.86) p = 0.002**	143 (2.8 %)
Death from any cause	103 (2.0 %) 0.68 (0.53; 0.87) p = 0.002**	153 (3.0 %)

a Modified intent-to-treat population of all randomized patients.

b Compared with placebo; p-value for log-rank test.

* Statistical superiority.

** Nominal significance.

Table 2. Safety outcomes from the phase III ATLAS ACS 2 TIMI 51 trial

Study objective	Patients with recent ACSa
Treatment dose	Rivaroxaban 2.5 mg twice daily, N = 5115, n (%) Relative risk (95% CI) p-valueb	Placebo N = 5125 n (%)
Major bleeding not related to coronary artery bypass grafting as defined by TIMI	65 (1.3%) 3.46 (2.08; 5.77) p = <0.001*	19 (0.4%)
Fatal bleeding	6 (0.1%) 0.67 (0.24; 1.89) p = 0.450	9 (0.2%)
Symptomatic intracranial hemorrhage	14 (0.3%) 2.83 (1.02; 7.86) p = 0.037	5 (0.1%)
Arterial hypotension requiring treatment with intravenous inotropic agents	3 (0.1%)	3 (0.1%)
Surgical intervention for uncontrolled bleeding	7 (0.1%)	9 (0.2%)
Transfusion of more than 4 units of blood within 48 hours	19 (0.4%)	6 (0.1%)

a The patient population in which safety is being evaluated and who are receiving treatment.

b Compared with placebo; p-value for the log-rank test.

* Statistically significant result.

Coronary artery disease (CAD) / peripheral artery disease (PAD)

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

All patients (78.0% male, 22.0% female) were randomized in a 1:1:1 ratio to receive one of three treatment regimens: rivaroxaban 2.5 mg twice daily in combination with aspirin 100 mg once daily, rivaroxaban 5 mg twice daily, or aspirin 100 mg once daily alone, along with their corresponding placebos.

Patients not requiring long-term proton pump inhibitor therapy were randomized to receive pantoprazole or placebo.

Patients with CAD had either multivessel CAD and/or a history of myocardial infarction. For patients under 65 years of age, inclusion criteria included atherosclerosis involving at least two vascular beds or at least two additional risk factors.

Patients with peripheral artery disease had either prior surgical procedures such as coronary artery bypass grafting or percutaneous transluminal angioplasty, or amputation of the foot due to arterial vascular disease, or intermittent claudication with an ankle-brachial index < 0.90, or significant peripheral artery stenosis, or prior carotid revascularization, or asymptomatic carotid artery stenosis ≥ 50%.

Exclusion criteria included, among others, the need for dual antiplatelet therapy or other non-aspirin antiplatelet agents, or oral anticoagulants. Patients at high risk of bleeding, heart failure with ejection fraction < 30%, or NYHA (New York Heart Association) functional class III or IV, or any non-lacunar ischemic stroke within the past month, or history of hemorrhagic or lacunar stroke were also excluded.

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

In patients treated with rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily compared to aspirin 100 mg alone, there was a significantly higher incidence of the primary safety endpoint (major bleeding as defined by modified ISTH criteria) (see Table 4).

The benefit of rivaroxaban 2.5 mg twice daily in combination with aspirin 100 mg once daily compared to aspirin 100 mg alone for the primary efficacy endpoint was observed with RR [relative risk] = 0.89 (95% CI 0.7–1.1) in patients ≥ 75 years of age (event rate 6.3% vs. 7.0%) and RR = 0.70 (95% CI 0.6–0.8) in patients < 75 years of age (3.6% vs. 5.0%). The increased risk of major bleeding as defined by modified ISTH criteria was RR = 2.12 (95% CI 1.5–3.0) in patients ≥ 75 years (5.2% vs. 2.5%) and RR = 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 added to antithrombotic therapy in patients without clinical indication for proton pump inhibitors did not show benefit in preventing upper gastrointestinal tract injury (specifically, 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 outcomes from the phase III COMPASS study

Study endpoint	Patients with CAD/PAD a
Treatment regimen	Rivaroxaban 2.5 mg twice daily in combination with ASA 100 mg once daily N=9152		ASA 100 mg once daily N=9126		Relative risk (95% CI) p-value b)
	Patients with events	CR %	Patients with events	CR %	RR (95% CI)	p-value b
Stroke, myocardial infarction, or cardiovascular death	379 (4.1%)	5.20%	496 (5.4%)	7.17%	0.76 (0.66; 0.86)	p = 0.00004*
Stroke	83 (0.9%)	1.17%	142 (1.6%)	2.23%	0.58 (0.44; 0.76)	p = 0.00006
Myocardial infarction	178 (1.9%)	2.46%	205 (2.2%)	2.94%	0.86 (0.70; 1.05)	p = 0.14458
Cardiovascular death	160 (1.7%)	2.19%	203 (2.2%)	2.88%	0.78 (0.64; 0.96)	p = 0.02053
Death from any cause	313 (3.4%)	4.50%	378 (4.1%)	5.57%	0.82 (0.71; 0.96)
Acute limb ischemia	22 (0.2%)	0.27%	40 (0.4%)	0.60%	0.55 (0.32; 0.92)

a Statistical analysis of all randomized patients, primary analysis.

b Compared with ASA 100 mg; p-values for the log-rank test.

* Statistically significant reduction in the incidence of primary efficacy outcome events.

CI — confidence interval.

KM % — cumulative risk estimate calculated on day 900 using the Kaplan-Meier method.

Table 4. Safety outcomes from the phase III COMPASS trial

Study Object	Patients with CAD/PADa
Treatment Dose	Rivaroxaban 2.5 mg twice daily in combination with ASA 100 mg once daily, N=9152 n (cumulative risk, %)	ASA 100 mg once daily N=9126 n (cumulative risk, %)	Relative Risk (95% CI) p-valueb
Major bleeding (modified definition, ISTH)	288 (3.9%)	170 (2.5%)	1.70 (1.40;2.05) p < 0.00001
Fatal bleeding	15 (0.2%)	10 (0.2%)	1.49 (0.67;3.33) p = 0.32164
Symptomatic bleeding into a critical organ (non-fatal)	63 (0.9%)	49 (0.7%)	1.28 (0.88;1.86) p = 0.19679
Bleeding at surgical site requiring reoperation (non-fatal, not into critical organ)	10 (0.1%)	8 (0.1%)	1.24 (0.49;3.14) p = 0.65119
Bleeding leading to hospitalization (non-fatal, not into critical organ, not requiring reoperation)	208 (2.9%)	109 (1.6%)	1.91 (1.51;2.41) p < 0.00001
Bleeding with overnight hospitalization	172 (2.3%)	90 (1.3%)	1.91 (1.48;2.46) p < 0.00001
Bleeding without overnight hospitalization	36 (0.5%)	21 (0.3%)	1.70 (0.99;2.92) p = 0.04983
Major gastrointestinal bleeding	140 (2.0%)	65 (1.1%)	2.15 (1.60;2.89) p < 0.00001
Major intracranial bleeding	28 (0.4%)	24 (0.3%)	1.16 (0.67;2.00) p = 0.59858

a Statistical analysis of all randomized patients, primary analysis.

b Compared with aspirin 100 mg; p-value for log-rank test.

CI — confidence interval.

Cumulative risk — Kaplan-Meier estimate at 30 months.

ISTH — International Society on Thrombosis and Haemostasis.

Patients following recent lower extremity revascularization procedure for symptomatic PAD

In the pivotal double-blind, phase III VOYAGER PAD study, 6,564 patients following a recent successful lower extremity revascularization procedure (surgical or endovascular, including hybrid procedures) for symptomatic PAD were randomized in a 1:1 ratio to one of two antithrombotic therapy regimens: rivaroxaban 2.5 mg twice daily in combination with aspirin 100 mg once daily, or aspirin 100 mg once daily. Patients were allowed to receive standard-dose clopidogrel once daily as an additional therapy for up to 6 months. The objective of the study was to demonstrate the efficacy and safety of rivaroxaban in combination with aspirin for the prevention of myocardial infarction, ischemic stroke, cardiovascular death, acute limb ischemia, or major amputation due to vascular etiology in patients following recent successful lower extremity revascularization procedures for symptomatic PAD. Patients enrolled were aged ≥ 50 years with documented moderate to severe symptomatic atherosclerotic lower extremity PAD confirmed clinically (i.e., functional limitations), anatomically (i.e., visualization of PAD signs distal to the common iliac artery), and hemodynamically (ankle-brachial index [ABI] ≤ 0.80 or toe-brachial index [TBI] ≤ 0.60 for patients without prior limb revascularization, or ABI ≤ 0.85 or TBI ≤ 0.65 for patients with prior limb revascularization). Excluded were patients requiring dual antiplatelet therapy for > 6 months or any additional antiplatelet therapy other than aspirin and clopidogrel, or requiring oral anticoagulant therapy, as well as patients with a history of intracranial hemorrhage, stroke, or transient ischemic attack (TIA), and patients with estimated glomerular filtration rate < 15 mL/min.

The median duration of follow-up was 24 months, with a maximum follow-up period of 4.1 years. The median age of enrolled patients was 67 years, and 17% of patients were > 75 years of age. The median time from the index revascularization procedure to initiation of study treatment was 5 days in the overall population (6 days after surgery and 4 days after endovascular revascularization, including hybrid procedures). Overall, 53.0% of patients received background clopidogrel therapy for a short duration, with a median duration of 31 days. According to the study protocol, treatment could be initiated as soon as possible, but no later than 10 days after the successful index revascularization procedure and after achieving hemostasis.

Rivaroxaban 2.5 mg twice daily in combination with aspirin 100 mg once daily was superior to aspirin alone in reducing the incidence of the primary composite endpoint (myocardial infarction, ischemic stroke, cardiovascular death, acute limb ischemia, and major vascular-origin amputation) (see Table 5). The incidence of the primary safety endpoint (TIMI major bleeding) was higher in patients receiving rivaroxaban plus aspirin, without an increase in fatal or intracranial bleeding (see Table 6).

Secondary efficacy endpoints were tested in a pre-specified hierarchical order (see Table 5).

Table 5. Efficacy outcomes from the phase III VOYAGER PAD study

Study objective	Patients after recent revascularization procedure for symptomatic PADa)
Treatment dose	Rivaroxaban 2.5 mg twice daily in combination with aspirin 100 mg once daily N = 3286 n (cumulative risk, %)c)	Aspirin 100 mg once daily N = 3278 n (cumulative risk, %)c)	Relative risk (95% CI) pd)
Primary efficacy outcomeb)	508 (15.5%)	584 (17.8%)	0.85 (0.76; 0.96) p = 0.0043e)*
Myocardial infarction	131 (4.0%)	148 (4.5%)	0.88 (0.70; 1.12)
Cardiovascular death	71 (2.2%)	82 (2.5%)	0.87 (0.63; 1.19)
Death from any cause	199 (6.1%)	174 (5.3%)	1.14 (0.93; 1.40)
Acute limb ischemiaf	155 (4.7%)	227 (6.9%)	0.67 (0.55; 0.82)
Major amputation of vascular origin	103 (3.1%)	115 (3.5%)	0.89 (0.68; 1.16)
Secondary efficacy outcomes
Unplanned revascularization of the index limb due to recurrent limb ischemia	584 (17.8%)	655 (20.0%)	0.88 (0.79; 0.99) p = 0.0140e) *
Hospitalization due to coronary or peripheral (either lower limb) thrombotic complication	262 (8.0%)	356 (10.9%)	0.72 (0.62; 0.85) p < 0.0001e) *
Death from any cause	321 (9.8%)	297 (9.1%)	1.08 (0.92; 1.27)
VTE events	25 (0.8%)	41 (1.3%)	0.61 (0.37; 1.00)

a) Statistical analysis of all randomized patients, primary analysis; assessment by the Independent Clinical Events Committee.

b) Composite endpoint — cases of myocardial infarction, ischemic stroke, cardiovascular death (cardiovascular death and death of unknown cause), acute limb ischemia, and major amputation of vascular etiology.

c) Only the first occurrence of the event under analysis is counted within the subject's data.

d) HR (95% CI) is based on the Cox proportional hazards model, stratified by procedure type and use of clopidogrel, with treatment as the sole covariate.

e) One-sided p-value is based on the log-rank test, stratified by procedure type and use of clopidogrel, with treatment as the factor.

f) Acute limb ischemia is defined as a sudden significant worsening of limb perfusion, either with a new pulse deficit or requiring therapeutic intervention (i.e., thrombolysis or thrombectomy, or urgent revascularization), and requiring hospitalization.

* The reduction in efficacy endpoint was statistically significantly greater.

Table 6. Safety outcomes from the Phase III VOYAGER PAD study

Study object	Patients after recent lower extremity revascularization procedure due to symptomatic PAD a)
Treatment dose	Rivaroxaban 2.5 mg twice daily in combination with ASA 100 mg once daily N = 3256 n (cumulative risk, %)b)	ASA 100 mg once daily N = 3248 n (cumulative risk, %)b)	Relative risk (95% CI)c) p-value d)
Major bleeding as defined by TIMI (related to coronary artery bypass / not related to coronary artery bypass)	62 (1.9%)	44 (1.4%)	1.43 (0.97; 2.10) p = 0.0695
Fatal bleeding	6 (0.2%)	6 (0.2%)	1.02 (0.33; 3.15)
Intracranial bleeding	13 (0.4%)	17 (0.5%)	0.78 (0.38; 1.61)
Obvious bleeding associated with a drop in hemoglobin ≥ 50 g/L or hematocrit ≥ 15%	46 (1.4%)	24 (0.7%)	1.94 (1.18; 3.17)
ISTH major bleeding	140 (4.3%)	100 (3.1%)	1.42 (1.10; 1.84) p = 0.0068
Fatal bleeding	6 (0.2%)	8 (0.2%)	0.76 (0.26; 2.19)
Non-fatal bleeding in a critical organ	29 (0.9%)	26 (0.8%)	1.14 (0.67; 1.93)
ISTH clinically relevant non-major bleeding	246 (7.6%)	139 (4.3%)	1.81 (1.47; 2.23)

a) Statistical analysis (all randomized patients who received at least one dose of investigational medicinal product); assessment by Independent Clinical Endpoint Committee.

b) n = number of patients with events, N = number of patients at risk, % = 100 * n/N, n/100 patient-years = ratio of number of subjects with events to total risk time.

c) HR (95% CI) based on Cox proportional hazards model stratified by procedure type and clopidogrel use with treatment as single covariate.

d) Two-sided p-value based on log-rank test stratified by procedure type and clopidogrel use with treatment as factor.

Coronary artery disease (CAD) with heart failure

The COMMANDER HF study included 5022 patients with heart failure and significant coronary artery disease following 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 treatment duration was 504 days.

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

The primary efficacy analysis (i.e., composite of death from any cause, myocardial infarction [MI], or stroke) did not show a statistically significant difference between the rivaroxaban 2.5 mg twice daily group and the placebo group, with HR = 0.94 (95% CI 0.84–1.05), p = 0.270. The all-cause mortality rate did not differ between the rivaroxaban and placebo groups in terms of event counts (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 MI event rate 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), respectively, and the stroke event rate 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 main safety outcome (i.e., composite of fatal bleeding or critical organ bleeding potentially leading to persistent disability) occurred in 18 (0.7%) patients in the rivaroxaban 2.5 mg twice daily treatment group and in 23 (0.9%) patients in the placebo group (HR = 0.80; 95% CI 0.43–1.49; p = 0.484). In the rivaroxaban group, there was a statistically significant increase in the rate of major bleeding as defined by ISTH compared to placebo (event rate per 100 patient-years: 2.04 vs 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 treatment effects of rivaroxaban in the COMPASS study were similar to those observed in the overall study population (see section "Coronary artery disease (CAD)/peripheral artery disease (PAD)" above).

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 blinded endpoint assessment. The study was prematurely terminated after enrolling 120 patients due to an increased incidence of thromboembolic events in patients receiving rivaroxaban. The mean observation 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 recorded in patients randomized to warfarin. Major bleeding occurred in 4 patients (7%) in the rivaroxaban group and 2 patients (3%) in the warfarin group.

Pediatric use

The European Medicines Agency has waived the obligation to submit the results of studies with Xarelto® in all pediatric subgroups for the prevention of thromboembolic complications (see also section "Dosage and administration").

Pharmacokinetics.

Absorption

Rivaroxaban is rapidly absorbed; maximum concentration (Cmax) is reached within 2–4 hours after tablet intake.

Following oral administration, rivaroxaban is almost completely absorbed, and its bioavailability after 2.5 mg and 10 mg doses is high, ranging from 80–100%, independent of food intake. Administration of rivaroxaban 2.5 mg and 10 mg tablets with food does not affect the AUC and Cmax of rivaroxaban. Rivaroxaban 2.5 mg and 10 mg tablets may be taken with or without food.

The pharmacokinetics of rivaroxaban are approximately linear when administered at doses up to 15 mg once daily. Rivaroxaban pharmacokinetics are characterized by moderate variability; inter-individual variability (coefficient of variation) ranges from 30 to 40%.

Rivaroxaban absorption depends on the site of release in the gastrointestinal tract. Studies have shown a 29% reduction in AUC and a 56% reduction in Cmax when rivaroxaban granules with release of active substance in the proximal small intestine were administered compared to the tablet formulation. Exposure is further reduced when the active substance is released in the distal small intestine or ascending colon. Therefore, rivaroxaban should not be administered distal to the stomach due to the potential for reduced absorption and the consequent impact on exposure.

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

Distribution

In humans, the majority of rivaroxaban (92–95%) is bound to plasma proteins, with serum albumin being the main binding component. The volume of distribution is moderate, with a steady-state volume (Vss) of approximately 50 L.

Metabolism and elimination

Rivaroxaban is primarily eliminated in the form of metabolites (approximately ⅔ of the administered dose), with half excreted via the kidneys and the other half via feces. ⅓ of the dose is directly excreted renally in urine as unchanged active substance, primarily via active renal secretion.

Metabolism of rivaroxaban is mediated by CYP 3A4, CYP 2J2 isoenzymes, and enzymes independent of the cytochrome P system. The main sites of biotransformation are the morpholine group, which undergoes oxidative breakdown, and the amide groups, which undergo hydrolysis.

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

Unchanged rivaroxaban is the predominant component in human plasma; no significant or active circulating metabolites have been identified in plasma. Rivaroxaban, with a systemic clearance of approximately 10 L/h, can be classified as a drug with low clearance. After intravenous administration of a 1 mg dose, the elimination half-life is approximately 4.5 hours. Following oral administration, elimination is absorption-rate limited. The terminal elimination half-life of rivaroxaban from plasma is 5 to 9 hours in younger patients and 11 to 13 hours in elderly patients.

Special populations

Sex

No clinically relevant differences in pharmacokinetics or pharmacodynamics were observed between men and women.

Elderly patients

Plasma concentrations of rivaroxaban are higher in elderly patients than in younger patients; the mean AUC is approximately 1.5 times higher than in younger patients, primarily due to reduced (apparent) total renal clearance. Dose adjustment is not required.

Body weight

Low or high body weight (less than 50 kg or more than 120 kg) has only a minor effect on plasma concentrations of rivaroxaban (differences less than 25%). Dose adjustment is not required.

Ethnic characteristics

No clinically relevant differences in pharmacokinetics (PK) or pharmacodynamics (PD) of rivaroxaban were observed in patients of European, African-American, Latino, Japanese, or Chinese ethnic origin.

Hepatic impairment

In patients with liver cirrhosis and mild hepatic impairment (Child-Pugh class A), only minor differences in rivaroxaban pharmacokinetics were observed (approximately 1.2-fold increase in AUC), similar to parameters observed in the control group of healthy volunteers.

In patients with liver 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 drug increased by 2.6-fold. These patients also showed reduced urinary excretion of rivaroxaban, typical of patients with moderate renal impairment. There are no data available for 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. PT was also increased (2.1-fold) compared to healthy volunteers. Patients with moderate hepatic impairment were more sensitive to rivaroxaban, resulting in a steeper PK/PD concentration-PT relationship curve.

Rivaroxaban is contraindicated in patients with liver disease associated with coagulopathy and clinically relevant bleeding risk, including patients with Child-Pugh class B and C cirrhosis (see section "Contraindications").

Renal impairment

Increased exposure to rivaroxaban correlated with decreased renal function as measured by creatinine clearance.

In individuals with mild (creatinine clearance 50–80 mL/min), moderate (creatinine clearance 30–49 mL/min), or severe (creatinine clearance 15–29 mL/min) renal impairment, plasma concentrations of rivaroxaban (AUC) were 1.4, 1.5, and 1.6 times higher, respectively, compared to healthy volunteers. Corresponding increases in pharmacodynamic effects were observed.

In individuals with mild, moderate, or severe renal impairment, overall inhibition of Factor Xa activity was increased by 1.5, 1.9, and 2 times, respectively, compared to healthy volunteers; PT similarly increased by 1.3, 2.2, and 2.4 times, respectively. Data for patients with creatinine clearance < 15 mL/min are not available.

Due to high plasma protein binding, elimination of rivaroxaban during dialysis is unlikely. The use of rivaroxaban is not recommended in patients with creatinine clearance < 15 mL/min. Rivaroxaban should be used with caution in patients with severe renal impairment with creatinine clearance of 15–29 mL/min (see section "Special precautions").

Pharmacokinetic data observed in patients

In patients with CAD receiving rivaroxaban 2.5 mg twice daily for prevention of atherothrombotic events, the geometric mean plasma concentration (90% prediction interval) 2–4 hours and approximately 12 hours after dosing (a time approximately reflecting peak and trough concentrations 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 plasma rivaroxaban concentration and several pharmacodynamic endpoints (Factor Xa inhibition, PT, aPTT, Heptest) was evaluated after administration of a wide range of doses (5 to 30 mg twice daily). The relationship between rivaroxaban concentration and Factor Xa activity is best described by an Emax model. For PT, a linear segmented model generally provides the most reliable data. Depending on the reagent used for PT measurement, the slope coefficient may vary considerably. When Neoplastin reagent is used for PT measurement, baseline PT is approximately 13 seconds, and the slope coefficient is 3–4 seconds/(100 µg/L). Results from PK/PD relationship analyses in Phase II and Phase III studies were consistent with data obtained in healthy volunteers.

Pediatric use

The efficacy and safety of the medicinal product for the indications of CAD and CAD/PAD in pediatric patients have not been established.

Non-clinical safety data

Available non-clinical data from conventional studies of pharmacological safety, single-dose toxicity, phototoxicity, genotoxicity, carcinogenic potential, and reproductive toxicity indicate no specific risks to humans.

Adverse reactions observed during repeated-dose toxicity studies were primarily due to the excessive pharmacological activity of rivaroxaban.

No effects on fertility in male or female animals were observed. Reproductive toxicity related to the pharmacological mechanism of action of rivaroxaban (e.g., hemorrhagic lesions) was observed in animal studies. Embryo-fetal toxicity (post-implantation loss, delayed/advanced ossification, scattered light-colored spots) and increased incidence of general malformations and placental changes were observed at clinically relevant plasma concentrations. Decreased offspring viability was observed in pre- and postnatal studies in rats at doses toxic to the dams.

Clinical characteristics.

Indications.

The medicinal product Xarelto® should be administered in combination with acetylsalicylic acid (ASA) or in combination with ASA and clopidogrel or ticlopidine for the prevention of atherothrombotic events in adult patients following acute coronary syndrome (ACS) with elevated cardiac biomarkers (see sections "Contraindications", "Special precautions for use", "Pharmacodynamics").

The medicinal product Xarelto® should be administered in combination with acetylsalicylic acid (ASA) for the prevention of atherothrombotic events in adult patients with ischemic heart disease (IHD) or symptomatic peripheral artery disease (PAD) with high risk of ischemic events.

Contraindications.

• Hypersensitivity to rivaroxaban or to any of the excipients of the medicinal product.
• Clinically significant active bleeding.
• Conditions or lesions associated with a high risk of bleeding, including current or recent gastrointestinal ulcers, malignant neoplasms with high bleeding risk, recent traumatic brain or spinal cord injury, recent surgery on the brain, spinal cord or eyes, recent intracranial hemorrhage, detected or suspected esophageal varices, arteriovenous malformations, vascular aneurysms, or significant intraspinal or intracerebral vascular abnormalities.
• Concomitant use with other anticoagulants, such as unfractionated heparin, low-molecular-weight heparins (enoxaparin, dalteparin), heparin derivatives (fondaparinux), or oral anticoagulants (warfarin, dabigatran etexilate, apixaban), except under specific circumstances of transition to anticoagulant therapy (see section "Method of administration and dosage") or when unfractionated heparin is administered at doses required to maintain central venous or arterial catheter function (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant therapy with ACS using antiplatelet agents in patients with a history of stroke or transient ischemic attack (TIA) (see section "Special precautions for use").
• Concomitant therapy with IHD/PAD using ASA in patients with a history of hemorrhagic or lacunar stroke or any stroke occurring within the past month (see section "Special precautions for use").
• Liver disease associated with coagulopathy and clinically significant risk of bleeding, including Child-Pugh class B and C liver cirrhosis (see section "Pharmacokinetics").
• Pregnancy or breastfeeding period (see section "Use during pregnancy or breastfeeding").

Special safety precautions.

Tablet crushing

Rivaroxaban tablets may be crushed and suspended in 50 mL of water and administered via nasogastric or feeding tube after confirming correct placement of the tube in the stomach (the tube should then be flushed with water). Since rivaroxaban absorption depends on the site of release of the active substance, administration of rivaroxaban distal to the stomach should be avoided, as this may lead to reduced absorption and consequently reduced drug effect. After administration of 2.5 mg tablets, enteral feeding does not need to be initiated immediately.

Interaction with other medicinal products and other forms of interaction.

CYP3A4 and P-gp inhibitors

Concomitant administration 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 mean steady-state AUC of rivaroxaban and a 1.7-fold/1.6-fold increase in mean Cmax of rivaroxaban, accompanied by a significant enhancement of pharmacodynamic effects, which may increase the risk of bleeding. Therefore, the use of Xarelto® is not recommended in patients receiving concomitant systemic treatment with azole antifungal agents such as ketoconazole, itraconazole, voriconazole, and posaconazole, or HIV protease inhibitors. These drugs are potent inhibitors of CYP3A4 and P-gp (see section "Special precautions for use").

Substances that strongly inhibit only one of the elimination pathways of rivaroxaban, either CYP3A4 or P-gp, are expected to increase plasma concentrations of rivaroxaban to a lesser extent. For example, clarithromycin (500 mg twice daily), a potent CYP3A4 inhibitor and 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 likely not clinically significant for most patients but may be potentially significant for high-risk patients (for use in patients with renal impairment, see section "Special precautions for use").

Erythromycin (500 mg three times daily), a moderate inhibitor of CYP3A4 and P-gp, caused a 1.3-fold increase in mean steady-state AUC and Cmax of rivaroxaban. The interaction with erythromycin is likely not clinically significant for most patients but may be potentially significant for high-risk patients.

In patients with mild renal impairment, unlike those with normal renal function, administration of erythromycin (500 mg three times daily) resulted in a 1.8-fold increase in mean AUC and a 1.6-fold increase in Cmax of rivaroxaban. In patients with moderate renal impairment, erythromycin administration was associated with a doubling of mean AUC and a 1.6-fold increase in Cmax of rivaroxaban compared to patients with normal renal function. The effect of erythromycin is additive to the effects of renal impairment (see section "Special precautions for use").

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

Due to limited clinical data on dronedarone, concomitant use with rivaroxaban should be avoided.

Anticoagulants

After coadministration of enoxaparin (single dose 40 mg) and rivaroxaban (single dose 10 mg), an additive effect on anti-factor Xa activity was observed, without additional changes in coagulation test results (PT [prothrombin time], aPTT [activated partial thromboplastin time]). Enoxaparin did not alter the pharmacokinetics of rivaroxaban.

Due to the increased risk of bleeding, caution should be exercised in patients receiving concomitant anticoagulants (see section "Contraindications", "Special precautions for use").

Nonsteroidal anti-inflammatory drugs (NSAIDs) / platelet aggregation inhibitors

Clinically relevant prolongation of bleeding time was not observed after coadministration of 15 mg rivaroxaban and 500 mg naproxen. However, a more pronounced pharmacodynamic response may occur in individual subjects.

No clinically significant pharmacokinetic or pharmacodynamic interaction was observed after coadministration of rivaroxaban with acetylsalicylic acid (500 mg).

No pharmacokinetic interaction was detected between rivaroxaban 15 mg and clopidogrel (loading dose 300 mg followed by maintenance doses of 75 mg), but in one subgroup of patients, a relevant increase in bleeding time was observed, which did not correlate with platelet aggregation or levels of P-selectin or GPIIb/IIIa receptors.

Caution should be exercised in patients receiving concomitant NSAIDs (including acetylsalicylic acid) and platelet aggregation inhibitors, as these drugs generally increase the risk of bleeding (see section "Special precautions for use").

Selective serotonin reuptake inhibitors (SSRIs) / serotonin-norepinephrine reuptake inhibitors (SNRIs)

As with other anticoagulants, there is a potential for increased risk of bleeding in patients receiving SSRIs or SNRIs concomitantly due to their effects on platelets. During clinical trials, a quantitatively higher rate of major and non-major clinically relevant bleeding was observed in all treatment groups when SSRIs or SNRIs were used concomitantly with rivaroxaban.

Warfarin

When switching patients from warfarin (INR 2.0–3.0) to rivaroxaban (20 mg) or from rivaroxaban (20 mg) to warfarin (INR 2.0–3.0), the prothrombin time/INR (Neoplastin test) increased more than additively (individual INR values reached up to 12), while the effects on aPTT, factor Xa inhibition, and endogenous thrombin potential (ETP) were additive.

If it is necessary to assess the pharmacodynamic effects of rivaroxaban during the transition period, factor Xa inhibition, PiCT, and HepTest can be used, as warfarin does not affect these tests. Starting from day 4 after discontinuation of warfarin, all tests (including PT, aPTT, factor Xa inhibition, and ETP) reflect only the effect of rivaroxaban.

If it is necessary to assess the pharmacodynamic effects of warfarin during the transition period, the INR test can be used at the time of minimal plasma concentration of rivaroxaban (24 hours after the previous dose of rivaroxaban), as rivaroxaban has the least influence on INR results at this time.

No pharmacokinetic interaction was observed between warfarin and rivaroxaban.

CYP3A4 inducers

Concomitant administration of rivaroxaban and rifampicin, a strong CYP3A4 inducer, resulted in approximately a 50% reduction in mean AUC of rivaroxaban and a parallel decrease in its pharmacodynamic effects. Concomitant use of rivaroxaban with other strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, phenobarbital, or St. John's wort) may also lead to reduced plasma concentrations of rivaroxaban. Therefore, concomitant administration with potent CYP3A4 inducers should be avoided, except when close monitoring for signs of thrombosis is ensured.

Other concomitant medications

No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when rivaroxaban was coadministered with midazolam (CYP3A4 substrate), digoxin (P-gp substrate), atorvastatin (CYP3A4 and P-gp substrate), or omeprazole (proton pump inhibitor). Rivaroxaban does not inhibit or induce any of the major CYP isoforms, such as CYP3A4.

No clinically significant interactions with food have been observed (see section "Method of administration and dosage").

Effect on laboratory parameters

Effects on coagulation tests (PT, aPTT, HepTest) are expected based on the mechanism of action of rivaroxaban (see section "Pharmacological properties").

Special precautions for use.

In patients with ACS, the efficacy and safety of the medicinal product Xarelto® 2.5 mg twice daily in combination with the antiplatelet agent ASA or ASA with clopidogrel/ticlopidine have been studied.

In patients at high risk of ischemic events due to CAD/PAD, the efficacy and safety of Xarelto® 2.5 mg twice daily have been investigated when used in combination with ASA.

In patients after recent revascularization procedure of the lower extremity due to symptomatic PAD, the efficacy and safety of Xarelto® film-coated tablets 2.5 mg twice daily were studied in combination with antiplatelet agents ASA or ASA + clopidogrel for a short-term period. If necessary, dual antiplatelet therapy with clopidogrel should be short-term. Prolonged dual antiplatelet therapy should be avoided (see section "Pharmacological properties").

Treatment in combination with other antiplatelet agents, such as prasugrel or ticagrelor, has not been studied and is not recommended.

During the treatment period, clinical monitoring consistent with the practice of anticoagulant use is recommended.

Bleeding risk

As with other anticoagulants, patients taking Xarelto® should be closely monitored for signs of bleeding. The drug should be used with caution in conditions associated with an increased risk of bleeding. In case of serious bleeding, Xarelto® should be discontinued (see section "Overdose").

In clinical trials, mucosal bleeding (e.g., epistaxis, gingival bleeding, gastrointestinal bleeding, genitourinary bleeding, including abnormal vaginal bleeding or increased menstrual bleeding) and anemia occurred more frequently during long-term rivaroxaban therapy combined with single or dual antiplatelet therapy. Therefore, in addition to appropriate clinical monitoring, laboratory monitoring of hemoglobin/hematocrit levels may be appropriate in relevant cases to detect occult bleeding and assess the clinical significance of overt bleeding.

In certain patient groups, as specified below, there is an increased risk of bleeding. Due to this fact, the benefit-risk balance of using Xarelto® in combination with dual antiplatelet therapy in patients at increased risk of bleeding should be carefully considered with regard to the benefit in preventing atherothrombotic events. Additionally, such patients should be closely monitored after initiation of treatment for signs of hemorrhagic complications and anemia (see section "Adverse reactions").

Any unexplained decrease in hemoglobin levels or blood pressure requires identification of the source of bleeding.

Although rivaroxaban treatment does not require routine monitoring of its exposure, measurement of rivaroxaban levels using calibrated quantitative anti-Factor Xa assays may be useful in exceptional situations where information on rivaroxaban exposure may influence clinical decision-making, particularly in cases of overdose or emergency surgery (see section "Pharmacological properties").

Renal impairment

In patients with severe renal impairment (creatinine clearance < 30 mL/min), plasma concentrations of rivaroxaban may significantly increase (on average by 1.6-fold), increasing the risk of bleeding. Xarelto® should be used with caution in patients with creatinine clearance of 15–29 mL/min. The drug is not recommended for patients with creatinine clearance < 15 mL/min (see sections "Dosage and administration", "Pharmacological properties").

Xarelto® should be used with caution in patients with moderate renal impairment (creatinine clearance 30–49 mL/min) who are concomitantly taking drugs that increase plasma concentrations of rivaroxaban (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products

The use of Xarelto® in patients receiving systemic treatment with azole antifungal agents (e.g., ketoconazole, itraconazole, voriconazole, posaconazole) or HIV protease inhibitors (e.g., ritonavir) is not recommended. These medicinal products are potent inhibitors of both CYP3A4 and P-gp isoenzymes. As a result, they may increase plasma concentrations of rivaroxaban to clinically significant levels (on average by 2.6-fold), increasing the risk of bleeding (see section "Interaction with other medicinal products and other forms of interaction").

Rivaroxaban should be prescribed with caution in patients who are concurrently using medicinal products affecting hemostasis, such as NSAIDs, ASA, platelet aggregation inhibitors, or selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). In patients at risk of gastrointestinal ulceration, appropriate prophylactic treatment should be considered (see section "Interaction with other medicinal products and other forms of interaction").

Patients receiving Xarelto® and antiplatelet agents should continue concomitant NSAID therapy only if the benefit outweighs the bleeding risk.

Other bleeding risk factors

Xarelto®, like other antithrombotic agents, is not recommended for use in patients with an increased risk of bleeding, including those with:

• congenital or acquired coagulation disorders;
• uncontrolled severe arterial hypertension;
• other gastrointestinal disorders without active ulcers that may potentially lead to hemorrhagic complications (e.g., inflammatory bowel disease, esophagitis, gastritis, gastroesophageal reflux disease);
• retinal vasculopathy;
• bronchiectasis or history of pulmonary hemorrhage.

The drug should be used with caution in patients with ACS and CAD/PAD who have:

• age ≥ 75 years and are concurrently receiving ASA or ASA with clopidogrel or ticlopidine. The benefit-risk ratio of ongoing treatment should be regularly assessed in each individual patient;
• low body weight (< 60 kg) and are concurrently receiving ASA or ASA with clopidogrel or ticlopidine;
• CAD with severe symptomatic heart failure. Study data suggest that such patients may derive less benefit from rivaroxaban treatment (see section "Pharmacodynamics").

Patients with malignancy

Patients with malignant diseases may simultaneously have an increased risk of bleeding and thrombosis. The individual benefit of antithrombotic treatment should be weighed against the bleeding risk in patients with active malignancy, depending on tumor location, anticancer therapy, and disease stage. Tumors located in the gastrointestinal or genitourinary tract have been associated with an increased risk of bleeding during rivaroxaban treatment.

Rivaroxaban use is contraindicated in patients with malignant neoplasms at high risk of bleeding (see section "Contraindications").

Patients with prosthetic heart valves

Rivaroxaban should not be used for thromboprophylaxis in patients who have recently undergone transcatheter aortic valve replacement (TAVR). The safety and efficacy of Xarelto® have not been studied in patients with prosthetic heart valves, and there are no data confirming adequate anticoagulation with this drug in this patient group. Xarelto® is not recommended for treatment of such patients.

Patients with antiphospholipid syndrome

Direct oral anticoagulants, including rivaroxaban, are not recommended for patients with a history of thrombosis and diagnosed antiphospholipid syndrome. In particular, in patients with confirmed positive results for all three antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibodies, anti-β2-glycoprotein-I antibodies), therapy with direct oral anticoagulants may increase the risk of recurrent thrombotic events compared to vitamin K antagonists.

Patients with history of stroke and/or TIA

Patients with acute coronary syndrome

Xarelto® 2.5 mg is contraindicated in patients with ACS and a history of stroke or TIA (see section "Contraindications"). Limited data on efficacy in such patients suggest no benefit of this treatment in this subgroup.

Patients with ischemic heart disease/peripheral artery disease

Patients with ischemic heart disease/peripheral artery disease and a history of hemorrhagic or lacunar stroke, or ischemic non-lacunar stroke within the past month, have not been studied (see section "Contraindications").

Patients after recent revascularization of the lower extremity due to symptomatic PAD with prior stroke or TIA have not been studied. If a patient is receiving dual antiplatelet therapy, the use of Xarelto® 2.5 mg film-coated tablets should be avoided.

Spinal (epidural/spinal) anesthesia or puncture

With neuraxial anesthesia (epidural/spinal anesthesia) or spinal/epidural puncture, there is a risk of epidural or spinal hematoma, which may lead to prolonged or irreversible paralysis in patients receiving antithrombotic agents for thromboembolic prophylaxis.

The risk of these complications is increased with the use of indwelling epidural catheters or concomitant use of medicinal products affecting hemostasis. Traumatic or repeated epidural or spinal puncture may also increase the risk of such complications. Patients should be monitored for neurological symptoms (e.g., numbness or weakness in legs, bowel or bladder dysfunction). If neurological deficits occur, urgent diagnosis and treatment are required. The physician should evaluate the potential benefits and risks before performing such procedures in patients receiving or about to receive anticoagulants for thrombosis prophylaxis.

There is no clinical experience with the use of Xarelto® 2.5 mg and antiplatelet agents in such situations. Platelet aggregation inhibitors should be discontinued according to the instructions for medical use of the respective medicinal product.

To reduce the potential risk of bleeding associated with concomitant use of rivaroxaban and spinal (epidural/spinal) anesthesia or puncture, the pharmacokinetic profile of rivaroxaban should be considered. Placement or removal of an epidural catheter or lumbar puncture should ideally be performed when the anticoagulant effect of rivaroxaban is expected to be low (see section "Pharmacokinetic properties"). However, the exact time to achieve sufficient reduction in anticoagulant effect in an individual patient is unknown.

Dosing recommendations before and after invasive procedures and surgery

If invasive procedures or surgical interventions are necessary, administration of Xarelto® 2.5 mg should be discontinued at least 12 hours before the procedure, if possible and based on the physician's clinical judgment. If surgery can be delayed and the antiplatelet effect is not adequate, antiplatelet agents should be discontinued according to the instructions for medical use of the respective drug. If the procedure cannot be postponed, the increased risk of bleeding should be assessed based on the urgency of the intervention.

Xarelto® should be resumed as soon as possible after an invasive procedure or surgery, once adequate hemostasis is achieved and if the clinical situation allows, as determined by the physician (see section "Pharmacokinetics").

Elderly patients

The risk of bleeding may increase with age (see section "Pharmacological properties").

Dermatological reactions

Serious skin reactions, including Stevens-Johnson syndrome / toxic epidermal necrolysis and DRESS syndrome (drug reaction with eosinophilia and systemic symptoms), have been reported during post-marketing surveillance in association with rivaroxaban use (see section "Adverse reactions"). The risk of these reactions is likely highest at the beginning of therapy: most cases occurred within the first weeks of treatment. Rivaroxaban should be discontinued at the first signs of severe skin rash (e.g., generalization, intensification, and/or blistering) or any other signs of hypersensitivity combined with mucosal involvement.

Information on excipients

Xarelto® contains lactose. Patients with rare hereditary disorders of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., essentially "sodium-free".

Women of childbearing potential / contraception

Women of childbearing potential should use Xarelto® only with effective contraception.

Use during pregnancy or breastfeeding.

Pregnancy

The efficacy and safety of Xarelto® in pregnant women have not been established. Animal studies indicate reproductive toxicity (see section "Pharmacological properties"). Due to potential reproductive toxicity, bleeding risk, and data on placental transfer of rivaroxaban, Xarelto® is contraindicated during pregnancy (see section "Contraindications"). Women of childbearing potential should avoid pregnancy during rivaroxaban treatment.

Breastfeeding

The efficacy and safety of Xarelto® in breastfeeding women have not been established. Animal studies have shown that rivaroxaban is excreted in breast milk. Therefore, Xarelto® is contraindicated during breastfeeding (see section "Contraindications"). A decision should be made whether to discontinue breastfeeding or to discontinue/withhold therapy.

Fertility

Specific studies on the effect of rivaroxaban on human fertility have not been conducted. Fertility studies in male and female animals showed no adverse effects (see section "Pharmacological properties").

Women of childbearing potential / contraception

Women of childbearing potential should use Xarelto® only with effective contraception.

Ability to influence reaction speed when driving or operating machinery.

Xarelto® has negligible influence on the ability to drive or operate machinery. Adverse reactions such as syncope (uncommon) or dizziness (common) have been reported (see section "Adverse reactions").

Patients experiencing such adverse reactions should not drive or operate machinery.

Method of Administration and Dosage

Dosage

The recommended dose is 2.5 mg twice daily.

• Acute Coronary Syndrome (ACS)

Patients receiving the medicinal product Xarelto® 2.5 mg twice daily should also receive acetylsalicylic acid (ASA) at a daily dose of 75–100 mg, or ASA at a daily dose of 75–100 mg in combination with clopidogrel at a daily dose of 75 mg, or with a standard daily dose of ticlopidine.

Regular assessment of treatment should be performed for each individual patient, taking into account the balance between the risks of ischemic events and bleeding. Due to limited experience with the use of the drug for periods up to 24 months, the decision on treatment duration beyond 12 months should be made on an individual basis (see section “Pharmacological Properties”).

Treatment with Xarelto® should be initiated as soon as the condition related to ACS is stabilized (including revascularization procedures). Treatment with Xarelto® should not be started earlier than 24 hours after hospitalization, while parenteral anticoagulants are typically discontinued.

• Ischemic Heart Disease / Peripheral Artery Disease (PAD)

Patients receiving the medicinal product Xarelto® 2.5 mg twice daily should also receive acetylsalicylic acid (ASA) at a daily dose of 75–100 mg.

In patients following a successful lower limb revascularization procedure (surgical or endovascular, including hybrid procedures) due to symptomatic PAD, treatment should not be initiated until hemostasis is achieved (see section “Pharmacological Properties”).

The duration of treatment should be determined individually for each patient based on regular assessment of the patient’s condition, taking into account the balance between the risks of ischemic events and bleeding.

• ACS, IHD/PAD

Concomitant Use with Antiplatelet Therapy

In patients with acute thrombotic events or after vascular procedures, continuation of Xarelto® 2.5 mg twice daily should be evaluated considering the nature of the event or procedure and the antiplatelet therapy regimen.

The efficacy and safety of Xarelto® 2.5 mg twice daily in combination with dual antiplatelet therapy have been studied in patients:

• with recent ACS — in combination with ASA and clopidogrel/ticlopidine (see section “Indications”);
• after recent lower limb revascularization due to symptomatic PAD — in combination with ASA and, if appropriate, short-term clopidogrel (see sections “Special Warnings and Precautions for Use” and “Pharmacological Properties”).

Missed Dose

If a dose is missed, the patient should take the next dose according to the usual schedule. A double dose should not be taken to compensate for the missed dose.

Transition from Vitamin K Antagonists (VKAs) to Xarelto®

When transitioning patients from VKAs to Xarelto®, INR values may be falsely elevated after administration of Xarelto®. Since INR is not a validated method for assessing the anticoagulant activity of Xarelto®, it should not be used (see section “Interaction with Other Medicinal Products and Other Forms of Interaction”).

Transition from Xarelto® to Vitamin K Antagonists (VKAs)

There is a risk of subtherapeutic anticoagulation when switching from Xarelto® to VKAs. As with any transition to an alternative anticoagulant, continuous and adequate anticoagulation must be ensured. It should be noted that INR values may be elevated during Xarelto® treatment.

When switching from Xarelto® to a vitamin K antagonist (VKA), both Xarelto® and the VKA should be administered concurrently until the INR is ≥ 2.0. During the first two days of the transition period, standard dosing of the VKA may be used. Thereafter, VKA dosing should be adjusted based on INR values. While the patient is taking both Xarelto® and VKA, INR should be measured no sooner than 24 hours after the last dose of Xarelto® but before the next scheduled dose of Xarelto®. After discontinuation of Xarelto®, INR can be reliably measured at least 24 hours after the last dose of Xarelto® (see sections “Interaction with Other Medicinal Products and Other Forms of Interaction”, “Pharmacological Properties”).

Transition from Parenteral Anticoagulants to Xarelto®

Patients receiving parenteral anticoagulants should discontinue the anticoagulant and start taking Xarelto® 0–2 hours before the next scheduled dose of the parenteral agent (e.g., low molecular weight heparin) or immediately after discontinuation of a continuously infused parenteral agent (e.g., unfractionated heparin for intravenous infusion).

Transition from Xarelto® to Parenteral Anticoagulants

The first dose of the parenteral anticoagulant should be administered at the time the next dose of Xarelto® was due.

Use in Special Patient Populations

Patients with Renal Impairment

Limited clinical data in patients with severe renal impairment (creatinine clearance 15–29 mL/min) indicate a significant increase in rivaroxaban plasma concentrations. Therefore, Xarelto® should be used with caution in such patients.

The use of the drug is not recommended in patients with creatinine clearance <15 mL/min (see sections “Special Warnings and Precautions for Use” and “Pharmacokinetics”).

No dose adjustment is required in patients with mild (creatinine clearance 50–80 mL/min) or moderate (creatinine clearance 30–49 mL/min) renal impairment (see section “Pharmacokinetics”).

Patients with Hepatic Impairment

Xarelto® is contraindicated in patients with liver disease associated with coagulopathy and clinically relevant bleeding risk, including patients with Child-Pugh class B and C cirrhosis (see sections “Contraindications”, “Pharmacokinetics”).

Elderly Patients

No dose adjustment is required (see sections “Special Warnings and Precautions for Use” and “Pharmacokinetics”).

The risk of bleeding increases with age (see section “Special Warnings and Precautions for Use”).

Body Weight

No dose adjustment is required (see sections “Special Warnings and Precautions for Use” and “Pharmacokinetics”).

Gender

No dose adjustment is required (see section “Pharmacokinetics”).

Method of Administration

For oral use.

Xarelto® may be taken with or without food (see sections “Interaction with Other Medicinal Products and Other Forms of Interaction” and “Pharmacokinetics”).

Crushing the Tablet

For patients who have difficulty swallowing whole tablets, the Xarelto® tablet may be crushed and mixed with water or apple puree immediately before oral administration.

Crushed tablets may be administered via a gastric tube (see sections “Pharmacokinetics” and “Special Precautions for Safety”).

Children

The efficacy and safety of Xarelto® 2.5 mg film-coated tablets in children have not been established. Data are lacking. Therefore, Xarelto® 2.5 mg film-coated tablets are not recommended for use in children.

Overdose

Isolated cases of overdose up to 1960 mg have been reported. In the event of overdose, the patient should be carefully monitored for complications such as bleeding or other adverse reactions (see “Management of Bleeding” below). Due to limited absorption at doses significantly exceeding therapeutic levels (50 mg or higher), a saturation effect is expected without further increase in mean plasma concentration.

A specific reversal agent (andexanet alfa) is available that counteracts the pharmacological effects of rivaroxaban (see the summary of product characteristics for andexanet alfa). In cases of overdose, activated charcoal may be used to reduce rivaroxaban absorption.

Management of Bleeding

If a patient receiving rivaroxaban experiences bleeding complications, the next dose of rivaroxaban should be withheld or treatment discontinued, depending on the clinical situation. The elimination half-life of rivaroxaban is approximately 5–13 hours (see section “Pharmacokinetics”). Treatment should be individualized based on the severity and location of bleeding. If necessary, appropriate symptomatic treatment may be administered, such as mechanical compression for severe epistaxis, surgical hemostasis with bleeding control procedures, fluid and electrolyte replacement, hemodynamic support, transfusion of blood products (packed red blood cells or fresh frozen plasma depending on associated anemia or coagulopathy), or platelets.

If bleeding persists despite the above measures, consideration should be given to using a specific reversal agent (andexanet alfa), an inhibitor of factor Xa that counteracts the pharmacological effects of rivaroxaban, or other specific procoagulant agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (aPCC), or recombinant factor VIIa (rFVIIa).

However, clinical experience with these agents in rivaroxaban overdose is limited. Recommendations are also based on limited preclinical data. Dosing and titration of recombinant factor VIIa should be based on the degree of bleeding control achieved. In cases of massive bleeding, consultation with a hematologist should be considered depending on the clinical situation (see section “Pharmacological Properties”).

Protamine sulfate and vitamin K are not expected to influence the anticoagulant activity of rivaroxaban. Limited experience exists with tranexamic acid, and there is no experience with aminocaproic acid or aprotinin in patients receiving rivaroxaban. There is no scientific evidence or clinical experience supporting the use of the systemic hemostatic agent desmopressin to manage rivaroxaban overdose symptoms. Due to high plasma protein binding, rivaroxaban is not expected to be effectively removed by dialysis.

Adverse reactions.

General safety profile

The safety of rivaroxaban was studied in 13 pivotal Phase III trials (see Table 7).

Overall, 69,608 adult patients in nineteen Phase III trials and 488 pediatric patients in two Phase II and two Phase III trials were exposed to rivaroxaban.

Table 7. Number of patients, total daily dose, and maximum duration of treatment in adult and pediatric patients during Phase III studies

Indications	Number of patients*	Total daily dose	Maximum duration of treatment
Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery	6097	10 mg	39 days
Prevention of VTE in medically ill patients	3997	10 mg	39 days
Treatment of deep vein thrombosis (DVT), pulmonary embolism (PE), and prevention of recurrent DVT and PE	6790	Days 1–21: 30 mg Day 22 onwards: 20 mg After at least 6 months: 10 mg or 20 mg	21 months
Treatment of VTE and prevention of recurrent VTE in neonates and children (up to 18 years of age) following initiation of standard anticoagulant therapy	329	Dose adjusted by body weight to achieve exposure comparable to that observed in adults receiving 20 mg of rivaroxaban once daily for treatment of DVT	12 months
Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation	7750	20 mg	41 months
Prevention of atherothrombotic events in patients after acute coronary syndrome (ACS)	10225	5 mg or 10 mg, administered concomitantly with acetylsalicylic acid (ASA) or with ASA plus clopidogrel or ticlopidine	31 months
Prevention of atherothrombotic events in patients with coronary artery disease (CAD) or peripheral artery disease (PAD)	18244	5 mg with ASA or 10 mg	47 months
	3256**	5 mg with ASA	42 months

*Patients who received at least one dose of rivaroxaban.

**From the VOYAGER PAD study.

The most commonly observed adverse reactions in patients receiving rivaroxaban were bleeding events (see section "Special precautions for use" and the subsection below "Description of selected adverse reactions") (see Table 8). The most frequent reports were of epistaxis (4.5%) and gastrointestinal bleeding (3.8%).

Table 8. Frequency of bleeding* and anemia in patients who received rivaroxaban during completed Phase III studies involving adult and pediatric patients

Indications	Any bleeding	Anemia
Prophylaxis of venous thromboembolism (VTE) in adult patients undergoing hip or knee replacement surgery	6.8% of patients	5.9% of patients
Prophylaxis of venous thromboembolism in medically ill patients	12.6% of patients	2.1% of patients
Treatment of DVT, PE and prevention of recurrence	23% of patients	1.6% of patients
Treatment of VTE and prevention of VTE recurrence in neonates and children (under 18 years of age) following initiation of standard anticoagulant therapy	39.5% of patients	4.6% of patients
Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation	28 per 100 patient-years	2.5 per 100 patient-years
Prevention of atherothrombotic events in patients after acute coronary syndrome	22 per 100 patient-years	1.4 per 100 patient-years
Prevention of atherothrombotic events in patients with CAD/PAD	6.7 per 100 patient-years	0.15 per 100 patient-years**
	8.38 per 100 patient-years#	0.74 per 100 patient-years***#

* For all rivaroxaban studies, all bleeding events were collected, reported, and evaluated.

** In the COMPASS study, the frequency of anemia was low due to the use of a systematic approach to collect information on adverse events.

*** A systematic approach was used to collect adverse events.

From the VOYAGER PAD study.

The adverse reactions observed during administration of Xarelto® in adult and pediatric patients are listed in Table 9 below. Adverse reactions are classified by system organ classes (MedDRA) and frequency. The frequency of adverse reactions is defined as follows: very common (≥ 1/10); common (≥ 1/100 to <1/10); uncommon (≥ 1/1000 to <1/100); rare (≥ 1/10,000 to <1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from the available data).

Table 9. All adverse reactions observed in adult patients participating in Phase III studies or in the post-marketing period* and in pediatric patients in two Phase II and two Phase III studies

Common	Uncommon	Occasional	Rare	Frequency unknown
Disorders of the blood and lymphatic system
Anaemia (including corresponding laboratory parameters)	Thrombocytosis (including increased platelet count)A, thrombocytopenia
Immune system disorders
	Allergic reaction, allergic dermatitis, angioneurotic and allergic oedema		Anaphylactic reactions, including anaphylactic shock
Nervous system disorders
Dizziness, headache	Intracerebral and intracranial haemorrhage, syncope
Eye disorders
Eye haemorrhage (including conjunctival haemorrhage)
Cardiac disorders
	Tachycardia
Vascular disorders
Arterial hypotension, haematoma
Respiratory, thoracic and mediastinal disorders
Nosebleed, haemoptysis			Eosinophilic pneumonia
Gastrointestinal disorders
Gingival bleeding, gastrointestinal haemorrhage (including rectal bleeding), abdominal and gastrointestinal pain, dyspepsia, nausea, constipationA, diarrhoea, vomitingA	Dry mouth
Hepatobiliary disorders
Elevated transaminase levels	Liver failure, elevated bilirubin levels, elevated alkaline phosphatase activity in bloodA, elevated gamma-glutamyl transferase (GGT) activityA	Jaundice, elevated conjugated bilirubin levels (with or without concomitant elevation of ALT activity), cholestasis, hepatitis (including hepatocellular injury)
Skin and subcutaneous tissue disorders
Itching (including uncommon cases of generalized pruritus), rash, ecchymosis, skin and subcutaneous haemorrhage	Urticaria		Stevens-Johnson syndrome / toxic epidermal necrolysis, DRESS syndrome
Musculoskeletal, connective tissue and bone disorders
Limb painA	Haemarthrosis	Muscle haemorrhage		Compartment syndrome due to haemorrhage
Renal and urinary disorders
Genitourinary haemorrhage (including haematuria and menorrhagiaB), renal function impairment (including elevated blood creatinine and elevated blood urea levels)				Renal failure / acute renal failure due to haemorrhage causing hypoperfusion, kidney injury associated with anticoagulant use
General disorders
PyrexiaA, peripheral oedema, general deterioration in health and reduced activity (including fatigue and asthenia)	Malaise (including feeling unwell)	Localized oedemaA
Investigations
	Elevated lactate dehydrogenase (LDH) levelsA, elevated lipase levelsA, elevated amylase levelsA
Injury, poisoning and procedural complications
Post-procedural haemorrhage (including postoperative anaemia and wound bleeding), bruising, wound secretionA		Vascular pseudoaneurysmC

A Observed during VTE prophylaxis in adult patients undergoing elective hip or knee replacement surgery.

B Observed very commonly during treatment of DVT, PE, and prevention of recurrent events in women under 55 years of age.

C Reported as uncommon when used for prevention of atherothrombotic events in patients who have had ACS (after PCI).

* A predefined, selective approach to collecting adverse reaction data was applied in certain phase III studies. The frequency of adverse reactions did not increase, and no new adverse reactions were identified following analysis of these studies.

Description of selected adverse reactions

Due to the pharmacological mechanism of action of rivaroxaban, the use of Xarelto® may be associated with an increased risk of internal or external bleeding in any tissues and organs, which may lead to post-hemorrhagic anemia. The symptoms and severity (including fatal outcomes) depend on the location and extent of bleeding and/or anemia (see section "Overdose. Management of bleeding"). During clinical trials, mucosal bleeding (e.g., epistaxis, gingival bleeding, gastrointestinal bleeding, genitourinary bleeding, including abnormal vaginal bleeding or increased menstrual bleeding) and anemia occurred more frequently with long-term rivaroxaban treatment compared to vitamin K antagonists. Therefore, in addition to appropriate clinical monitoring, laboratory monitoring of hemoglobin/hematocrit levels should be considered in appropriate cases to detect occult bleeding and assess the clinical significance of overt bleeding. The risk of bleeding may be higher in certain patient groups, such as patients with uncontrolled severe arterial hypertension and/or those receiving concomitant medications affecting hemostasis (see section "Special precautions. Risk of bleeding"). Increased intensity and/or duration of menstrual bleeding may occur. Manifestations of hemorrhagic complications may include weakness, pallor, dizziness, headache, unexplained swelling, dyspnea, or shock of unknown origin. In some cases, symptoms of myocardial ischemia such as chest pain or angina were observed as a consequence of anemia.

With the use of Xarelto®, secondary complications known to result from severe bleeding, such as compartment syndrome and renal failure due to hypoperfusion, or kidney damage associated with anticoagulant use, have been reported. Therefore, when evaluating patients receiving anticoagulants, the risk of bleeding should be carefully considered.

Reporting of suspected adverse reactions

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

Shelf life.

3 years.

Crushed tablets. Crushed rivaroxaban tablets are stable in water and apple puree for up to 4 hours.

Storage conditions.

Store at temperatures not exceeding 30 °C, in a place inaccessible to children.

Packaging.

14 tablets in a blister. 1 or 4 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Bayer AG.

Bayer HealthCare Manufacturing S.r.l.

Bayer Bitterfeld GmbH.

Manufacturer's location and address of business site.

Kaiser-Wilhelm-Allee, 51368, Leverkusen, Germany.

Via delle Groane, 126-20024, Garbagnate Milanese, Italy.

Ortsteil Gräppin, Seilgastertstraße 1, 06803 Bitterfeld-Wolfen, Germany.