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

Composition:

Active substance: rivaroxaban;

One film-coated tablet contains 15 mg of rivaroxaban;

One film-coated tablet contains 20 mg of rivaroxaban;

Excipients: microcrystalline cellulose, sodium croscarmellose, hypromellose 5 cP, hypromellose 15 cP, lactose monohydrate, magnesium stearate, sodium lauryl sulfate, macrogol 3350, titanium dioxide (E 171), iron oxide red (E 172).

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties:

15 mg film-coated tablets: red, round, biconvex tablets with a triangle and the number 15 on one side and a cross-shaped marking "BAYER" on the other;

20 mg film-coated tablets: red-brown, round, biconvex tablets with a triangle and the number 20 on one side and a cross-shaped marking "BAYER" on the other.

Pharmacotherapeutic group. Antithrombotic agents. ATC code B01AF01.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Rivaroxaban is a highly selective direct factor Xa inhibitor with sufficiently 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, dose-dependent inhibition of factor Xa activity has been observed. Using the Neoplastin test, rivaroxaban demonstrates a dose-dependent effect on prothrombin time that strongly correlates with plasma concentrations (r=0.98). Results may vary when other tests/kits are used. Instrument readings should be recorded in seconds, as the INR (International Normalized Ratio) is calibrated and validated only for coumarins and cannot be used for other anticoagulants.

In patients receiving rivaroxaban for the treatment of DVT (deep vein thrombosis), PE (pulmonary embolism), and prevention of DVT and PE recurrence, the 5th/95th percentiles for prothrombin time (Neoplastin) 2–4 hours after tablet intake (i.e., at peak effect) range from 17 to 32 seconds for 15 mg tablets taken twice daily, and from 15 to 30 seconds for 20 mg tablets taken once daily. At minimum rivaroxaban concentration (8–16 hours after tablet intake), the 5th/95th percentiles for the 15 mg twice-daily dose range from 14 to 24 seconds, and for the 20 mg once-daily dose (18–30 hours after tablet intake) from 13 to 20 seconds.

In patients with non-valvular atrial fibrillation receiving rivaroxaban for stroke and systemic embolism prevention, the 5th/95th percentiles for prothrombin time (Neoplastin) 1–4 hours after tablet intake (i.e., at peak effect) range from 14 to 40 seconds in patients receiving 20 mg once daily, and from 10 to 50 seconds in patients with moderate renal impairment receiving 15 mg once daily. At minimum concentration (16–36 hours after tablet intake), the 5th/95th percentiles are 12 to 26 seconds in patients receiving 20 mg once daily and 12 to 26 seconds in patients with moderate renal impairment receiving 15 mg once daily.

In a clinical pharmacology study evaluating the reversal of rivaroxaban pharmacodynamics in healthy adult volunteers (n=22), the effect of single doses (50 IU/kg) of two types of prothrombin complex concentrates (PCC) was assessed: 3-factor PCC (factors II, IX, and X) and 4-factor PCC (factors II, VII, IX, and X). With 3-factor PCC, mean PT (prothrombin time) (Neoplastin) decreased by approximately 1.0 second at 30 minutes, while with 4-factor PCC the decrease was about 3.5 seconds. However, 3-factor PCC had a more potent and rapid 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 rivaroxaban's pharmacodynamic effects. Routine monitoring of coagulation parameters is not required during rivaroxaban therapy. However, if clinically necessary, rivaroxaban levels can be measured using calibrated quantitative anti-factor Xa assays (see section "Pharmacokinetics").

Pediatric patients

PT (using the Neoplastin test), PCC, and anti-factor Xa assay (calibrated quantitative) show a close correlation with rivaroxaban plasma concentrations in children. The correlation between anti-Xa and plasma concentrations is linear with a slope close to 1. Individual discrepancies with higher or lower anti-Xa values compared to corresponding plasma concentrations may occur. Routine monitoring of coagulation parameters during clinical treatment with rivaroxaban is not necessary. However, if clinically indicated, rivaroxaban concentrations can be measured using calibrated quantitative anti-factor Xa assays in µg/L (see Table 10 in the "Pharmacokinetics" section for observed plasma concentration ranges of rivaroxaban in children). The lower limit of quantification should be considered when using the anti-Xa assay for quantitative assessment of rivaroxaban plasma concentration in children. Threshold values for efficacy or safety have not been established.

Clinical efficacy and safety

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

The clinical trial program for rivaroxaban was designed to demonstrate the efficacy of rivaroxaban in preventing stroke and systemic embolism in patients with non-valvular atrial fibrillation.

In the pivotal double-blind ROCKET AF trial, 14,264 patients were enrolled, with one group receiving rivaroxaban 20 mg once daily (patients with creatinine clearance 30–49 mL/min received 15 mg once daily) and the other group receiving warfarin titrated to a target INR of 2.5 (therapeutic range 2.0–3.0). The mean duration of treatment was 19 months, with the longest treatment duration up to 41 months. 34.9% of patients received concomitant acetylsalicylic acid therapy and 11.4% received class III antiarrhythmic agents, including amiodarone.

Rivaroxaban was non-inferior to warfarin in the primary composite endpoint (stroke and systemic embolism outside the central nervous system). Among patients treated per-protocol during the treatment period, 188 primary events (1.71% per year) occurred in the rivaroxaban group and 241 (2.16% per year) in the warfarin group (risk ratio [RR] 0.79; 95% confidence interval [CI], 0.66–0.96; p<0.001 for non-inferiority). Among all patients, primary events occurred in 269 patients taking rivaroxaban (2.12% per year) and 306 patients taking warfarin (2.42% per year) (RR 0.88; 95% CI, 0.74–1.03; p<0.001 for non-inferiority; p=0.117 for superiority). Results for secondary endpoints evaluated in hierarchical order during ITT analysis are presented in Table 1.

In the warfarin-treated group, the INR was within the therapeutic range (2.0–3.0) on average 55% of the time (median 58%; interquartile range: 43–71%). The efficacy of rivaroxaban did not differ according to the time in therapeutic range at the study center (time within target INR range 2.0–3.0) across equally sized quartiles (p=0.74 for interaction). Within the highest quartile based on center values, the risk ratio for rivaroxaban compared to warfarin was 0.74 (95% CI; 0.49–1.12).

The rate of the primary safety outcome (major and non-major clinically relevant bleeding) was similar in both treatment groups (see Table 2).

Table 1. Efficacy outcomes from the phase III ROCKET AF study

Study population	Efficacy analysis in patients with non-valvular atrial fibrillation, by assigned treatment
Therapeutic dose	Rivaroxaban 20 mg once daily (15 mg once daily in patients with moderate renal impairment) Event rate (per 100 patient-years)	Warfarin, titrated to a target INR of 2.5 (therapeutic range 2.0–3.0) Event rate (per 100 patient-years)	Relative risk (95% CI) p-value, superiority analysis
Stroke and systemic embolism outside the CNS	269 (2.12)	306 (2.42)	0.88 (0.74–1.03) 0.117
Stroke, systemic embolism outside the CNS, and vascular death	572 (4.51)	609 (4.81)	0.94 (0.84–1.05) 0.265
Stroke, systemic embolism outside the CNS, vascular death, and myocardial infarction	659 (5.24)	709 (5.65)	0.93 (0.83–1.03) 0.158
Stroke	253 (1.99)	281 (2.22)	0.90 (0.76–1.07) 0.221
Systemic embolism outside the CNS	20 (0.16)	27 (0.21)	0.74 (0.42–1.32) 0.308
Myocardial infarction	130 (1.02)	142 (1.11)	0.91 (0.72–1.16) 0.464

Table 2. Safety outcomes from the ROCKET AF phase III study

Study population	Patients with non-valvular atrial fibrillationa)
Therapeutic dose	Rivaroxaban 20 mg once daily (for patients with moderate renal impairment – 15 mg once daily) Event rate (per 100 patient-years)	Warfarin, titrated to a target INR of 2.5 (therapeutic range 2.0–3.0) Event rate (per 100 patient-years)	Relative risk (95% CI) p-value
Major and non-major clinically relevant bleeding	1,475 (14.91)	1,449 (14.52)	1.03 (0.96–1.11) 0.442
Major bleeding	395 (3.60)	386 (3.45)	1.04 (0.90–1.20) 0.576
Fatal bleeding*	27 (0.24)	55 (0.48)	0.50 (0.31–0.79) 0.003
Bleeding into critical organ*	91 (0.82)	133 (1.18)	0.69 (0.53–0.91) 0.007
Intracranial hemorrhage*	55 (0.49)	84 (0.74)	0.67 (0.47–0.93) 0.019
Hemoglobin decrease*	305 (2.77)	254 (2.26)	1.22 (1.03–1.44) 0.019
Transfusion of 2 or more units of packed red blood cells or whole blood*	183 (1.65)	149 (1.32)	1.25 (1.01–1.55) 0.044
Non-major clinically relevant bleeding	1,185 (11.80)	1,151 (11.37)	1.04 (0.96–1.13) 0.345
All-cause mortality	208 (1.87)	250 (2.21)	0.85 (0.70–1.02) 0.073

a) Safety population (on-treatment).

* Conditionally significant event.

In addition to the phase III ROCKET AF study, a prospective, non-interventional, post-marketing, open-label cohort study with centralized endpoint adjudication (XANTUS) was conducted, including thromboembolic events and major bleeding. To evaluate stroke prevention and systemic embolism outside the central nervous system (CNS) in real-world clinical practice, 6,704 patients with non-valvular atrial fibrillation were enrolled. In the XANTUS study, the mean CHADS2 stroke risk score was 1.9, and the mean HAS-BLED bleeding risk score was 2.0, compared to mean CHADS2 and HAS-BLED scores of 3.5 and 2.8, respectively, in the ROCKET AF study. Major bleeding occurred at a rate of 2.1 events per 100 patient-years. Fatal bleeding occurred at a rate of 0.2 events per 100 patient-years, and intracranial bleeding at a rate of 0.4 events per 100 patient-years. Stroke or systemic embolism (CNS) occurred at a rate of 0.8 events per 100 patient-years. These real-world observations are consistent with the established safety profile for this indication.

In a post-marketing, non-interventional study involving over 162,000 patients with non-valvular atrial fibrillation from four countries, rivaroxaban was used for stroke and systemic embolism prevention. The incidence of ischemic stroke was 0.70 (95% CI 0.44–1.13) per 100 patient-years. Bleeding events leading to hospitalization occurred at the following rates: 0.43 (95% CI 0.31–0.59) per 100 patient-years for intracranial bleeding, 1.04 (95% CI 0.65–1.66) for gastrointestinal bleeding, 0.41 (95% CI 0.31–0.53) for genitourinary bleeding, and 0.40 (95% CI 0.25–0.65) for other bleeding.

Patients undergoing cardioversion

A prospective, randomized, open-label, multicenter, endpoint-adjudicated study (X-VERT) was conducted in 1,504 patients (previously treated with oral anticoagulants or not previously anticoagulated) with non-valvular atrial fibrillation scheduled for cardioversion, comparing the efficacy of rivaroxaban versus dose-adjusted vitamin K antagonist (randomized 2:1) for prevention of cardiovascular complications.

Transesophageal echocardiography (TEE)-guided cardioversion (1–5 days of prior anticoagulation) or conventional cardioversion (at least three weeks of prior anticoagulation) was performed. The primary efficacy endpoint (composite of stroke, transient ischemic attack, systemic embolism outside the CNS, myocardial infarction, and cardiovascular death) occurred in 5 (0.5%) patients in the rivaroxaban group (n=978) and in 5 (1.0%) patients in the vitamin K antagonist group (n=492; relative risk 0.50; 95% CI 0.15–1.73; modified treatment-assigned population). Events related to the primary safety endpoint (major bleeding) occurred in 6 (0.6%) and 4 (0.8%) patients, respectively, in the rivaroxaban (n=988) and vitamin K antagonist (n=499) treatment groups (relative risk 0.76; 95% CI 0.21–2.67; safety-evaluable population). In this exploratory study, efficacy and safety were comparable between the rivaroxaban and vitamin K antagonist treatment groups during cardioversion.

Patients with non-valvular atrial fibrillation who underwent percutaneous coronary intervention (PCI) with stent placement

A randomized, open-label, multicenter study (PIONEER AF-PCI) was conducted in 2,124 patients with non-valvular atrial fibrillation who underwent PCI with stent placement due to primary atherosclerotic disease, to compare the safety of two rivaroxaban regimens with one vitamin K antagonist (VKA) regimen. Patients were randomized in a 1:1:1 ratio to treatment regimens with a total treatment duration of 12 months. Patients with a history of stroke or transient ischemic attack (TIA) were excluded.

Group 1 received rivaroxaban 15 mg once daily (10 mg once daily for patients with creatinine clearance 30–49 mL/min) in combination with a P2Y12 receptor inhibitor. Group 2 received rivaroxaban 2.5 mg twice daily in combination with dual antiplatelet therapy [DAPT; e.g., clopidogrel 75 mg (or alternative P2Y12 inhibitor) plus low-dose acetylsalicylic acid (ASA)] for 1, 6, or 12 months, followed by rivaroxaban 15 mg (or 10 mg for patients with creatinine clearance 30–49 mL/min) once daily in combination with low-dose ASA. Group 3 received individually adjusted-dose VKA in combination with DAPT for 1, 6, or 12 months, followed by individually adjusted-dose VKA in combination with low-dose ASA.

The primary safety endpoint—clinically significant bleeding—occurred in 109 (15.7%), 117 (16.6%), and 167 (24.0%) patients in Group 1, Group 2, and Group 3, respectively (RR 0.59; 95% CI 0.47–0.76; p<0.001 and RR 0.63; 95% CI 0.50–0.80; p<0.001, respectively). The secondary endpoint (composite of cardiovascular events, cardiovascular death, myocardial infarction, or stroke) occurred in 41 (5.9%), 36 (5.1%), and 36 (5.2%) patients in Group 1, Group 2, and Group 3, respectively. Each rivaroxaban regimen was associated with a significant reduction in the risk of clinically significant bleeding compared to the VKA regimen in patients with non-valvular atrial fibrillation who underwent PCI with stent placement.

The primary objective of the PIONEER AF-PCI study was to assess safety. Data on efficacy (including thromboembolic events) in this population are limited.

Treatment of DVT, PE, and prevention of recurrent DVT and PE

The rivaroxaban clinical trial program was designed to demonstrate the efficacy of rivaroxaban as a medicinal product for initial and long-term treatment of acute DVT and PE, and for prevention of their recurrence.

Over 12,800 patients were studied in four phase III randomized controlled clinical trials (EINSTEIN DVT, EINSTEIN PE, EINSTEIN Extension, and EINSTEIN CHOICE), with an additional pre-specified pooled analysis of the EINSTEIN DVT and EINSTEIN PE studies. The total duration of comprehensive treatment in all studies was up to 21 months.

In the EINSTEIN DVT study, 3,449 patients with acute DVT were enrolled to treat DVT and prevent recurrent DVT and PE (patients with clinical signs of PE were excluded from this study). Treatment duration was 3, 6, or 12 months, depending on the physician’s clinical assessment.

For the first 3 weeks of therapy, rivaroxaban 15 mg twice daily was administered for DVT treatment. After this period, patients received rivaroxaban 20 mg once daily.

In the EINSTEIN PE study, 4,832 patients with acute PE were enrolled to treat PE and prevent recurrence of DVT and PE. Treatment duration was 3, 6, or 12 months, depending on the physician’s clinical assessment.

For initial treatment of acute PE, rivaroxaban 15 mg twice daily was administered for three weeks, followed by rivaroxaban 20 mg once daily.

In both the EINSTEIN DVT and EINSTEIN PE studies, the comparator regimen consisted of enoxaparin therapy for at least 5 days in combination with a vitamin K antagonist until the INR/PT ratio reached a therapeutic range (≥2.0). Subsequently, treatment continued with a vitamin K antagonist at a dose required to maintain the INR/PT ratio within the therapeutic range of 2.0–3.0.

The EINSTEIN Extension study included 1,197 patients with DVT or PE to prevent recurrence of DVT and PE. Additional treatment duration was 6 or 12 months for patients who completed a 6- or 12-month course of venous thromboembolism therapy, depending on the physician’s clinical assessment. Rivaroxaban 20 mg once daily was compared with placebo.

In the EINSTEIN DVT, EINSTEIN PE, and EINSTEIN Extension studies, identical pre-specified primary and secondary efficacy endpoints were used. The primary efficacy endpoint was recurrent VTE (venous thromboembolism), clinically manifest, defined as the composite of recurrent DVT or fatal or non-fatal PE.

The secondary efficacy endpoint was defined as the composite of recurrent DVT, non-fatal PE, and all-cause mortality.

The EINSTEIN CHOICE study included 3,396 patients with confirmed symptomatic DVT and/or PE to prevent fatal PE or non-fatal symptomatic recurrent DVT or PE, who had completed 6–12 months of anticoagulant therapy. Patients with an indication for long-term therapeutic-dose anticoagulation were excluded. Treatment duration was up to 12 months depending on individual randomization date (median: 351 days). Rivaroxaban 20 mg once daily and 10 mg once daily were compared with 100 mg acetylsalicylic acid once daily.

The primary efficacy endpoint was symptomatic recurrent VTE, defined as the composite of recurrent DVT or fatal or non-fatal PE.

In the EINSTEIN DVT study (see Table 3), rivaroxaban demonstrated non-inferior efficacy compared to enoxaparin/vitamin K antagonist for the primary efficacy endpoint (p<0.0001) (non-inferiority criterion); risk ratio: 0.680 (0.443–1.042), p=0.076 (superiority criterion). The risk ratio for pre-specified net clinical benefit (primary efficacy endpoint plus major bleeding) was 0.67 [(95% CI: 0.47–0.95), nominal p=0.024] in favor of rivaroxaban. INR values were within the therapeutic range on average 60.3% of the time over a mean treatment duration of 189 days, and 55.4%, 60.1%, and 62.8% of the time in the groups with planned treatment durations of 3, 6, and 12 months, respectively. In the enoxaparin/vitamin K antagonist group, there was no clear relationship between the center-level average time in therapeutic range (TTR) (time maintaining target INR range 2.0–3.0) in equal-sized tertiles and the rate of recurrent VTE (p=0.932 for interaction). Within the highest tertile by center, the risk ratio for rivaroxaban versus warfarin was 0.69 (95% CI: 0.35–1.35).

The incidence of the primary safety endpoint (major or clinically significant non-major bleeding) and the secondary safety endpoint (major bleeding) was similar in both treatment groups.

Table 3. Efficacy and safety outcomes from the phase III EINSTEIN DVT study

Study population	3,449 patients with symptomatic acute deep vein thrombosis
Treatment doses and duration	Rivaroxaban 3, 6 or 12 months N=1,731	Enoxaparin/vitamin K antagonistb 3, 6 or 12 months N=1,718
Symptomatic recurrent VTE*	36 (2.1%)	51 (3.0%)
Symptomatic recurrent PE	20 (1.2%)	18 (1.0%)
Symptomatic recurrent DVT	14 (0.8%)	28 (1.6%)
Symptomatic PE and DVT	1 (0.1%)	0
Fatal PE/deaths where PE could not be excluded	4 (0.2%)	6 (0.3%)
Major or clinically relevant non-major bleeding	139 (8.1%)	138 (8.1%)
Major bleeding	14 (0.8%)	20 (1.2%)

a Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily.

b Enoxaparin for at least 5 days, followed by a vitamin K antagonist, the administration of which is initiated during enoxaparin treatment.

* p < 0.0001 (non-inferior efficacy according to pre-specified risk ratio margin of 2.0); risk ratio: 0.680 (0.443–1.042), p = 0.076 ("superiority").

In the EINSTEIN PE study (see Table 4), rivaroxaban demonstrated non-inferior efficacy compared to enoxaparin/vitamin K antagonist for the primary efficacy outcome (p = 0.0026 (non-inferiority criterion); risk ratio: 1.123 (0.749–1.684)). The risk ratio for pre-specified net clinical benefit (primary efficacy outcome plus major bleeding) was 0.849 [(95% CI: 0.633–1.139), nominal p = 0.0275]. INR values were within the therapeutic range on average 63% of the time over a median treatment duration of 215 days, and 57%, 62%, and 65% of the time in groups with planned treatment durations of 3, 6, and 12 months, respectively. In the enoxaparin/vitamin K antagonist group, there was no clear relationship between the mean TTR (time in therapeutic range of INR 2.0–3.0) at center level across equally sized tertiles and the rate of recurrent VTE (p = 0.082 for interaction). Within the highest tertile according to center, the risk ratio for rivaroxaban compared to warfarin was 0.642 (95% CI: 0.277–1.484).

The incidence of the principal safety outcome (major or clinically relevant non-major bleeding) was slightly lower in the rivaroxaban group (10.3% (249/2412)) than in the enoxaparin/vitamin K antagonist group [11.4% (274/2405)]. The incidence of the secondary safety outcome (major bleeding) was lower in the rivaroxaban group [1.1% (26/2412)] compared to the enoxaparin/vitamin K antagonist group [2.2% (52/2405)], with a risk ratio of 0.493 (95% CI: 0.308–0.789).

Table 4. Efficacy and safety outcomes from the phase III EINSTEIN PE study

Study population	4,832 patients with acute symptomatic PE
Treatment doses and duration	Rivaroxaban 3, 6 or 12 months N = 2419	Enoxaparin/vitamin K antagonistb 3, 6 or 12 months N = 2413
Symptomatic recurrent VTE*	50 (2.1%)	44 (1.8%)
Symptomatic recurrent PE	23 (1.0%)	20 (0.8%)
Symptomatic recurrent DVT	18 (0.7%)	17 (0.7%)
Symptomatic PE and DVT	0	2 (<0.1%)
Fatal PE/death from PE not ruled out	11 (0.5%)	7 (0.3%)
Major or clinically relevant non-major bleeding	249 (10.3%)	274 (11.4%)
Major bleeding	26 (1.1%)	52 (2.2%)

and Rivaroxaban 15 mg twice daily for 3 weeks, followed by 20 mg once daily.

b Enoxaparin for at least 5 days, with transition to a vitamin K antagonist initiated during enoxaparin treatment.

* p < 0.0026 (non-inferiority based on a pre-specified risk ratio margin of 2.0); risk ratio: 1.123 (0.749–1.684).

A pooled analysis of the EINSTEIN DVT and PE studies was performed based on pre-specified parameters (see Table 5).

Table 5. Efficacy and safety outcomes from the pooled analysis of phase III EINSTEIN DVT and EINSTEIN PE studies

Study population	8,281 patients with acute symptomatic DVT or PE
Treatment doses and duration	Rivaroxaban 3, 6 or 12 months N = 4150	Enoxaparin/vitamin K antagonistb 3, 6 or 12 months N = 4131
Symptomatic recurrent VTE*	86 (2.1%)	95 (2.3%)
Symptomatic recurrent PE	43 (1.0%)	38 (0.9%)
Symptomatic recurrent DVT	32 (0.8%)	45 (1.1%)
Symptomatic PE and DVT	1 (<0.1%)	2 (<0.1%)
Fatal PE/mortality cases where PE could not be excluded	15 (0.4%)	13 (0.3%)
Major or clinically relevant non-major bleeding	388 (9.4%)	412 (10.0%)
Major bleeding	40 (1.0%)	72 (1.7%)

and Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily.

b Enoxaparin for at least 5 days, followed by a vitamin K antagonist, the administration of which is initiated during enoxaparin treatment.

* p < 0.0001 (non-inferior efficacy based on the pre-specified risk ratio of 1.75); risk ratio: 0.886 (0.661–1.186).

The risk ratio for the pre-specified net clinical benefit (primary efficacy outcome plus major bleeding) based on pooled analysis was 0.771 [(95% CI: 0.614–0.967), nominal p = 0.0244].

In the EINSTEIN Extension study (see Table 6), rivaroxaban demonstrated superiority over placebo with respect to primary and secondary efficacy outcomes. The incidence of the main safety outcome (major bleeding) in patients receiving rivaroxaban 20 mg once daily was numerically slightly higher than in patients receiving placebo. The incidence of the secondary safety outcome (major or clinically relevant non-major bleeding) was higher in patients receiving rivaroxaban 20 mg once daily compared to those receiving placebo.

Table 6. Efficacy and safety outcomes from the phase III EINSTEIN Extension study

Study population	1197 patients with ongoing treatment or prevention of recurrence of venous thromboembolism
Treatment doses and duration	Rivaroxaban 6 or 12 months N = 602	Placebo 6 or 12 months N = 594
Symptomatic recurrent VTE*	8 (1.3%)	42 (7.1%)
Symptomatic recurrent PE	2 (0.3%)	13 (2.2%)
Symptomatic recurrent DVT	5 (0.8%)	31 (5.2%)
Fatal PE/Deaths where PE cannot be excluded	1 (0.2%)	1 (0.2%)
Major bleeding	4 (0.7%)	0 (0.0%)
Clinically relevant non-major bleeding	32 (5.4%)	7 (1.2%)

and rivaroxaban 20 mg once daily.

* p < 0.0001 ("exceeded"); risk ratio: 0.185 (0.087–0.393).

In the EINSTEIN CHOICE study (see Table 7), rivaroxaban at doses of 20 mg and 10 mg demonstrated superiority over acetylsalicylic acid 100 mg with respect to primary and secondary efficacy outcomes. The main safety outcome (major bleeding) was similar in patients receiving rivaroxaban 20 mg or 10 mg compared to acetylsalicylic acid 100 mg.

Table 7. Efficacy and safety outcomes from the phase III EINSTEIN CHOICE study

Study population	3396 patients with long-term prevention of recurrent VTE
Treatment regimens	Rivaroxaban 20 mg once daily N = 1107	Rivaroxaban 10 mg once daily N = 1127	ASA 100 mg once daily N = 1131
Median duration of therapy [interquartile range]	349 [189–362] days	353 [190–362] days	350 [186–362] days
Symptomatic recurrent VTE*	17 (1.5 %)*	13 (1.2 %)**	50 (4.4 %)
Symptomatic recurrent PE	6 (0.5 %)	6 (0.5 %)	19 (1.7 %)
Symptomatic recurrent DVT	9 (0.8 %)	8 (0.7 %)	30 (2.7 %)
Fatal PE/deaths where PE could not be excluded	2 (0.2%)	0	2 (0.2%)
Symptomatic recurrent VTE, myocardial infarction, stroke, or systemic embolism outside the CNS	19 (1.7 %)	18 (1.6 %)	56 (5.0 %)
Major bleeding	6 (0.5 %)	5 (0.4 %)	3 (0.3 %)
Clinically relevant non-major bleeding	30 (2.7%)	22 (2.0%)	20 (1.8%)
Symptomatic recurrent VTE or major bleeding (net clinical benefit)	23 (2.1 %)+	17 (1.5 %)++	53 (4.7 %)

*p < 0.0001 (superiority of) rivaroxaban 20 mg once daily compared to aspirin 100 mg once daily; risk ratio = 0.34 (0.20–0.59).

**p < 0.0001 (superiority of) rivaroxaban 10 mg once daily compared to aspirin 100 mg once daily; risk ratio = 0.26 (0.14–0.47).

• Rivaroxaban 20 mg once daily compared to aspirin 100 mg once daily; risk ratio = 0.44 (0.27–0.71), p = 0.0009 (nominal).

++ Rivaroxaban 10 mg once daily compared to aspirin 100 mg once daily; risk ratio = 0.32 (0.18–0.55), p < 0.0001 (nominal).

In addition to the phase III EINSTEIN program studies, a prospective, non-interventional, open-label cohort study (XALIA) with centralized endpoint adjudication, including recurrent VTE, major bleeding, and fatal events, was conducted. To evaluate the safety of long-term rivaroxaban use in clinical practice compared to conventional anticoagulant therapy, 5,142 patients with acute DVT were enrolled in the study. In the rivaroxaban group, the incidence of major bleeding was 0.7%, recurrent VTE was 1.4%, and all-cause mortality was 0.5%. Baseline patient characteristics differed, including age, cancer, and renal impairment. A pre-specified propensity score stratified analysis was applied to adjust for baseline differences; however, residual bias may still influence the results. When rivaroxaban was compared with conventional therapy, the adjusted risk ratios for major bleeding, recurrent VTE, and all-cause mortality were 0.77 (95% CI 0.40–1.50), 0.91 (95% CI 0.54–1.54), and 0.51 (95% CI 0.24–1.07), respectively. These real-world results are consistent with the established safety profile for this indication.

In a post-marketing, non-interventional study involving over 40,000 patients without a history of cancer from four countries, rivaroxaban was prescribed for the treatment or prevention of DVT and PE. The event rate per 100 patient-years for symptomatic/clinically evident VTE/thromboembolic events leading to hospitalization ranged from 0.64 (95% CI 0.40–0.97) in the United Kingdom to 2.30 (95% CI 2.11–2.51) in Germany. Bleeding events leading to hospitalization occurred at a rate of 0.31 (95% CI 0.23–0.42) per 100 patient-years for intracranial bleeding, 0.89 (95% CI 0.67–1.17) for gastrointestinal bleeding, 0.44 (95% CI 0.26–0.74) for urogenital bleeding, and 0.41 (95% CI 0.31–0.54) for other bleeding events.

Treatment of DVT and prevention of recurrent DVT in pediatric patients

Overall, 727 children with confirmed acute VTE, of whom 528 received rivaroxaban, were studied in six open-label, multicenter pediatric trials. Weight-based dosing in patients from birth to 18 years of age resulted in rivaroxaban exposure similar to that observed in adult patients with DVT receiving rivaroxaban 20 mg once daily, as confirmed in a phase III study (see section "Pharmacokinetics").

The phase III EINSTEIN Junior study was a randomized, active-controlled, open-label, multicenter clinical trial involving 500 pediatric patients (from birth to <18 years of age) with confirmed acute VTE. The study included 276 children aged 12 to <18 years, 101 children aged 6 to <12 years, 69 children aged 2 to <6 years, and 54 children aged <2 years.

VTE events were classified as: catheter-related VTE (CR-VTE; 90/335 patients in the rivaroxaban group, 37/165 in the comparator group); cerebral venous sinus thrombosis (CVST; 74/335 patients in the rivaroxaban group, 43/165 in the comparator group); and all others, including DVT and PE (non-CR-VTE; 171/335 in the rivaroxaban group, 85/165 in the comparator group). The most common presentation of thrombosis was non-CR-VTE in 211 (76.4%) children aged 12 to <18 years; CVST in 48 (47.5%) and 35 (50.7%) children aged 6 to <12 years and 2 to <6 years, respectively; and CR-VTE in 37 (68.5%) children aged <2 years. No children under 6 months of age with CVST were included in the rivaroxaban group. CNS infection was present in 22 patients with CVST (13 in the rivaroxaban group and 9 in the comparator group).

In 438 (87.6%) children, VTE was provoked by persistent, transient, or both persistent and transient risk factors.

Patients received initial treatment with therapeutic doses of unfractionated heparin (UFH), low molecular weight heparin (LMWH), or fondaparinux for at least 5 days and were then randomized in a 2:1 ratio to receive either weight-adjusted rivaroxaban or to the comparator group (receiving heparins or vitamin K antagonists) for 3 months during the main treatment period of the study (1 month for children <2 years with CR-VTE). At the end of the main treatment period, diagnostic imaging performed at study enrollment was repeated if clinically feasible. Investigational treatment could be discontinued at this point or, at the investigator’s discretion, continued for up to 12 months (up to 3 months for children <2 years with CR-VTE).

The primary efficacy outcome was symptomatic recurrent VTE. The primary safety outcome was the composite of major bleeding and clinically relevant non-major bleeding (CRNMB). All efficacy and safety outcomes were centrally adjudicated by an independent, treatment-blinded committee. Efficacy and safety results are presented in Tables 1 and 2 below.

Recurrent VTE occurred in 4 of 335 patients in the rivaroxaban group and in 5 of 165 patients in the comparator group. The composite of major bleeding and CRNMB was observed in 10 of 329 patients (3%) receiving rivaroxaban and in 3 of 162 patients (1.9%) receiving the comparator drug. Events comprising the net clinical benefit endpoint (composite of symptomatic recurrent VTE and major bleeding) were recorded in 4 of 335 patients in the rivaroxaban group and in 7 of 165 patients in the comparator group. Thrombus recanalization, classified as "normalization" on repeat imaging, was observed in 128 of 335 patients receiving rivaroxaban and in 43 of 165 patients in the comparator group. These results were generally consistent across age groups. During treatment, any bleeding occurred in 119 (36.2%) children in the rivaroxaban group and in 45 (27.8%) children in the comparator group.

Table 8. Efficacy results at the end of the main treatment period

Phenomenon	Rivaroxaban N=335*	Comparator drug N=165*
Recurrent VTE (primary efficacy outcome)	4 (1.2%; 95% CI 0.4% – 3.0%)	5 (3.0%; 95% CI 1.2% – 6.6%)
Composite of symptomatic recurrent VTE + asymptomatic worsening on repeat imaging	5 (1.5%; 95% CI 0.6% – 3.4%)	6 (3.6%; 95% CI 1.6% – 7.6%)
Composite of symptomatic recurrent VTE + asymptomatic worsening + no improvement on repeat imaging	21 (6.3%; 95% CI 4.0% – 9.2%)	19 (11.5%; 95% CI 7.3% – 17.4%)
Normalization on repeat imaging	128 (38.2%; 95% CI 33.0% – 43.5%)	43 (26.1%; 95% CI 19.8% – 33.0%)
Composite of symptomatic recurrent VTE + major bleeding (net clinical benefit)	4 (1.2%; 95% CI 0.4% – 3.0%)	7 (4.2%; 95% CI 2.0% – 8.4%)
Fatal or non-fatal pulmonary embolism	1 (0.3%; 95% CI 0.0% – 1.6%)	1 (0.6%; 95% CI 0.0% – 3.1%)

* Full analysis set, all children who were randomized.

Table 9. Safety results at the end of the main treatment period

	Rivaroxaban N=329*	Comparator drug N=162*
Composite of major bleeding + CRNM bleeding (primary safety endpoint)	10 (3.0%; 95% CI 1.6% - 5.5%)	3 (1.9%; 95% CI 0.5% - 5.3%)
Major bleeding	0 (0.0%; 95% CI 0.0% - 1.1%)	2 (1.2%; 95% CI 0.2% - 4.3%)
Any treatment-emergent bleeding	119 (36.2%)	45 (27.8%)

* Safety population, all children who were randomized and received at least one dose of the investigational medicinal product.

The efficacy and safety profile of rivaroxaban was largely similar between the pediatric VTE population and the adult VTE/PE population; however, the proportion of subjects with any bleeding was higher in the pediatric VTE population compared to the adult DVT/PE population.

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 for 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 receive 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 requirement to submit results of studies on the use of Xarelto® in all subgroups of the pediatric population for the treatment of thromboembolic complications. For information on use in pediatric patients, see section "Pediatric use".

Pharmacokinetics

Absorption

The following information is based on data obtained in adults.

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

Absolute bioavailability of rivaroxaban after administration is high, ranging from 80–100% for 2.5 mg and 10 mg tablets, independent of food intake. Food intake does not affect AUC (area under the concentration-time curve) or Cmax of rivaroxaban at doses of 2.5 mg and 10 mg.

When administered in the fasting state, a bioavailability of 66% was determined for 20 mg rivaroxaban tablets due to reduced absorption. When the 20 mg dose of rivaroxaban was administered with food, the mean AUC increased by 39% compared to administration in the fasting state, indicating nearly complete absorption and high bioavailability after oral intake. Rivaroxaban 15 mg and 20 mg should be taken with food (see section "Dosage and administration").

Pharmacokinetics of rivaroxaban are approximately linear when administered at doses up to 15 mg once daily in the fasting state. When administered with food, the pharmacokinetics of 15 mg and 20 mg rivaroxaban tablets are dose-proportional. At higher doses, absorption of rivaroxaban is limited by solubility, resulting in reduced bioavailability and absorption extent.

Rivaroxaban pharmacokinetics are characterized by moderate variability; individual variability (coefficient of variation) ranges from 30% to 40%.

Absorption of rivaroxaban depends on the site of drug release in the gastrointestinal tract. A 29% and 56% reduction in AUC and Cmax, respectively, was observed when administering rivaroxaban granules with drug release in the proximal small intestine compared to the tablet formulation. Exposure is further reduced when active substance is released in the distal small intestine or ascending colon. Administration of rivaroxaban distal to the stomach should be avoided, as it may lead to reduced absorption and consequently reduced exposure.

Bioavailability (AUC and Cmax) of 20 mg rivaroxaban administered orally as crushed tablets mixed with apple puree or water, administered via a gastric tube immediately after a liquid meal, was comparable to that of intact tablets. Given the expected dose-proportional pharmacokinetic profile of rivaroxaban, the results of this bioavailability study are likely applicable to lower doses of rivaroxaban as well.

Pediatric patients

Children received rivaroxaban tablets or oral suspension during or immediately after feeding or food intake, together with a typical volume of liquid to ensure reliable dosing. As in adults, rivaroxaban is readily absorbed after oral administration as tablets or granules for oral suspension in children. No differences in rate or extent of absorption were observed between the tablet and granules for oral suspension. There are no pharmacokinetic (PK) data after intravenous administration in children; therefore, absolute bioavailability of rivaroxaban in children is unknown. A decrease in relative bioavailability with increasing dose (mg/kg body weight) was observed, indicating absorption limitation at higher doses, even when administered with food.

Rivaroxaban 15 mg and 20 mg tablets should be taken with food or during feeding (see section "Dosage and administration").

Distribution

Plasma protein binding in adults is high, approximately 92–95%, with albumin being the main binding component. The volume of distribution is moderate, with a steady-state volume of distribution (Vss) of approximately 50 L.

Pediatric patients

In vitro data do not indicate significant differences in plasma protein binding of rivaroxaban in children across different age groups compared to adults. There are no PK data after intravenous administration of rivaroxaban in children. Vss, estimated by population pharmacokinetic modeling in children (age range 0 to < 18 years) after oral administration of rivaroxaban, is body-weight dependent and can be described by an allometric function, with a mean value of 113 L for a subject weighing 82.8 kg.

Metabolism and elimination

In adults, approximately two-thirds of the administered dose of rivaroxaban is metabolized, with half of the metabolites excreted renally and the other half via feces. The remainder (one-third) of the administered dose is excreted unchanged in urine, primarily through active renal secretion.

Metabolism of rivaroxaban is mediated by CYP3A4, CYP2J2 isoenzymes, and cytochrome CYP-independent mechanisms. The main sites of biotransformation are the morpholine group, which undergoes oxidative degradation, and amide groups, which undergo hydrolysis. Based on in vitro data, rivaroxaban is a substrate of the transporter proteins P-gp (P-glycoprotein) and Bcrp (breast cancer resistance protein).

The major compound in human plasma is unchanged rivaroxaban; significant or active circulating metabolites have not been identified. Rivaroxaban, with a systemic clearance of approximately 10 L/h, is considered a drug with low clearance. After intravenous administration of a 1 mg dose, the elimination half-life is approximately 4.5 hours. After oral administration, elimination is absorption rate-limited. The terminal half-life of rivaroxaban in plasma ranges from 5 to 9 hours in young patients and from 11 to 13 hours in elderly patients.

Pediatric patients

Data on metabolism specific to children are lacking. There are no pharmacokinetic data after intravenous administration of rivaroxaban in children. Clearance, estimated by population pharmacokinetic modeling in children (age range 0 to < 18 years) after oral administration of rivaroxaban, is body-weight dependent and can be described by an allometric function, with a mean value of 8 L/h for a subject weighing 82.8 kg. Mean geometric elimination half-life (t1/2) values, estimated by population pharmacokinetic modeling, decrease with decreasing age, ranging from 4.2 hours in adolescents to approximately 3 hours in children aged 2 to 12 years, and to 1.9 and 1.6 hours in children aged 0.5 to < 2 years and < 0.5 years, respectively.

Special patient groups

Gender. In adults, clinically significant differences in pharmacokinetics between males and females were not observed (see section "Dosage and administration").

A post hoc analysis did not reveal relevant differences in rivaroxaban exposure between male and female pediatric patients.

Elderly patients. In elderly patients, plasma concentrations of rivaroxaban are higher than in younger patients; the mean AUC is approximately 1.5 times higher than in younger patients, primarily due to reduced total and renal clearance. Dose adjustment is not required.

Body weight categories. In adults, body weight that is too low or too high (less than 50 kg or more than 120 kg) has only a minor effect on plasma concentrations of rivaroxaban (less than 25%). Dose adjustment is not required.

In pediatric patients, rivaroxaban is dosed according to body weight. A post hoc analysis in children did not reveal a relevant impact of underweight or obesity on rivaroxaban exposure.

Ethnic differences. In adults, clinically significant differences in pharmacokinetics (PK) and pharmacodynamics (PD) were not observed among patients of Caucasian, African American, Latino, Japanese, or Chinese ethnic origin.

A post hoc analysis did not reveal relevant ethnic differences in rivaroxaban exposure among Japanese, Chinese, or Asian pediatric patients outside Japan and China compared to the overall pediatric population.

Hepatic impairment. In adult patients with liver cirrhosis and mild hepatic impairment (Child-Pugh class A), the pharmacokinetics of rivaroxaban differed only slightly (mean 1.2-fold increase in AUC) from those in healthy control 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 2.6-fold. These patients also showed reduced urinary excretion of rivaroxaban, similar to that observed in patients with moderate renal impairment. There are no data in patients with severe hepatic impairment.

Factor Xa inhibition was more pronounced (2.6-fold difference) in patients with moderate hepatic impairment compared to healthy volunteers; aPTT was also prolonged (2.1-fold). Patients with moderate hepatic impairment were more sensitive to rivaroxaban, resulting in a steeper pharmacokinetic/pharmacodynamic (PK/PD) concentration-aPTT relationship.

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").

There are no clinical data in pediatric patients with hepatic impairment.

Renal impairment. In adults, exposure to rivaroxaban increased inversely proportional to the degree of renal function decline, as measured by creatinine clearance. In patients 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-fold higher, respectively, compared to healthy volunteers. Correspondingly, pharmacodynamic effects were increased. In patients with mild, moderate, or severe renal impairment, overall inhibition of factor Xa activity was 1.5-, 1.9-, and 2-fold higher, respectively, compared to healthy volunteers; aPTT was similarly prolonged by 1.3-, 2.2-, and 2.4-fold, respectively. Data in patients with creatinine clearance < 15 mL/min are lacking.

Due to high plasma protein binding, rivaroxaban is not expected to be eliminated by dialysis.

The use of rivaroxaban is not recommended in patients with creatinine clearance < 15 mL/min. Rivaroxaban should be used with caution in patients with creatinine clearance of 15–29 mL/min (see section "Special warnings and precautions for use").

There are no clinical data on use in children aged 1 year and older with moderate or severe renal impairment (glomerular filtration rate < 50 mL/min/1.73 m²).

Pharmacokinetic data observed in patients. In patients receiving rivaroxaban 20 mg once daily for VTE prophylaxis, the mean geometric concentration (90% prediction interval) 2–4 hours and approximately 24 hours after administration (time points approximately reflecting peak and trough concentrations between doses) was 215 (22–535) and 32 (6–239) µg/L, respectively.

In pediatric patients with acute VTE receiving rivaroxaban (at a body weight-adjusted dose resulting in exposure similar to that in adult patients with DVT receiving 20 mg once daily), mean geometric concentrations (90% interval) at sampling times approximately reflecting peak and trough concentrations between doses are summarized in Table 3.

Table 10. Summary statistics (geometric mean (90% interval)) of steady-state plasma concentrations of rivaroxaban (µg/L) by dosing regimen and age

Time intervals
Once daily	N	12 -< 18 years	N	6 -< 12 years
2.5–4 hours after	171	241.5 (105–484)	24	229.7 (91.5–777)
20–24 hours after	151	20.6 (5.69–66.5)	24	15.9 (3.42–45.5)
Twice daily	N	6 -< 12 years	N	2 -< 6 years	N	0.5 -< 2 years
2.5–4 hours after	36	145.4 (46.0–343)	38	171.8 (70.7–438)	2	n.r.
10–16 hours after	33	26.0 (7.99–94.9)	37	22.2 (0.25–127)	3	10.7 (n.r.–n.r.)
Three times daily	N	2 -< 6 years	N	birth -< 2 years	N	0.5 -< 2 years	N	birth -< 0.5 years
0.5–3 hours after	5	164.7 (108–283)	25	111.2 (22.9–320)	13	114.3 (22.9–346)	12	108.0 (19.2–320)
7–8 hours after	5	33.2 (18.7–99.7)	23	18.7 (10.1–36.5)	12	21.4 (10.5–65.6)	11	16.1 (1.03–33.6)
n.r. = not calculated Values below the lower limit of quantification (LLOQ) were replaced with ½ LLOQ for statistical calculations (LLOQ = 0.5 µg/L).

Pharmacokinetic/pharmacodynamic relationships. The pharmacokinetic/pharmacodynamic (PK/PD) relationship between rivaroxaban plasma concentration and several pharmacodynamic endpoints (factor Xa inhibition, PT, aPTT, HepTest) was evaluated across a wide dose range (5–30 mg twice daily). The relationship between rivaroxaban concentration and factor Xa activity was best described by an Emax model. For PT, the most reliable data were obtained using a linear segmented regression model. Depending on the different reagents used for PT determination, the slope coefficient may vary substantially. When Neoplastin reagent was used for PT measurement, the baseline PT was approximately 13 seconds, and the slope coefficient ranged from 3 to 4 seconds per (100 μg/L). PK/PD analyses from phase II and III studies were consistent with data obtained in healthy volunteers.

Paediatric population. The efficacy and safety of the medicinal product for the prevention of stroke and systemic embolism in paediatric patients under 18 years of age with non-valvular atrial fibrillation have not been studied.

Preclinical safety data

Available preclinical data from traditional studies of pharmacological safety, single-dose toxicity, phototoxicity, genotoxicity, carcinogenic potential, and reproductive toxicity indicate no specific risk to humans.

In repeated-dose toxicity studies, observed effects were primarily related to the exaggerated pharmacodynamic action of rivaroxaban. No effects on fertility were observed in male and female rats. Reproductive toxicity related to the pharmacological mechanism of action of rivaroxaban (haemorrhagic complications) was observed in animal studies.

A study of rivaroxaban in young rats treated for 3 months starting from postnatal day 4 showed a dose-independent increase in the frequency of peri-insular haemorrhages. There was no evidence of target organ toxicity.

Clinical characteristics.

Indications.

Adults

Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation and one or more risk factors such as congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, or prior stroke or transient ischemic attack.

Treatment of deep vein thrombosis (DVT), pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults (see section "Special precautions" regarding patients with PE who have unstable hemodynamic parameters).

Children

Treatment of venous thromboembolism (VTE) and prevention of recurrent VTE in children under 18 years of age and with body weight between 30 and 50 kg, following at least 5 days of initial parenteral anticoagulant therapy.

Contraindications.

• Hypersensitivity to rivaroxaban or to any of the excipients of the medicinal product.
• Clinically significant active bleeding.
• Conditions associated with a high risk of bleeding, including current or recent gastrointestinal ulcers, malignant tumors with a high risk of bleeding, recent head or spinal trauma, recent surgery on the brain, spinal cord or eyes, recent intracranial hemorrhage, esophageal varices (confirmed or suspected), arteriovenous malformations, aneurysms, or significant intraspinal or intracerebral vascular anomalies.
• Concomitant use with any other anticoagulants, including unfractionated heparin, low-molecular-weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, dabigatran etexilate, apixaban, etc.), except under specific circumstances of transition to alternative anticoagulant therapy (see section "Dosage and administration") or cases where unfractionated heparin is administered at doses required to maintain patency of a central venous or arterial catheter (see section "Interaction with other medicinal products and other forms of interaction").
• Liver disease associated with coagulopathy and clinically relevant bleeding risk, including Child-Pugh class B and C liver cirrhosis (see section "Pharmacokinetics").
• Pregnancy or breastfeeding (see section "Use during pregnancy or breastfeeding").

Special safety precautions.

Crushing of tablets

Rivaroxaban tablets may be crushed and suspended in 50 mL of water and administered via nasogastric or feeding tube after confirmation of correct tube placement in the stomach. The tube should then be flushed with water. Since absorption of rivaroxaban 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 diminished effect of the active substance. After administration of crushed rivaroxaban tablets (15 or 20 mg), enteral feeding should be initiated immediately.

Interaction with other medicinal products and other forms of interaction.

The extent of interaction in the pediatric population is unknown. The interaction data below were obtained in adults; for the pediatric population, the warnings provided in the section "Special precautions" should be considered.

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 marked enhancement of the pharmacodynamic effects of the drug, thereby increasing the risk of bleeding. Therefore, the use of Xarelto® is not recommended in patients receiving concomitant systemic antifungal azole agents such as ketoconazole, itraconazole, voriconazole, or posaconazole, or HIV protease inhibitors. These agents are potent inhibitors of both CYP3A4 and P-gp (see section "Special precautions").

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), which strongly inhibits CYP3A4 and moderately inhibits P-gp, 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 for most patients, but may potentially be significant for high-risk patients (for use in patients with renal impairment, see section "Special precautions").

Erythromycin (500 mg three times daily), which moderately inhibits CYP3A4 and P-gp, caused a 1.3-fold increase in mean steady-state AUC and Cmax of rivaroxaban. The interaction with erythromycin is unlikely to be clinically significant for most patients, but may potentially be 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) was associated with 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 resulted in 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 that of renal impairment (see section "Special precautions").

Fluconazole (400 mg once daily), considered a moderate inhibitor of CYP3A4, caused a 1.4-fold increase in mean AUC and a 1.3-fold increase in Cmax of rivaroxaban. The interaction with fluconazole is unlikely to be clinically significant for most patients, but may potentially be significant for high-risk patients (for use in patients with renal impairment, see section "Special precautions").

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

Anticoagulants

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

Due to the increased risk of bleeding, concomitant use with other anticoagulants should be approached with caution (see sections "Contraindications", "Special precautions").

Non-steroidal anti-inflammatory drugs (NSAIDs)/platelet aggregation inhibitors

After concomitant administration of rivaroxaban (15 mg) and 500 mg naproxen, no clinically relevant prolongation of bleeding time was observed. However, a more pronounced pharmacodynamic response may occur in individual subjects.

No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when Xarelto® was co-administered with 500 mg acetylsalicylic acid.

No pharmacokinetic interaction was detected between rivaroxaban (15 mg) and clopidogrel (loading dose 300 mg followed by maintenance dose 75 mg), but in a 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 receptor.

Caution is required when prescribing rivaroxaban to patients who are concomitantly using NSAIDs (including acetylsalicylic acid) and platelet aggregation inhibitors, as these drugs generally increase the risk of bleeding (see section "Special precautions").

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

As with other anticoagulants, the risk of bleeding is increased in patients receiving SSRIs or SNRIs due to their effects on platelets. During clinical trials, a higher number of clinically significant bleeding events were observed in all treatment groups when SSRIs or SNRIs were used concomitantly with rivaroxaban.

Warfarin

When switching patients from vitamin K antagonist warfarin (INR 2–3) to rivaroxaban (20 mg), or from rivaroxaban (20 mg) to warfarin (INR 2.0–3.0), prothrombin time and INR (Neoplastin) increased more than additively (individual INR values up to 12 were observed), whereas the effects on aPTT, factor Xa inhibition, and endogenous thrombin potential (ETP) were additive.

If monitoring of the pharmacodynamic effects of rivaroxaban is desired during the transition period, anti-Xa activity assays, PiCT, and HepTest may 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 monitoring of the pharmacodynamic effects of warfarin is desired during the transition period, INR measurement may be performed at the trough concentration of rivaroxaban (24 hours after the previous dose of rivaroxaban), as rivaroxaban has the least influence on INR test results at this time.

No pharmacokinetic interaction was observed between warfarin and rivaroxaban.

CYP3A4 inducers

Concomitant administration of rivaroxaban and rifampicin, a strong inducer of CYP3A4 and P-gp, 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 inducers of CYP3A4 (e.g., phenytoin, carbamazepine, phenobarbital, or St. John's wort) may also lead to decreased plasma concentrations of rivaroxaban. Therefore, concomitant administration with potent CYP3A4 inducers should be avoided, except when close patient monitoring for signs and symptoms of thrombosis is ensured.

Other concomitant medicinal products

No clinically significant pharmacokinetic or pharmacodynamic interactions were observed with concomitant administration of rivaroxaban and midazolam (CYP3A4 substrate), digoxin (P-glycoprotein substrate), atorvastatin (CYP3A4 and P-gp substrate), or omeprazole (proton pump inhibitor). Rivaroxaban does not inhibit or induce any major cytochrome P450 isoenzymes, such as CYP3A4.

Effect on laboratory parameters

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

Special precautions for use

During the treatment period, clinical monitoring appropriate to the practice of anticoagulant use is recommended.

Risk of bleeding

As with other anticoagulants, patients receiving XARELTO® should be under careful monitoring for signs of bleeding. The drug should be used with caution in diseases 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, bleeding from the genitourinary system, including abnormal vaginal bleeding or increased menstrual bleeding) and anaemia occurred more frequently during long-term therapy with rivaroxaban than with vitamin K antagonists. Due to this, in addition to appropriate clinical monitoring, laboratory testing of haemoglobin/haematocrit levels should be considered in relevant cases to detect occult internal bleeding and to assess the clinical significance of overt bleeding.

Certain patient categories, as listed below, have an increased risk of bleeding. These patients should be closely monitored after initiation of treatment for symptoms of haemorrhagic complications and anaemia (see section "Adverse reactions").

Any unexplained decrease in haemoglobin level or arterial 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 surgical interventions (see section "Pharmacological properties").

Limited data are available in children with cerebral venous and sinus thrombosis who have CNS infection (see "Pharmacodynamics"). The risk of bleeding should be carefully assessed before and during rivaroxaban therapy.

Renal impairment

In adult patients with severe renal impairment (creatinine clearance < 30 mL/min), plasma concentrations of rivaroxaban may be substantially increased (on average by 1.6-fold), which may lead to an increased 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 renal impairment who are concurrently receiving other medicinal products that increase plasma concentrations of rivaroxaban (see section "Interaction with other medicinal products and other forms of interaction").

The use of XARELTO® is not recommended in children with moderate or severe renal impairment (glomerular filtration rate < 50 mL/min/1.73 m²) due to lack of clinical data.

Interaction with other medicinal products

Concomitant systemic treatment with azole antifungal agents (e.g., ketoconazole, itraconazole, voriconazole, posaconazole) or HIV protease inhibitors (e.g., ritonavir) is not recommended during XARELTO® therapy. These agents are potent inhibitors of both CYP3A4 isoenzymes and P-gp, and may increase plasma concentrations of rivaroxaban to clinically significant levels (on average by 2.6-fold), potentially increasing the risk of bleeding. Clinical data are lacking in children receiving concomitant systemic treatment with strong inhibitors of CYP3A4 and P-gp (see section "Interaction with other medicinal products and other forms of interaction").

Caution is required when prescribing rivaroxaban to patients receiving medicinal products affecting haemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid, and platelet aggregation inhibitors, or selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). If there is a risk of gastrointestinal ulceration, appropriate prophylactic treatment should be considered (see section "Interaction with other medicinal products and other forms of interaction").

Other risk factors for bleeding

Like other antithrombotic agents, rivaroxaban is not recommended in patients with an increased risk of bleeding, including in the presence of:

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

Patients with oncological disease

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

Rivaroxaban 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 that XARELTO® provides adequate anticoagulation in this patient group. The use of XARELTO® is not recommended for treatment of these 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 tests for all three antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibodies, anti-beta-2-glycoprotein I antibodies), therapy with direct oral anticoagulants may be associated with an increased risk of recurrent thrombotic events compared to vitamin K antagonists.

Patients with non-valvular atrial fibrillation who have undergone PCI with stent placement

Clinical data from an interventional study are available, primarily assessing the safety of use in patients with non-valvular atrial fibrillation who have undergone PCI with stent placement. Data on efficacy in this population are limited (see sections "Dosage and administration" and "Pharmacodynamics"). There are no data for this patient group with a history of stroke/TIA.

Patients with PE and unstable haemodynamic parameters or those requiring thrombolysis or pulmonary embolectomy

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

Spinal (epidural/spinal) anaesthesia or puncture

With neuraxial anaesthesia (epidural/spinal anaesthesia) or spinal/epidural puncture, there is a risk of developing epidural or spinal haematoma, which may lead to long-term or permanent paralysis in patients receiving antithrombotic agents for thromboembolic complication prophylaxis.

The risk of these complications is increased with the use of permanent epidural catheters or concomitant use of medicinal products affecting haemostasis. Traumatic or repeated epidural or spinal punctures also increase the risk of such complications. Patients should be monitored for symptoms of neurological disorders (e.g., numbness or weakness in the legs, bowel or bladder dysfunction). In case of neurological deficit, urgent diagnosis and treatment are required. The physician must assess 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 15 mg and 20 mg rivaroxaban in such situations.

To reduce the potential risk of bleeding associated with concomitant use of rivaroxaban and spinal (epidural/spinal) anaesthesia 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 "Pharmacokinetics"). However, the exact time to achieve sufficient reduction in anticoagulant effect is not known for each individual patient and should be weighed against the urgency of the diagnostic procedure.

Based on general pharmacokinetic characteristics, removal of an epidural catheter should be delayed by at least twice the elimination half-life, i.e., no sooner than 18 hours after the last dose of rivaroxaban in young adult patients and 26 hours in elderly patients (see section "Pharmacokinetics"). Rivaroxaban should not be taken within the first 6 hours after removal of the epidural catheter.

In case of traumatic puncture, administration of rivaroxaban should be delayed for 24 hours.

There are no data on the timing of placement or removal of neuraxial catheters in children during treatment with XARELTO®. In such cases, rivaroxaban should be discontinued and consideration should be given to using a parenteral anticoagulant with short duration of action.

Dosing recommendations before and after invasive procedures and surgery

If invasive procedures or surgical interventions are necessary, XARELTO® 15 mg and 20 mg should be discontinued at least 24 hours before the procedure, if possible, and based on the physician's clinical judgment. If the procedure cannot be delayed, the presence of an increased risk of bleeding and the urgency of the intervention should be assessed.

XARELTO® should be resumed after an invasive procedure or surgical intervention as soon as adequate haemostasis is achieved and the overall clinical situation permits, as determined by the physician (see section "Pharmacokinetics").

Geriatric patients

The risk of bleeding increases with age (see section "Pharmacokinetics").

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 in the post-marketing period in association with rivaroxaban use (see section "Adverse reactions"). The risk of these reactions is likely highest at the beginning of therapy: most reactions occurred within the first weeks of treatment. Rivaroxaban should be discontinued at the first signs of severe skin rashes (e.g., generalization, intensification, and/or blister formation) or at the onset of any other signs of hypersensitivity in combination with mucosal involvement.

Information on excipients

XARELTO® contains lactose. This medicinal product should not be used in patients with rare hereditary conditions of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

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

Use during pregnancy or breastfeeding

Pregnancy. The efficacy and safety of XARELTO® in pregnant women have not been studied.

Animal studies indicate reproductive toxicity (see section "Pharmacological properties"). Due to the potential reproductive toxicity, high risk of bleeding, and placental transfer of rivaroxaban, XARELTO® is contraindicated during pregnancy (see section "Contraindications").

Women of childbearing potential should avoid pregnancy during treatment with rivaroxaban.

Breastfeeding. The efficacy and safety of XARELTO® in women during breastfeeding have not been studied. Animal studies have shown that rivaroxaban is excreted in milk. Therefore, XARELTO® is contraindicated during breastfeeding (see section "Contraindications"). A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from therapy.

Fertility. Specific studies evaluating the effect of rivaroxaban on human fertility have not been conducted. In fertility studies in male and female rats, no effect was observed (see section "Pharmacological properties").

Ability to influence the speed of reactions when driving or operating machinery

XARELTO® has a negligible influence on the ability to drive or operate machinery. Adverse reactions such as syncope (frequency: uncommon) or dizziness (frequency: 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

Prevention of Stroke and Systemic Embolism in Adults

The recommended dose is one 20 mg Xarelto® tablet once daily, which is also the maximum recommended dose.

Long-term treatment with Xarelto® should be continued as long as the benefit of preventing stroke and systemic embolism outweighs the risk of bleeding (see section "Special Warnings and Precautions for Use").

If a dose is missed, the patient should take Xarelto® as soon as possible. The next day, the patient should continue with the once-daily regimen according to the recommended dosage. A double dose should not be taken on the same day to compensate for the missed tablet.

Treatment of DVT, PE and Prevention of Recurrent DVT and PE in Adults

For the first 3 weeks in the treatment of acute DVT and PE, the recommended dose is one 15 mg Xarelto® tablet twice daily. This should be followed by 20 mg Xarelto® once daily for long-term treatment and prevention of recurrent DVT and PE.

Short-term therapy (for at least 3 months) should be prescribed for patients with DVT or PE associated with transient risk factors (e.g., recent surgery or trauma). Long-term therapy should be prescribed for patients with DVT or PE not associated with transient risk factors, idiopathic DVT or PE, or with a history of recurrent DVT or PE.

When extended prevention of recurrent DVT or PE is indicated (after completion of at least 6 months of treatment for DVT and PE), the recommended dose is 10 mg once daily. For patients at high risk of recurrent DVT or PE, those with significant comorbidities, or those who experienced a recurrence of DVT or PE while receiving Xarelto® 10 mg once daily, prophylactic use of Xarelto® 20 mg once daily may be considered.

The duration of treatment should be determined individually, following careful assessment of the benefits of therapy versus the potential risk of bleeding (see section "Special Warnings and Precautions for Use").

	Period	Dosing regimen	Total daily dose
Treatment and prevention of VTE and PE recurrences	Days 1–21	15 mg twice daily	30 mg
	Day 22 and onwards	20 mg once daily	20 mg
Prevention of VTE and PE recurrences	After completion of at least 6 months of therapy for VTE and PE	10 mg once daily or 20 mg once daily	10 mg or 20 mg

In case a dose of Xarelto® 15 mg is missed during treatment with 15 mg of the medicinal product twice daily (days 1–21), the patient should immediately take a dose of Xarelto® to ensure a total daily intake of 30 mg of Xarelto®. In this case, two 15 mg tablets may be taken simultaneously. The following day, the usual regimen of 15 mg twice daily should be continued as recommended.

If a dose is missed during once-daily treatment, the patient should take Xarelto® immediately and continue the next day with once-daily dosing according to the recommended regimen. A double dose should not be taken on the same day to compensate for the missed tablet.

Treatment of venous thromboembolism (VTE) and prevention of VTE recurrence in children

Treatment with Xarelto® in children should be initiated after at least 5 days of initial parenteral anticoagulant therapy (see section "Pharmacological properties").

The dose is calculated based on body weight.

Body weight from 30 to 50 kg: the recommended dose is 15 mg once daily. This is the maximum daily dose.

Body weight of 50 kg or more: the recommended dose is 20 mg once daily. This is the maximum daily dose.

For patients with body weight below 30 kg, see the instructions for medical use of Xarelto® granules for oral suspension preparation.

The child's weight should be monitored and the dose adjusted regularly. This is necessary to maintain the therapeutic dose. Dose adjustment should only be based on changes in body weight.

Treatment should continue for at least 3 months. If clinically indicated, treatment may be extended up to 12 months. There are no data on dose reduction in children after 6 months of treatment. The benefit-risk balance of continuing therapy beyond 3 months should be evaluated on an individual basis, considering the risk of recurrent thrombosis compared to the potential risk of bleeding.

If a dose is missed, it should be taken as soon as possible on the same day. If this is not feasible, the patient should skip the missed dose and continue with the next scheduled dose. The patient should not take two doses to compensate for the missed dose.

Transition from vitamin K antagonists to Xarelto®

• Prevention of stroke and systemic embolism: vitamin K antagonist therapy should be discontinued and Xarelto® initiated when the international normalized ratio (INR) is ≤ 3.
• Treatment of DVT, PE, and prevention of their recurrence in adults, and treatment of venous thromboembolism (VTE) and prevention of VTE recurrence in children: vitamin K antagonist therapy should be discontinued and Xarelto® initiated when INR reaches ≤ 2.5.

When transitioning patients from vitamin K antagonists to Xarelto®, INR values may be falsely elevated after Xarelto® administration. INR is not a validated method for assessing the anticoagulant activity of Xarelto® and should not be used (see section "Interaction with other medicinal products and other forms of interaction").

Transition from Xarelto® to vitamin K antagonists

There is a risk of inadequate anticoagulation during the transition period from Xarelto® to a vitamin K antagonist. As with any switch to an alternative anticoagulant, continuous adequate anticoagulation must be ensured. It should be noted that INR values may be falsely elevated during Xarelto® treatment.

When transitioning from Xarelto® to a vitamin K antagonist, the vitamin K antagonist should be started concurrently with Xarelto® and both should be continued until the INR is ≥ 2. Standard dosing of the vitamin K antagonist may be used during the first two days of transition. Subsequently, the vitamin K antagonist dose should be adjusted based on INR values.

While the patient is taking both Xarelto® and a vitamin K antagonist, INR should be measured no sooner than 24 hours after the last dose of Xarelto® (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").

Children

Children transitioning from Xarelto® to a vitamin K antagonist should continue taking Xarelto® for 48 hours after the first dose of the vitamin K antagonist. After two days of concomitant administration, INR should be measured before the next scheduled dose of Xarelto®. Concomitant administration of Xarelto® and the vitamin K antagonist should be continued until INR is ≥ 2.0. After discontinuation of Xarelto®, INR can be reliably measured at least 24 hours after the last dose of Xarelto® (see above and section "Interaction with other medicinal products and other forms of interaction").

Transition from parenteral anticoagulants to Xarelto®

In adult and pediatric patients receiving parenteral anticoagulants, Xarelto® should be initiated 0–2 hours before the next scheduled administration of the parenteral agent (e.g., low-molecular-weight heparin) or at the time of discontinuation of a continuously administered parenteral agent (e.g., unfractionated heparin for intravenous infusion).

Transition from Xarelto® to parenteral anticoagulants

Discontinue Xarelto® and administer the first dose of the parenteral anticoagulant at the time the next dose of Xarelto® would have been taken.

Special patient categories

Patients with renal impairment

Adults. 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 these patients. The use of Xarelto® is not recommended in patients with creatinine clearance < 15 mL/min (see sections "Special precautions for use" and "Pharmacokinetics").

For patients with moderate (creatinine clearance 30–49 mL/min) or severe (creatinine clearance 15–29 mL/min) renal impairment, the following dosing regimens are recommended:

• For prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation, the recommended dose is 15 mg once daily (see section "Pharmacokinetics").
• For treatment of DVT, PE, and prevention of recurrent DVT and PE: during the first 3 weeks, patients should receive Xarelto® 15 mg twice daily. After this period, the recommended dose is 20 mg once daily. If the risk of bleeding in the patient outweighs the risk of recurrent DVT and PE, consideration should be given to reducing the dose from 20 mg once daily to 15 mg once daily. The recommendation for using the 15 mg dose is based on pharmacokinetic modeling and has not been studied in clinical settings (see sections "Special precautions for use", "Pharmacological properties").

If the recommended dose is 10 mg once daily, dose adjustment is not required.

No dose adjustment is needed in patients with mild renal impairment (creatinine clearance 50–80 mL/min) (see section "Pharmacokinetics").

Children.

• Children with moderate renal impairment (glomerular filtration rate 50–80 mL/min/1.73 m²): dose adjustment is not required based on data in adults and limited data in pediatric patients (see "Pharmacokinetics").
• Children with severe renal impairment (glomerular filtration rate < 50 mL/min/1.73 m²): use of Xarelto® is not recommended due to lack of clinical data (see section "Special precautions for use").

Patients with hepatic impairment

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

There are no clinical data in children with hepatic impairment.

Elderly patients

Dose adjustment is not required (see section "Pharmacokinetics").

Body weight

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

For children, the dose is determined based on body weight.

Gender

Dose adjustment is not required (see section "Pharmacokinetics").

Use in patients undergoing cardioversion

Initiating or continuing Xarelto® is permitted in patients who may require cardioversion.

When performing cardioversion under transesophageal echocardiography (TEE) control in patients who have not previously received anticoagulants, Xarelto® should be initiated at least 4 hours before cardioversion to ensure adequate anticoagulation (see sections "Pharmacodynamics" and "Pharmacokinetics"). For all patients, confirmation must be obtained prior to cardioversion that they have been taking Xarelto® as prescribed. When making decisions about initiation and duration of treatment, recommendations from established guidelines on anticoagulant therapy in patients undergoing cardioversion should be considered.

Patients with non-valvular atrial fibrillation who underwent PCI with stent placement

There is limited experience with the use of reduced-dose Xarelto® 15 mg once daily [or Xarelto® 10 mg once daily in patients with moderate renal impairment (creatinine clearance 30–49 mL/min)] in combination with a P2Y12 inhibitor for up to 12 months in patients with non-valvular atrial fibrillation who require oral anticoagulation and have undergone PCI with stent placement (see sections "Special precautions for use" and "Pharmacodynamics").

Method of administration

Adults

For oral use.

Xarelto® 15 mg and 20 mg tablets should be taken with food (see section "Pharmacokinetics").

Crushing tablets

For patients unable to swallow whole tablets, the tablet may be crushed and mixed with water or soft food such as applesauce immediately before oral administration. After administration of crushed Xarelto® 15 mg or 20 mg tablets, food should be taken immediately.

Crushed tablets may be administered via a gastric tube (see sections "Pharmacokinetics" and "Special safety precautions").

Children

Children with body weight from 30 to 50 kg.

For oral use.

Patients should be advised to swallow the tablet with liquid. It should also be taken with food (see "Pharmacokinetics"). Tablets should be taken approximately 24 hours apart.

If the patient immediately spits out or vomits the dose within 30 minutes of administration, a new dose should be given. However, if the patient vomits more than 30 minutes after taking the dose, the dose should not be repeated, and the next dose should be taken according to schedule.

The tablet should not be split in an attempt to obtain a partial dose.

Crushing tablets

For patients unable to swallow whole tablets, Xarelto® granules for oral suspension should be used.

If the oral suspension is not immediately available when doses of rivaroxaban 15 mg or 20 mg are prescribed, it may be prepared by crushing a 15 mg or 20 mg tablet, mixing it with water or applesauce immediately before administration, and administering it orally (see "Pharmacokinetics" and section "Special safety precautions").

Children.

The safety and efficacy of Xarelto® in children under 18 years of age have not been established for the indication of prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. Data in this population are lacking. Therefore, use of the medicinal product in children under 18 years of age for this indication is not recommended, except for the treatment of venous thromboembolism (VTE) and prevention of VTE recurrence.

Overdose.

Rare cases of overdose up to 1960 mg have been reported in adults. In case of overdose, the patient should be carefully monitored for complications such as bleeding or other adverse reactions (see below "Treatment of bleeding"). Data in children are limited. 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 levels in adults, but there are no data on supratherapeutic doses in children.

A specific antidote (andexanet alfa) that counteracts the pharmacological effects of rivaroxaban is available for adults but has not been established for children (see brief product characteristics of andexanet alfa). In case of overdose, activated charcoal may be used to reduce absorption of rivaroxaban.

Treatment of bleeding

In case of bleeding complications, the next dose of rivaroxaban should be delayed or treatment discontinued, depending on the situation. The elimination half-life of rivaroxaban is approximately 5–13 hours in adults. The half-life in children, estimated using population pharmacokinetic modeling approaches, is shorter (see section "Pharmacological properties"). Treatment should be individualized based on the severity and location of bleeding. If necessary, appropriate symptomatic treatment should be provided, such as mechanical compression for severe epistaxis, surgical hemostasis with bleeding control procedures, restoration of fluid and electrolyte balance and hemodynamic support, blood transfusion (packed red blood cells or fresh frozen plasma, depending on the condition: anemia or coagulopathy) or platelets.

If bleeding persists after the above measures, consideration should be given to using a specific antidote (andexanet alfa), an inhibitor of factor Xa that counteracts the pharmacological effects of rivaroxaban, or procoagulant agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (aPCC), or recombinant factor VIIa (r-FVIIa). However, experience with these agents in adults and children in cases of rivaroxaban overdose is limited. Recommendations are also based on limited non-clinical data. Dose adjustment of recombinant factor VIIa should be performed and titration should be based on the degree of bleeding control. In cases of massive bleeding, consultation with a hematologist should be considered, depending on the situation (see section "Pharmacological properties").

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

Adverse reactions.

The safety of rivaroxaban was evaluated in 13 pivotal Phase III studies (see Table 11). Overall, 69,608 adult patients in nineteen Phase III studies and 488 pediatric patients in two Phase II and two Phase III studies were exposed to rivaroxaban.

Table 11. Number of patients enrolled in the studies, total daily dose, and maximum treatment duration in adult and pediatric patients in 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	6,097	10 mg	39 days
Prophylaxis of VTE in medically ill patients	3,997	10 mg	39 days
Treatment of deep vein thrombosis (DVT), pulmonary embolism (PE), and prevention of VTE recurrence	6,790	Day 1–21: 30 mg Day 22 and onwards: 20 mg After at least 6 months: 10 mg or 20 mg	21 months
Treatment of VTE and prevention of VTE recurrence 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 equivalent to that in adults receiving 20 mg rivaroxaban once daily for treatment of DVT	12 months
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation	7,750	20 mg	41 months
Prevention of atherothrombotic events in patients after ACS	10,225	5 mg or 10 mg as appropriate, in combination with ASA or in combination with ASA and clopidogrel or ticlopidine	31 months
Prevention of atherothrombotic events in patients with CAD/PAD	18,244	5 mg with ASA or 10 mg	47 months
	3,256**	5 mg with ASA	42 months

* Patients who received at least 1 dose of rivaroxaban.

** From the VOYAGER PAD study.

The most commonly reported adverse reactions in patients receiving rivaroxaban were bleeding events (see section "Dosage and Administration" and the subsection "Information on selected adverse reactions" below). The most frequent bleeding events reported were nosebleeds (4.5%) and gastrointestinal bleeding (3.8%).

Table 12. Incidence of bleeding* and anemia in patients who received rivaroxaban during completed phase III studies involving adult and pediatric patients

Indications	Any bleeding	Anemia
Prevention of venous thromboembolism (VTE) in adult patients undergoing hip or knee replacement surgery	6.8% of patients	5.9% of patients
Prevention 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) after 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 adult patients after acute coronary syndrome (ACS)	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 reviewed.

** In the COMPASS study, the frequency of anemia was low due to the use of a selective approach to adverse event collection.

*** A selective approach was used for collecting information on adverse events.

From the VOYAGER PAD study.

Table 13 below presents the frequency of adverse reactions occurring during treatment with the medicinal product Xarelto® in adult and pediatric patients. Adverse reactions are systematized and described using the organ system classification (MedDRA). Within each group, adverse reactions are listed in order of decreasing severity: 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 available data).

Table 13. All adverse reactions observed in adult patients after initiation of treatment during Phase III studies or in the post-marketing period* and in pediatric patients in two Phase II and two Phase III studies

Common	Uncommon	Rare	Very rare	Frequency not known
Disorders of the blood and lymphatic system
Anaemia (including relevant 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), gastrointestinal and abdominal pain, dyspepsia, nausea, constipationA, diarrhoea, vomitingA	Dry mouth
Hepatobiliary disorders
Elevated transaminase levels	Liver failure, elevated bilirubin levels, elevated alkaline phosphatase levelsA, elevated gamma-glutamyl transferase (GGT) levelsA	Jaundice, elevated conjugated bilirubin levels (with or without concurrent elevation of ALT), cholestasis, hepatitis (including hepatocellular injury)
Skin and subcutaneous tissue disorders
Pruritus (including infrequent cases of generalized pruritus), rash, ecchymosis, skin and subcutaneous haemorrhage	Urticaria		Stevens-Johnson syndrome/toxic epidermal necrolysis, DRESS syndrome
Musculoskeletal and connective tissue disorders
Limb painA	Haemarthrosis	Muscle haemorrhage		Compartment syndrome due to haemorrhage
Renal and urinary disorders
Genitourinary haemorrhage (including haematuria and menorrhagiaB), renal failure (including elevated blood creatinine, elevated blood urea)				Renal failure/acute renal failure due to haemorrhage leading to hypoperfusion, kidney injury associated with anticoagulant use
General disorders and administration site conditions
PyrexiaA, peripheral oedema, general malaise and decreased activity (including fatigue and asthenia)	Feeling unwell (including malaise)	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 prevention of VTE in adult patients undergoing elective hip or knee replacement surgery.

B Observed during treatment of DVT, PE and prevention of their recurrence as very common in women under 55 years of age.

C Were reported as uncommon during prevention of atherothrombotic events in patients who had suffered ACS (after percutaneous intervention).

* A predefined selective approach to collecting information on adverse reactions was applied in individual Phase III studies. The frequency of adverse reactions did not increase, and no new adverse reactions were identified following analysis of these studies.

Information on specific 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. Signs, symptoms, and severity (including potentially fatal outcomes) vary depending 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, bleeding from genitourinary organs, 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 testing of hemoglobin/hematocrit levels is recommended in relevant cases to detect internal bleeding and assess clinical significance of overt bleeding. The risk of bleeding may be higher in certain patient groups, for example, in patients with uncontrolled severe hypertension and/or in patients receiving concomitant medication affecting hemostasis (see section "Special precautions. Risk of bleeding"). Menstrual bleeding may become more intense and/or prolonged. Manifestations of hemorrhagic complications may include weakness, pallor, dizziness, headache, unexplained swelling, dyspnea, or shock of unknown etiology. In some cases, symptoms of myocardial ischemia such as chest pain or angina were observed as a consequence of anemia.

There have been reports of secondary complications known to result from severe bleeding, such as compartment syndrome and renal failure due to hypoperfusion, or kidney injury associated with anticoagulant use. Therefore, when assessing patients receiving anticoagulants, the risk of bleeding should be carefully considered.

Pediatric patients

Safety evaluation in children and adolescents is based on safety data from two open-label active-controlled Phase II studies and one Phase III study involving children up to 18 years of age. Safety results were generally similar between rivaroxaban and the comparator drug across different pediatric age groups. Overall, the safety profile in 412 children and adolescents who received rivaroxaban was similar to that in adults and consistent across age subgroups, although assessment is limited by the small number of patients.

In pediatric patients, headache (very common, 16.7%), fever (very common, 11.7%), epistaxis (very common, 11.2%), vomiting (very common, 10.7%), tachycardia (common, 1.5%), increased bilirubin levels (common, 1.5%), and increased conjugated bilirubin (uncommon, 0.7%) were reported more frequently compared to adults. As in the adult population, menorrhagia was observed in 6.6% (common) of post-menarche female adolescents. Thrombocytopenia, which was observed in the post-marketing period in adults, was common (4.6%) in pediatric clinical studies. Adverse reactions in pediatric patients were mostly mild or moderate in severity.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at 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.

Keep out of reach of children at temperatures not exceeding 30 °C.

Packaging.

Film-coated tablets, 15 mg:

14 tablets in a blister, 1 (14×1) or 3 (14×3) blisters in a cardboard pack.

Film-coated tablets, 20 mg:

10 or 14 tablets in a blister, 2 (14×2) or 10 (10×10) blisters in a cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

Bayer AG.

Bayer Bitterfeld GmbH.

Manufacturer's address and location of operations.

Kaiser-Wilhelm-Allee, 51368 Leverkusen, Germany.

Ortsteil Gräbendorf, Seilgasse 1, 06803 Bitterfeld-Wolfen, Germany.