Xarelto film-coated tablets 15 mg blister No. 14

Instructions for use Xarelto film-coated tablets 15 mg blister No. 14

Composition

active ingredient: rivaroxaban;

1 film-coated tablet contains 15 mg of rivaroxaban;

1 film-coated tablet contains 20 mg of rivaroxaban;

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

Dosage form

Film-coated tablets.

Main physicochemical properties:

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

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

Pharmacotherapeutic group

Antithrombotic agents. ATX code B01A F01.

Pharmacological properties

Pharmacodynamics.

Mechanism of action

Rivaroxaban is a highly selective direct inhibitor of factor Xa, which has a fairly high oral bioavailability. Blocking the activity of factor Xa interrupts the intrinsic and extrinsic pathways of the coagulation cascade, and, as a result, thrombin formation and thrombus formation are inhibited. Rivaroxaban does not directly inhibit the activity of thrombin (activated factor II) and does not affect platelets.

Pharmacodynamic effects

When used in humans, a dose-dependent inhibition of factor Xa activity was observed. When using the Neoplastin test, rivaroxaban exhibits a dose-dependent effect on prothrombin time, which is significantly correlated with plasma concentrations (r=0.98). When using other tests/kits, the results will be different. The device reading should be taken in seconds, since 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 recurrent DVT and PE, the 5/95th percentiles for prothrombin (Neoplastin) 2–4 hours after tablet intake (i.e. at the time of maximum effect) ranged from 17 to 32 s for 15 mg tablets twice daily or 15 to 30 s for 20 mg tablets once daily, respectively. At trough rivaroxaban concentrations (8–16 hours after tablet intake), the 5/95th percentiles for 15 mg rivaroxaban twice daily ranged from 14 to 24 s, and for 20 mg rivaroxaban once daily (18–30 hours after tablet intake) ranged from 13 to 20 s.

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

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

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

The PC (using the Neoplastin assay), the RCC and the 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. There may be individual discrepancies with higher or lower anti-Xa values compared to the corresponding plasma concentrations. There is no need for routine monitoring of coagulation parameters during clinical treatment with rivaroxaban. 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 the ranges of observed rivaroxaban plasma concentrations in children). The lower limit of quantification should be considered when the anti-Xa test is used to quantify rivaroxaban plasma concentrations in children. No efficacy or safety thresholds have been established.

Clinical efficacy and safety

Prevention of stroke and systemic embolism in nonvalvular atrial fibrillation

The rivaroxaban clinical trial program was designed to demonstrate the efficacy of rivaroxaban for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

The pivotal double-blind ROCKET AF study enrolled 14,264 patients, some of whom received rivaroxaban 20 mg once daily (patients with creatinine clearance 30–49 mL/min – 15 mg once daily), and others received warfarin titrated to a target international normalized ratio (INR) of 2.5 (therapeutic range 2.0–3.0). The median duration of treatment was 19 months, with a maximum duration of treatment of up to 41 months. 34.9% of patients received concomitant acetylsalicylic acid therapy and 11.4% received class III antiarrhythmics, including amiodarone.

Rivaroxaban was noninferior to warfarin in the primary composite endpoint (stroke and systemic embolism outside the central nervous system). Among patients treated as per protocol during the drug treatment period, 188 primary stroke and systemic embolism events (1.71% per year) occurred on rivaroxaban and 241 (2.16% per year) on warfarin (hazard ratio (HR) 0.79; 95% confidence interval (CI), 0.66–0.96; P<0.001 for noninferiority). Among all patients, primary events were identified in 269 patients receiving rivaroxaban (2.12% per year) and 306 patients receiving warfarin (2.42% per year) (HR 0.88; 95% CI, 0.74–1.03; P < 0.001 for noninferiority; P = 0.117 for superiority). Results for secondary endpoints examined in hierarchical order in the ITT analysis are shown in Table 1.

Among patients in the warfarin 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 by the time in therapeutic range at the center (time in the target range of INR 2.0–3.0) across quartiles of equal size (P = 0.74 for interaction). Within the highest quartile of center values, the hazard ratio for rivaroxaban compared with warfarin was 0.74 (95% CI, 0.49–1.12).

The incidence of the primary safety endpoint (major and non-major clinically significant bleeding) was similar in both treatment groups (see Table 2).

Table 1. Efficacy indicators from the ROCKET AF Phase III study

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

Warfarin titrated to a target INR of 2.5 (therapeutic range 2.0–3.0)

Event rate (per 100 patient-years)

a) Safety study population (during treatment).

* Conditionally significant phenomenon.

In addition to the phase III ROCKET AF study, a prospective, uncontrolled, post-marketing, non-interventional, open-label cohort study (XANTUS) was conducted with a central assessment of endpoints, including thromboembolic events and major bleeding. To examine clinical practice in the prevention of stroke and systemic embolism outside the central nervous system (CNS), 6704 patients with non-valvular atrial fibrillation were enrolled. In XANTUS, the mean stroke risk assessment scale (CHADS2) score was 1.9, and the mean bleeding risk assessment scale (HAS-BLED) score was 2.0, while in ROCKET AF, the mean CHADS2 and HAS-BLED scores were 3.5 and 2.8, respectively. Major bleeding events in XANTUS occurred in 2.1 cases per 100 patient-years. Fatal bleeding was observed in 0.2 cases per 100 patient-years and intracranial bleeding in 0.4 cases per 100 patient-years. Stroke or systemic embolism (CNS) was observed in 0.8 cases per 100 patient-years. These observations in clinical practice 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 the prevention of stroke and systemic embolism. The incidence of ischemic stroke was 0.70 (95% CI 0.44–1.13) per 100 patient-years. Bleeding leading to hospitalization occurred at a rate of 0.43 (95% CI 0.31–0.59) events 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 urogenital bleeding, and 0.40 (95% CI 0.25–0.65) for other bleeding.

Patients undergoing cardioversion

A prospective, randomized, open-label, multicenter, blinded, exploratory trial (X-VERT) was conducted in 1504 patients (previously treated with oral anticoagulants or previously untreated) with nonvalvular atrial fibrillation and scheduled for cardioversion, comparing the efficacy of rivaroxaban and an adjusted dose of a vitamin K antagonist (randomized 2:1) in preventing cardiovascular events.

Transesophageal echocardiography (TEEC)-guided cardioversion (1–5 days prior to treatment) or conventional cardioversion (at least 3 weeks prior to treatment) was used. The primary efficacy endpoint (combination of stroke, transient ischemic attack, extra-CNS systemic embolism, myocardial infarction, and cardiovascular death) occurred in 5 (0.5%) patients in the rivaroxaban group (n=978) and 5 (1.0%) patients in the vitamin K antagonist group (n=492; relative risk 0.50; 95% CI 0.15–1.73; modified intent-to-treat population). The primary safety endpoint (major bleeding) was observed 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 sample). In this exploratory study, efficacy and safety were comparable in the rivaroxaban and vitamin K antagonist treatment groups during cardioversion.

A randomized, open-label, multicenter study (PIONEER AF-PCI) was conducted in 2124 patients with nonvalvular atrial fibrillation who underwent PCI with stent placement for primary atherosclerotic disease to compare the safety of two rivaroxaban regimens and one VKA regimen. Patients were randomized to the regimens in a 1:1:1 ratio for a total duration of 12 months. Patients with a history of stroke or transient ischemic attack (TIA) were excluded from the study.

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 DAT [dual antiplatelet therapy, e.g. clopidogrel 75 mg (or an alternative P2Y12 receptor inhibitor) with low-dose acetylsalicylic acid (ASA)] for 1 or 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 used an individually adjusted dose of VKA in combination with PATT for 1 or 6 or 12 months followed by the use of an individually adjusted dose of VKA in combination with low-dose ASA.

The primary safety endpoint of clinically significant bleeding was observed in 109 (15.7%), 117 (16.6%) and 167 (24.0%) patients in group 1, group 2 and group 3, respectively (HR 0.59; 95% CI 0.47-0.76; p<0.001 and HR 0.63; 95% CI 0.50-0.80; p<0.001, respectively). The secondary endpoint (combination of cardiovascular events, cardiovascular death, myocardial infarction or stroke) was observed in 41 patients (5.9%), 36 (5.1%) and 36 (5.2%) in group 1, group 2 and group 3, respectively. Each of the rivaroxaban regimens was associated with a significant reduction in the risk of clinically significant bleeding compared with the VKA regimen in patients with nonvalvular atrial fibrillation undergoing PCI with stent placement.

The primary objective of the PIONEER AF-PCI trial was to assess safety. Efficacy data (including thromboembolic events) are limited in this population.

Treatment of DVT, PE and prevention of recurrence of DVT and PE

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

Four phase III randomized controlled clinical trials (EINSTEIN DVT, EINSTEIN PE, EINSTEIN Extension, and EINSTEIN CHOICE) enrolled over 12,800 patients and included a pooled analysis of the EINSTEIN DVT and EINSTEIN PE trials. The total duration of treatment in all trials was a maximum of 21 months.

The EINSTEIN DVT trial studied 3,449 patients with acute DVT to treat DVT and prevent recurrent DVT and PE (patients with clinical PE were excluded). Treatment durations were 3, 6, and 12 months, based on the physician's clinical judgment.

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

The EINSTEIN PE trial studied 4,832 patients with acute PE for the treatment of PE and the prevention of recurrent DVT and PE. The duration of treatment was 3, 6, and 12 months, depending on the physician's clinical judgment.

Rivaroxaban 15 mg twice daily was used as initial therapy for acute PE for three weeks, followed by rivaroxaban 20 mg once daily.

In both studies, EINSTEIN DVT and EINSTEIN PE, the comparator regimens consisted of at least 5 days of enoxaparin therapy in combination with a vitamin K antagonist until the HR/INR was in the therapeutic range (≥2.0). Treatment was then continued with the vitamin K antagonist at a dose necessary to maintain the HR/INR within the therapeutic range of 2.0–3.0.

The EINSTEIN Extension trial studied 1197 patients with DVT or PE for the prevention of recurrent DVT and PE. Treatment duration was an additional 6 or 12 months in patients who had completed 6 or 12 months of venous thromboembolism therapy, depending on the physician's clinical judgment. Rivaroxaban 20 mg once daily was compared with placebo.

The EINSTEIN DVT, EINSTEIN PE, and EINSTEIN Extension trials used the same pre-specified primary and secondary efficacy endpoints. The primary efficacy endpoint was recurrent VTE (venous thromboembolism), with clinical manifestations 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 primary efficacy outcome was symptomatic recurrent VTE, defined as the composite of recurrent DVT or fatal or non-fatal PE.

In the EINSTEIN DVT trial (see Table 3), rivaroxaban was non-inferior to enoxaparin/vitamin K antagonist on the primary efficacy endpoint (p<0.0001) (non-inferior); hazard ratio: 0.680 (0.443–1.042), p=0.076 (superior). The hazard ratio for the prespecified net clinical benefit (primary efficacy endpoint plus major bleeding) was 0.67 [(95% CI: 0.47–0.95), nominal p=0.024] in favour of rivaroxaban. INR values were within the therapeutic range on average 60.3% of the time with a median treatment duration of 189 days and 55.4%, 60.1% and 62.8% of the time in the groups with a planned treatment duration of 3, 6 and 12 months, respectively. In the enoxaparin/vitamin K antagonist group, there was no clear relationship between the level of median period in the therapeutic range (PTT) at the center (time to maintain the target INR range of 2.0–3.0) in tertiles of equal size and the rate of recurrent VTE (p = 0.932 for interaction). Within the highest tertile by center, the hazard ratio for rivaroxaban compared with 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 secondary safety endpoint (major bleeding) was similar in both treatment groups.

Table 3. Efficacy and safety data from the EINSTEIN DVT Phase III study

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, starting during the enoxaparin period.

* p < 0.0001 (non-inferior efficacy at a pre-specified hazard ratio of 2.0); hazard ratio: 0.680 (0.443–1.042), p = 0.076 (“superior”).

In the EINSTEIN PE trial (see Table 4), rivaroxaban was non-inferior to enoxaparin/vitamin K antagonist for the primary efficacy endpoint (p = 0.0026 (non-inferior); hazard ratio: 1.123 (0.749–1.684)). The hazard ratio for the prespecified net clinical benefit (primary efficacy endpoint 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 with a median treatment duration of 215 days and 57%, 62% and 65% of the time in the groups with a planned treatment duration of 3, 6 and 12 months, respectively. In the enoxaparin/vitamin K antagonist group, there was no clear association between the mean center PDD (time to maintain target INR range 2.0–3.0) in tertiles of equal size and the rate of recurrent VTE (p = 0.082 for interaction). Within the highest center tertile, the hazard ratio for rivaroxaban compared with warfarin was 0.642 (95% CI: 0.277–1.484).

The incidence of the primary safety endpoint (major or clinically significant 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 endpoint (major bleeding) was lower in the rivaroxaban group [1.1% (26/2412)] than in the enoxaparin/vitamin K antagonist group [2.2% (52/2405)] with a hazard ratio of 0.493 (95% CI: 0.308–0.789).

Table 4. Efficacy and safety indicators from the EINSTEIN PE Phase III study

249

(10.3%)

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, starting during the enoxaparin period.

* p < 0.0026 (non-inferiority at a pre-specified hazard ratio of 2.0); hazard ratio: 1.123 (0.749–1.684).

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

Table 5. Efficacy and safety indicators according to the pooled analysis of the results of the phase III studies EINSTEIN DVT and EINSTEIN PE

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, starting during the enoxaparin period.

* p < 0.0001 (non-inferiority at a pre-specified hazard ratio of 1.75); hazard ratio: 0.886 (0.661–1.186).

The hazard ratio for the prespecified net clinical benefit (primary efficacy outcome plus major bleeding) in the pooled analysis was 0.771 [(95% CI: 0.614–0.967), nominal p-value = 0.0244].

In the EINSTEIN Extension study (see Table 6), rivaroxaban demonstrated superiority over placebo on primary and secondary efficacy endpoints. The incidence of the primary safety endpoint (major bleeding) was quantitatively slightly higher in patients treated with rivaroxaban 20 mg once daily than in patients treated with placebo. The incidence of the secondary safety endpoint (major or clinically relevant non-major bleeding) was higher in patients treated with rivaroxaban 20 mg once daily than in patients treated with placebo.

Table 6. Efficacy and safety data from the EINSTEIN Extension Phase III study

and Rivaroxaban 20 mg once daily.

* p < 0.0001 (“superior”); hazard ratio: 0.185 (0.087–0.393).

In the EINSTEN CHOICE study (see Table 7), rivaroxaban 20 mg and 10 mg demonstrated superiority over acetylsalicylic acid 100 mg on the primary and secondary efficacy endpoints. The primary safety endpoint (major bleeding) was similar in patients receiving rivaroxaban 20 mg or 10 mg compared to acetylsalicylic acid 100 mg.

Table 7. Efficacy and safety indicators according to the EINSTEIN CHOICE Phase III study

*p < 0.0001 (“superior”) rivaroxaban 20 mg once daily compared with ASA 100 mg once daily; hazard ratio = 0.34 (0.20–0.59).

**p < 0.0001 (“superior”) rivaroxaban 10 mg once daily compared with ASA 100 mg once daily; hazard ratio = 0.26 (0.14–0.47).

+ Rivaroxaban 20 mg once daily vs ASA 100 mg once daily; hazard ratio = 0.44 (0.27–0.71), p = 0.0009 (nominal).

++ Rivaroxaban 10 mg once daily vs. ASA 100 mg once daily; hazard ratio = 0.32 (0.18–0.55), p < 0.0001 (nominal).

In addition to the EINSTEIN phase III trials, a prospective, non-interventional, open-label cohort study (XALIA) was conducted with a central assessment of endpoints including recurrent VTE, major bleeding and death. To investigate the safety of long-term use of rivaroxaban in clinical practice compared with conventional anticoagulation therapy, the study enrolled 5142 patients with acute DVT. In the rivaroxaban group, the incidence of major bleeding was 0.7%, recurrent VTE was 1.4%, and all-cause mortality was 0.5%. There were differences in baseline characteristics of the patients, including age, cancer and renal insufficiency. A pre-planned stratified analysis using the propensity score was used to adjust for differences in baseline characteristics, but residual bias may still influence the results. The adjusted hazard ratios for major bleeding, recurrent VTE and all-cause mortality with rivaroxaban compared with conventional therapy 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 results are consistent with the established safety profile for this indication in clinical practice.

In a post-marketing, non-interventional study of over 40,000 patients with no history of cancer from four countries who were prescribed rivaroxaban for the treatment or prevention of DVT and PE, the event rates per 100 patient-years for symptomatic/clinically significant VTE/thromboembolic events leading to hospitalisation ranged from 0.64 (95% CI 0.40–0.97) in the UK to 2.30 (95% CI 2.11–2.51) in Germany. Bleeding leading to hospitalization occurred at an event 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.

Treatment of DVT and prevention of DVT recurrence in pediatric patients

A total of 727 children with confirmed acute VTE, of whom 528 received rivaroxaban, were studied in 6 open-label, multicenter pediatric studies. Weight-based dosing in patients from birth to 18 years of age resulted in rivaroxaban exposures similar to those observed in adult patients with DVT treated with rivaroxaban 20 mg once daily, as confirmed in a phase III study (see section 5.2).

The EINSTEIN Junior Phase III study is a randomized, active-controlled, open-label, multicenter clinical trial in 500 pediatric patients (ages birth to < 18 years) with confirmed acute VTE. 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 were enrolled.

The VTE event was classified as: VTE associated with the use of a central venous catheter (CVC-VTE; 90/335 patients in the Rivaro group