Xarelto film-coated tablets 20 mg No. 100

Instructions for Xarelto film-coated tablets 20 mg No. 100

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

In humans, a dose-dependent inhibition of factor Xa activity has been observed. Rivaroxaban exhibits a dose-dependent effect on prothrombin time using the Neoplastin assay, which correlates significantly with plasma concentrations (r = 0.98). Results will vary with other assays/kits. The instrument should be read 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 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 from 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 4.8).

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).

Clinical efficacy and safety

Prevention of stroke and systemic embolism in nonvalvular atrial fibrillation

The pivotal double-blind ROCKET AF study enrolled 14,264 patients, some of whom received Xarelto 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.

Xarelto was non-inferior to warfarin in the primary composite endpoint (stroke and systemic embolism outside the central nervous system). Among patients who received treatment according to the protocol during the drug period, 188 primary events of stroke and systemic embolism (1.71% per year) developed on rivaroxaban and 241 (2.16% per year) on warfarin (hazard ratio (HR), 0.79; 95% confidence interval (CI), 0.66–0.96; P

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

a) Safety study population (during treatment).

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), 6785 patients with non-valvular atrial fibrillation were enrolled. In XANTUS, the mean stroke risk score (CHADS2) was 2.0, and the mean bleeding risk score (HAS-BLED) 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 at a rate of 2.1 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.

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.

Cardioversion was performed under the guidance of transesophageal echocardiography (TEE-EG).

(1–5 days prior to treatment) or conventional cardioversion (at least three weeks prior to treatment). 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.

Patients with nonvalvular atrial fibrillation who underwent percutaneous coronary intervention (PCI) with stent placement

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

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 Xarelto clinical trial program was designed to demonstrate the efficacy of Xarelto 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.

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 PC/INR was in the therapeutic range (≥ 2.0). Treatment was then continued with the vitamin K antagonist at a dose necessary to maintain the PC/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. Xarelto 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 EINSTEIN CHOICE trial studied 3396 patients with confirmed symptomatic DVT and/or PE for the prevention of fatal PE or non-fatal symptomatic recurrent DVT or PE who had completed 6–12 months of anticoagulation therapy. Patients with an indication for long-term anticoagulation therapy at therapeutic doses were excluded from the study. The duration of treatment was up to 12 months depending on the individual randomization date (median: 351 days). Xarelto 20 mg once daily and 10 mg once daily were compared with acetylsalicylic acid 100 mg once daily.

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 = 0.076 (for “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. There was no significant difference in the enoxaparin/vitamin K antagonist group. There was no clear association between the mean duration in therapeutic range (PTT) at the center (time in 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.

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

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

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 EINSTEIN DVT and EINSTEIN PE phase III studies

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

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 Xarelto 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 Xarelto 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

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

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

*P 20 mg once daily versus ASA 100 mg once daily; hazard ratio = 0.34 (0.20–0.59).

**P Ò 10 mg once daily compared with ASA 100 mg once daily; hazard ratio = 0.26 (0.14–0.47).

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

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

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 for 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.

Patients with positive test results for three antiphospholipid antibodies

Rivaroxaban was compared with warfarin in patients with a history of thrombosis and diagnosed antiphospholipid syndrome (APS) at high risk of thromboembolic events (positive results for all three antiphospholipid antibodies: lupus anticoagulant, anticardiolipin antibodies, anti-beta-2-glycoprotein I antibodies) in a randomized, open-label, multicenter, investigator-sponsored clinical trial with blinded endpoint assessment. The study was stopped early after 120 patients were enrolled due to an increase in the incidence of thromboembolic events in patients taking rivaroxaban. The median follow-up period was 569 days, and 59 patients were randomized to rivaroxaban 20 mg (15 mg for patients with creatinine clearance <100 ml/min).

Use in children

The European Medicines Agency has waived the obligation to submit the results of studies with Xarelto in all subsets of the paediatric population for the treatment of thromboembolic complications. For information on the use of the medicinal product in children, see the section “Children”.

Pharmacokinetics

Absorption

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

The absolute bioavailability of rivaroxaban after dosing is high and is 80-100% for the 2.5 mg and 10 mg tablets, regardless of food intake. Food intake does not affect the AUC (area under the concentration-time curve) or Cmax of rivaroxaban at a dose of 2.5 mg and 10 mg.

When taken in the fasted state, due to reduced absorption, a bioavailability of 66% was determined for rivaroxaban 20 mg tablets. When Xarelto 20 mg was administered with food, the mean AUC was found to increase by 39% compared to when the tablets were taken in the fasted state, indicating almost complete absorption and high oral bioavailability. Xarelto 15 mg and 20 mg should be taken with food (see section 4.2).

The pharmacokinetics of rivaroxaban are close to linear when administered in doses up to 15 mg once daily on an empty stomach. When administered with food, the pharmacokinetics of Xarelto 15 mg and 20 mg tablets are dose proportional. At higher doses, the absorption of rivaroxaban is limited by solubility parameters, with a decrease in bioavailability and extent of absorption at higher doses.

The pharmacokinetics of rivaroxaban are characterized by moderate variability; the interindividual variability (coefficient of variation) is between 30% and 40%.

The absorption of rivaroxaban depends on the site of drug release in the gastrointestinal tract. There is a 29% and 56% decrease in AUC and Cmax when using rivaroxaban granules, with active substance release in the proximal small intestine compared to the tablet formulation. Exposure is further reduced when the active substance is released in the distal small intestine or ascending colon. Administration of rivaroxaban distal to the stomach should be avoided as this may lead to reduced absorption and a corresponding impact on exposure.

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

Distribution

Binding to human plasma proteins is high, about 92–95%, with serum albumin being the major binding component. The volume of distribution is moderate, with a Vss (volume of distribution at steady state) of almost 50 liters.

Metabolism and excretion

Almost 2/3 of the administered dose of rivaroxaban is metabolized with the subsequent excretion of half of the metabolites by the kidneys and the other half in the feces. The remaining (1/3) of the administered dose is excreted directly by the kidneys as unchanged active substance in the urine, mainly by active renal secretion.

Rivaroxaban is metabolized by CYP3A4, CYP2J2 isoenzymes and CYP-independent mechanisms. The main sites of metabolism are