Xarelto film-coated tablets 10 mg blister No. 10

Instructions for use Xarelto film-coated tablets 10 mg blister No. 10

Composition

active ingredient: rivaroxaban;

1 film-coated tablet contains 10 mg of rivaroxaban;

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

Dosage form

Film-coated tablets.

Main physicochemical properties: round biconvex tablets, film-coated, light red in color with a triangle and the number 10 on one side and a cross-shaped inscription BAYER on the other.

Pharmacotherapeutic group

Antithrombotic agents. Direct inhibitors of factor Xa. Rivaroxaban. ATC 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 is significantly correlated 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 undergoing major orthopedic surgery, the 5/95th percentile for prothrombin (Neoplastin assay) 2–4 hours after tablet intake (i.e., at the time of maximal effect) ranges from 13 to 25 s (baseline values before surgery: 12–15 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 Pharmacokinetics).

Clinical efficacy and safety

Prevention of venous thromboembolism (VTE) in adult patients undergoing hip or knee replacement surgery

The clinical development program for rivaroxaban was designed to demonstrate the efficacy of rivaroxaban for the prevention of VTE, i.e., proximal and distal deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients undergoing major lower extremity orthopedic surgery. The RECORD program, which included controlled, randomized, double-blind, phase III clinical trials, enrolled over 9,500 patients (7,050 patients undergoing total hip replacement and 2,531 patients undergoing total knee replacement). Rivaroxaban 10 mg once daily was administered at least 6 hours after surgery. Its efficacy was compared with enoxaparin 40 mg once daily, the first dose of which was administered 12 hours before surgery.

In all phase III studies (see Table 1), rivaroxaban significantly reduced the incidence of all VTE (venographically detected or symptomatic DVT, non-fatal PE, or fatal outcome) and serious VTE (proximal DVT, non-fatal PE, and VTE-related death), the pre-planned primary efficacy endpoints. In addition, in all three studies, the incidence of symptomatic VTE (symptomatic DVT, non-fatal PE, and VTE-related death) was lower in patients in the rivaroxaban group compared with patients receiving enoxaparin. The primary safety endpoint, major bleeding, was similar in patients receiving rivaroxaban 10 mg and enoxaparin 40 mg.

Table 1. Results of phase III clinical trials regarding efficacy and safety

Analysis of pooled results from phase III studies confirmed the data obtained in separate studies comparing the efficacy of rivaroxaban 10 mg once daily and enoxaparin 40 mg once daily in reducing the incidence of all VTE, serious VTE, and symptomatic VTE.

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 for the initial and long-term treatment of acute DVT and PE and the prevention of their recurrence.

Four phase III randomized controlled trials (Einstein DVT, Einstein PE, Einstein Extension, and Einstein Choice) enrolled over 12,800 patients, with a pooled analysis of the Einstein DVT and Einstein PE trials at baseline. The total duration of treatment in all trials was a maximum of 21 months.

The Einstein DVT trial studied 3449 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. Treatment durations were 3, 6, and 12 months, depending on the physician's clinical judgment.

For the initial treatment of acute PE, rivaroxaban was used at a dose of 15 mg twice daily for three weeks. Treatment was then continued with rivaroxaban at a dose of 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 INR/PTT was in the therapeutic range (≥2.0). Treatment was then continued with the vitamin K antagonist at a dose necessary to maintain the INR/PTT 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 prespecified primary and secondary efficacy endpoints. The primary efficacy endpoint was recurrent VTE with clinical manifestations, defined as the composite of recurrent DVT or fatal or nonfatal PE. The secondary efficacy endpoint was defined as the composite of recurrent DVT, nonfatal 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 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). The effect of rivaroxaban 20 mg once daily and 10 mg once daily was compared with the effect of 100 mg acetylsalicylic acid once daily.

In the Einstein DVT trial (see Table 2), 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 2. 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, which is started 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 3), 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 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 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 3. Efficacy and safety data 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, which is started 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 study results was performed using pre-specified parameters (see Table 4).

Table 4. Efficacy and safety indicators from a pooled analysis 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, which is started 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 endpoint 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 5), rivaroxaban demonstrated superiority over placebo on both 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 5. Efficacy and safety indicators from the Einstein Extension Phase III study

a) Rivaroxaban 20 mg once daily.

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

In the Einstein Choice study (see Table 6), 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 6. Efficacy and safety indicators from 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 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.

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. The incidence of bleeding leading to hospitalization was 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 with positive test results for three antiphospholipid antibodies

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

Use in children

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

Pharmacokinetics

Absorption

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

Rivaroxaban is almost completely absorbed after oral administration and its bioavailability after oral administration of 2.5 mg and 10 mg is high (80-100%) regardless of food intake. Administration of rivaroxaban 2.5 mg and 10 mg tablets with food does not affect the AUC (area under the concentration-time curve) and Cmax of rivaroxaban. Xarelto® tablets 2.5 mg and 10 mg can be taken without regard to food intake (see section 4.2).

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.

Bioavailability (AUC and Cmax) was comparable for rivaroxaban 20 mg administered orally as a crushed tablet mixed with applesauce or water, administered via gastric tube immediately after a liquid meal, and for administration of the whole tablet. Given the predicted 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, approximately 92% to 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 approximately 50 L.

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 and CYP-independent mechanisms. The main sites of biotransformation are the morpholine group, which undergoes oxidative degradation, and the amide groups, which are subject to hydrolysis. Based on in vitro data, rivaroxaban is a substrate for the transport proteins P-gp (P-glycoprotein) and Bcrp (breast cancer resistance protein).

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

Special patient groups

Gender: No clinically significant differences in pharmacokinetics have been identified between men and women (see section 4.2).

Elderly patients: In elderly patients, plasma concentrations of rivaroxaban are higher than in young patients, with mean AUC values approximately 1.5 times higher than in young patients, mainly due to reduced total and renal clearance. No dose adjustment is required.

Different weight categories: Too low or too high body weight (less than 50 kg and more than 120 kg) has only a minor effect on rivaroxaban plasma concentrations (less than 25%). No dose adjustment is required.

Ethnic differences: No clinically significant differences in pharmacokinetics (PK) and pharmacodynamics (PD) were observed in patients of Caucasian, African American, Hispanic, Japanese, or Chinese ethnicity.

Hepatic impairment. In patients with cirrhosis and mild hepatic impairment (Child-Pugh class A), the pharmacokinetics of rivaroxaban differed only slightly from those in healthy controls (mean 1.2-fold increase in rivaroxaban AUC). In patients with cirrhosis and moderate hepatic impairment (Child-Pugh class B), the mean AUC of rivaroxaban was significantly increased (2.3-fold) compared with that in healthy volunteers. The AUC of unbound material was increased 2.6-fold. These patients also showed a decrease in urinary excretion of rivaroxaban, similar to that observed in patients with moderate renal impairment.

There are no data in patients with severe hepatic impairment.

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

Renal impairment. There was an increase in rivaroxaban exposure, which was inversely correlated with the decrease in renal function as measured by creatinine clearance. In subjects 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, rivaroxaban plasma concentrations (AUC) were 1.4, 1.5 and 1.6 times higher than in healthy volunteers. Accordingly, an increase in pharmacodynamic effects was observed. In subjects with mild, moderate or severe renal impairment, the overall inhibition of factor Xa activity was 1.5, 1.9 and 2 times higher, respectively, compared to healthy volunteers; The HR was similarly increased by 1.3, 2.2 and 2.4 fold, respectively. Data are not available for patients with creatinine clearance < 15 mL/min.

Due to its high plasma protein binding, rivaroxaban is not expected to be dialysable.

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

Pharmacokinetic data observed in patients: In patients receiving rivaroxaban for VTE prevention at a dose of 10 mg once daily, the geometric mean concentration (90% prediction interval) at 2–4 hours and at almost 24 hours after administration (the time approximately reflecting the achievement of maximum and minimum concentrations in the dose interval) was 101 (7–273) and 14 (4–51) μg/L, respectively.

Pharmacokinetic/pharmacodynamic relationships. The pharmacokinetic/pharmacodynamic (PK/PD) relationship between rivaroxaban plasma concentrations and some pharmacodynamic endpoints (factor Xa inhibition, PC, APTT, HepTest) was evaluated over a wide dose range (5–30 mg twice daily). The relationship between rivaroxaban concentration and factor Xa activity is best described using the Emax model. For PC, the most reliable data is obtained using a linear intercept model. Depending on the different PC reagents, the slope may have significantly different values. When using the Neoplastin reagent for PC measurement, the initial PC was about 13 s, and the slope was from 3 to 4 s/(100 μg/L). The results of the PK/PD analyses in the Phase II and III studies were consistent with those obtained in healthy volunteers. In patients, baseline levels of factor Xa and PC were affected by surgery, resulting in differences in the slope of the concentration/PC ratio between post-operative and steady-state values.

Children's age. The efficacy and safety of the drug for the prevention of venous thromboembolism in children and adolescents (under 18 years of age) have not been studied.

Preclinical safety data

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

In repeated dose toxicity studies, effects were observed that were mainly related to the exaggerated pharmacodynamic effects of rivaroxaban.

No effects on fertility were recorded in female or male rats. During the