Xiltess^® (Tablets) Instructions for Use

ATC Code

B01AF01 (Rivaroxaban)

Active Substance

Rivaroxaban (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Anticoagulant – direct factor Xa inhibitor

Pharmacotherapeutic Group

Antithrombotic agents; direct factor Xa inhibitors

Pharmacological Action

Mechanism of action

Rivaroxaban is a highly selective direct factor Xa inhibitor with high oral bioavailability. Inhibition of factor Xa disrupts the intrinsic and extrinsic pathways of the coagulation cascade, inhibiting thrombin formation and thrombus formation. Rivaroxaban does not inhibit thrombin (activated factor II) and has not demonstrated an effect on platelets.

Pharmacodynamic effects

Dose-dependent inhibition of factor Xa activity is observed in humans. Rivaroxaban has a dose-dependent effect on prothrombin time, which correlates well with plasma concentrations (r = 0.98) when the Neoplastin reagent is used for the assay. Results will differ when other reagents are used. Prothrombin time should be measured in seconds, as the INR (International Normalized Ratio) is calibrated and validated only for coumarin derivatives and cannot be used for other anticoagulants.

In patients receiving Rivaroxaban for the treatment and prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE), the 5th/95th percentiles for prothrombin time (Neoplastin) 2-4 hours after tablet intake (i.e., at peak effect) ranged from 17 to 32 seconds for 15 mg rivaroxaban twice daily, and from 15 to 30 seconds for 20 mg rivaroxaban once daily. In the interval 8-16 hours after tablet intake, the 5th/95th percentiles ranged from 14 to 24 seconds for 15 mg twice daily, and 18-30 hours after tablet intake – from 13 to 20 seconds for 20 mg once daily. In patients with non-valvular atrial fibrillation taking 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) ranged from 14 to 40 seconds in patients taking 20 mg once daily, and from 10 to 50 seconds in patients with moderate renal impairment taking 15 mg once daily. In the interval 16-36 hours after tablet intake, the 5th/95th percentiles ranged from 12 to 26 seconds in patients taking 20 mg once daily, and from 12 to 26 seconds in patients with moderate renal impairment taking 15 mg once daily.

In a clinical pharmacology study of rivaroxaban pharmacodynamics in healthy adult volunteers (n = 22), an effect of single doses (50 IU/kg) of two different types of prothrombin complex concentrate was identified: 3-factor (factors II, IX and X) and 4-factor (factors II, VII, IX and X). The 3-factor prothrombin complex concentrate reduced mean prothrombin time (Neoplastin) values by approximately 1.0 second over 30 minutes compared to a reduction of approximately 3.5 seconds observed with the 4-factor prothrombin complex concentrate. In contrast, the 3-factor prothrombin complex concentrate had a more pronounced and rapid overall effect on the reversibility of changes in endogenous thrombin generation than the 4-factor prothrombin complex concentrate (see section “Overdose”). Rivaroxaban also dose-dependently increases aPTT and HepTest result; however, these parameters are not recommended for assessing the pharmacodynamic effects of rivaroxaban. Monitoring of coagulation parameters is not required in routine clinical practice during treatment with rivaroxaban. However, if clinically justified, the concentration of rivaroxaban can be measured using a calibrated quantitative anti-Xa activity assay (see section “Pharmacokinetics”).

Children

Prothrombin time (Neoplastin), aPTT, and anti-Xa activity measured by a calibrated quantitative test closely correlate with plasma concentrations in children. The correlation between anti-Xa activity and plasma concentration is linear with a slope close to 1. Individual discrepancies of higher or lower anti-Xa activity values compared to the corresponding plasma concentrations may occur. Monitoring of coagulation parameters is not required during treatment with rivaroxaban. However, if clinically justified, rivaroxaban concentrations can be measured in μg/L using calibrated quantitative anti-Xa activity tests (see Table 10 in the “Pharmacokinetics” section for the ranges of observed rivaroxaban plasma concentrations in children). When using an anti-Xa activity test to quantify rivaroxaban plasma concentrations in children, the lower limit of quantification must be considered. Threshold values for efficacy or safety criteria have not been established.

Clinical efficacy and safety

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

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

In the double-blind ROCKET AF study, 14,264 patients were randomized to receive either Rivaroxaban 20 mg once daily (15 mg once daily in patients with CrCl 30-49 ml/min) or dose-adjusted warfarin with a target INR of 2.5 (therapeutic range 2.0 to 3.0). The median duration of therapy was 19 months, with a total follow-up duration of up to 41 months.

34.9% of patients received acetylsalicylic acid, and 11.4% received class III antiarrhythmic drugs, including amiodarone.

Rivaroxaban was non-inferior to warfarin for the primary composite endpoint of the rate of stroke and systemic embolism outside the CNS. In the per-protocol population, stroke or systemic embolism occurred in 188 patients on rivaroxaban (1.71% per year) and 241 on warfarin (2.16% per year) (hazard ratio (HR) 0.79, 95% CI: 0.66-0.96; p <0.001 for non-inferiority analysis). Among all randomized patients in the intention-to-treat analysis, primary endpoint events occurred in 269 patients on rivaroxaban (2.12% per year) and 306 on warfarin (2.42% per year) (HR 0.88, 95% CI: 0.74-1.03, p <0.001 for the non-inferiority hypothesis, p = 0.117 for the superiority hypothesis). Secondary endpoint results were analyzed in hierarchical order and the results obtained in the intention-to-treat analysis are presented in Table 1.

Among patients in the warfarin group, INR values were within the therapeutic range (2.0 to 3.0) for a mean of 55% of the time (median – 58%, interquartile range – 43 to 71). The effects of rivaroxaban did not differ across TTR (Time in Therapeutic Range INR 2.0-3.0) quartiles of equal size (p = 0.74 for interaction). Within the upper versus center quartile, the hazard ratio (HR) for rivaroxaban compared to warfarin was 0.74 (95% CI: 0.49-1.12).

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

Table 1 Efficacy in the Phase III ROCKET AF study

Table 2: Safety in the Phase III ROCKET AF study

_{a) Safety population, treated}

_{* Nominally significant}

In addition to the Phase III ROCKET AF study, a multicenter prospective post-marketing open observational cohort study (XANTUS) was conducted with centralized independent assessment of key outcomes, including thromboembolic events and major bleeding. The study included 6785 patients with non-valvular atrial fibrillation who were prescribed Rivaroxaban for the prevention of stroke and systemic embolism outside the CNS in real-world clinical practice. The mean CHADS2 and HASBLED scores were 2.0 in the XANTUS study, compared to mean CHADS2 and HAS-BLED scores of 3.5 and 2.8 in ROCKET AF, respectively. The rate of major bleeding was 2.1 per 100 patient-years.

Fatal bleeding was reported at a rate of 0.2 per 100 patient-years and intracranial hemorrhage at a rate of 0.4 per 100 patient-years. Stroke or systemic embolism outside the CNS was reported at a rate of 0.8 per 100 patient-years.

Data obtained in real-world clinical practice are consistent with the previously established safety profile for this indication.

Patients undergoing cardioversion

X-VERT was a multicenter prospective randomized open-label study with blinded endpoint evaluation, in which 1504 patients with non-valvular atrial fibrillation (not previously treated with an oral anticoagulant) who were scheduled for cardioversion were randomized in a 2:1 ratio to rivaroxaban and dose-adjusted warfarin groups for the prevention of cardiovascular events. Methods used were: transesophageal echocardiography-guided cardioversion with 1-5 days of pre-anticoagulation or conventional cardioversion with at least three weeks of pre-anticoagulation. The primary efficacy endpoint (all strokes, transient ischemic attack, systemic embolism outside the CNS, myocardial infarction, and death from cardiovascular causes) was noted in 5 (0.5%) patients in the rivaroxaban group (n = 978) and 5 (1.0%) patients in the VKA group (n = 492), relative risk 0.50; 95% CI: 0.15-1.73, modified intention-to-treat population. The primary safety endpoint (major bleeding) was observed in 6 (0.6%) patients in the rivaroxaban group (n = 988) and 4 (0.8%) in the VKA group (n = 499); relative risk 0.76, 95% CI: 0.21-2.67 in the safety population. This study showed comparable efficacy and safety of rivaroxaban compared to VKA during cardioversion.

Patients with non-valvular atrial fibrillation after PCI with stent implantation

A multicenter open-label randomized study (PIONEER AF-PCI) was conducted in 2124 patients with non-valvular atrial fibrillation with coronary artery disease who underwent PCI with stent implantation. The aim of the study was to compare the safety of two rivaroxaban regimens with one VKA regimen. Patients were randomized in a 1:1:1 ratio for therapy with a total duration of 12 months. Patients with a history of stroke or TIA were excluded from the study.

Group 1 received Rivaroxaban 15 mg once daily (10 mg once daily in patients with CrCl 30-49 ml/min) plus a P2Y12 platelet receptor inhibitor. Group 2 received Rivaroxaban 2.5 mg twice daily plus DAPT (dual antiplatelet therapy, i.e., clopidogrel 75 mg [or an alternative P2Y12 platelet receptor inhibitor] plus low-dose acetylsalicylic acid [ASA]) for 1, 6, or 12 months, and then Rivaroxaban 15 mg (or 10 mg for patients with CrCl 30-49 ml/min) once daily plus low-dose ASA. Group 3 received dose-adjusted VKA plus DAPT for 1, 6, or 12 months, and then dose-adjusted VKA plus low-dose ASA.

The primary safety endpoint: clinically significant bleeding was observed in 109 (15.7%), 117 (16.6%), and 167 (24.0%) patients in groups 1, 2, and 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 death from cardiovascular disease, MI, or stroke) was observed in 41 (5.9%), 36 (5.1%), and 36 (5.2%) patients in group 1, 2, and 3, respectively. Both rivaroxaban regimens demonstrated a statistically significant reduction in clinically significant bleeding compared to the VKA regimen in patients with non-valvular atrial fibrillation after PCI with stent placement. Since the primary objective of PIONEER AF-PCI was safety assessment, efficacy data (including the rate of thromboembolic events) in the studied population are limited.

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

The rivaroxaban clinical research program was designed to demonstrate the efficacy of rivaroxaban in the initial and continued treatment of acute DVT and PE and for the prevention of recurrent DVT and PE. More than 12,800 patients were studied in 4 randomized, controlled phase III clinical trials (Einstein DVT, Einstein PE, Einstein Extension, and Einstein Choice), and, in addition, a pre-planned pooled analysis of the results of the Einstein DVT and Einstein PE studies was conducted. The total combined treatment duration across all studies was up to 21 months.

In the Einstein DVT study, 3449 patients with acute DVT received treatment for DVT and prevention of recurrent DVT and PE (patients presenting with clinically overt PE were not included in this study). The treatment duration was 3, 6, or 12 months based on the investigator’s clinical assessment. For the initial 3 weeks of acute DVT treatment, Rivaroxaban 15 mg twice daily was used, followed by Rivaroxaban 20 mg once daily.

In the Einstein PE study, 4832 patients with acute PE received treatment for PE and prevention of recurrent DVT and PE. The treatment duration was 3, 6, or 12 months based on the investigator’s clinical assessment. For the initial treatment of acute PE, Rivaroxaban 15 mg twice daily was used for 3 weeks, followed by Rivaroxaban 20 mg once daily.

In both the Einstein DVT and Einstein PE studies, the comparator was enoxaparin, which was used for at least 5 days in combination with a vitamin K antagonist until the prothrombin time/INR reached the therapeutic range (≥ 2.0). Treatment was continued with a VKA at a dose adjusted to maintain prothrombin time/INR within the therapeutic range of 2.0-3.0. In the Einstein Extension study, 1197 patients with DVT or PE were studied for the prevention of recurrent DVT and PE. The treatment duration was an additional 6 or 12 months (based on the investigator’s clinical assessment) in patients who had completed 6-month or 12-month treatment for VTE. Rivaroxaban 20 mg once daily was compared with placebo.

The Einstein DVT, PE, and Extension studies used the same predefined primary and secondary efficacy endpoints. The primary efficacy endpoint was symptomatic recurrent VTE, defined as a combination of recurrent DVT or fatal or non-fatal PE. The secondary efficacy endpoint was defined as a combination of recurrent DVT, non-fatal PE, and all-cause mortality.

In the Einstein Choice study, 3,396 patients with confirmed symptomatic DVT and/or PE who had completed 6-12 months of anticoagulant treatment were studied for the prevention of fatal PE or recurrent symptomatic DVT or non-fatal PE. Patients with an indication for continued therapeutic dose anticoagulation were not included in the study. Treatment duration was up to 12 months depending on the individual randomization date (median: 351 days). Rivaroxaban 20 mg once daily and rivaroxaban 10 mg once daily were compared with ASA 100 mg once daily.

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

In the Einstein DVT study (see Table 3), Rivaroxaban was as effective as enoxaparin/VKA for the primary efficacy endpoint (p < 0.0001 (non-inferiority criterion); HR = 0.680 (0.443-1.042), p = 0.076 (superiority criterion)). The predefined net clinical benefit (primary efficacy endpoint plus major bleeding) was registered with an HR of 0.67 ((95% CI: 0.47-0.95), nominal p = 0.027) in favor of rivaroxaban. INR values were within the therapeutic range for a mean of 60.3% of the time with a mean treatment duration of 189 days and 55.4%, 60.1%, and 62.8% of the time, respectively, in the 3, 6, and 12-month planned treatment groups. In the enoxaparin/VKA group, there was no clear association between the level of mean center TTR (time in the specified INR range 2.0-3.0) in equal-sized tertiles and the incidence of recurrent VTE (p = 0.932 for interaction). In the highest center tertile, the HR for rivaroxaban compared to warfarin was 0.69 (95% CI: 0.35-1.35).

The frequency of the primary (major or clinically relevant non-major bleeding) as well as the secondary safety endpoint (major bleeding) was similar in both treatment groups.

Table 3. Efficacy and safety assessment results in the phase III Einstein DVT study

^a) Rivaroxaban 15 mg twice daily for 3 weeks, then 20 mg once daily.

^b) Enoxaparin for at least 5 days with concurrent and subsequent VKA use.

* p < 0.0001 (non-inferior efficacy with a pre-specified RR = 2.0); RR = 0.680 (0.443-1.042), p = 0.076 (superior efficacy).

In the Einstein PE study (see Table 4), Rivaroxaban was non-inferior to enoxaparin/VKA regarding the primary efficacy endpoint (p = 0.0026 (non-inferiority criterion); RR = 1.123 (0.749-1.684)). The pre-specified net clinical benefit (primary efficacy endpoint plus major bleeding) was recorded with an RR = 0.849 ((95% CI: 0.633-1.139), nominal p=0.275). INR values were within the therapeutic range for a mean of 63% of the time, with a mean treatment duration of 215 days, and for 57%, 62%, and 65% of the time, respectively, in the treatment groups with planned durations of 3, 6, and 12 months. In the enoxaparin/VKA group, there was no clear association between the center mean TTR (Time in Target INR Range 2.0-3.0) in equal-sized tertiles and the incidence of recurrent VTE (p = 0.082 for interaction). In the highest center tertile, the RR for rivaroxaban compared to warfarin was 0.642 (95% CI: 0.277-1.484).

The frequency rates for the primary safety endpoint (major or clinically relevant non-major bleeding) were slightly lower in the rivaroxaban treatment group (10.3% (249/2,412)) compared to the enoxaparin/VKA treatment group (11.4% (274/2,405)). The frequency rates for the secondary safety endpoint (major bleeding) were lower in the rivaroxaban group (1.1% (26/2,412)) compared to the enoxaparin/VKA group (2.2% (52/2,405)) with an RR = 0.493 (95% CI: 0.308-0.789).

Table 4. Efficacy and safety assessment results in the phase III Einstein PE study

A) Rivaroxaban 15 mg twice daily for 3 weeks, then 20 mg once daily.

B) Enoxaparin for at least 5 days with concurrent and subsequent VKA use.

* p < 0.0026 (non-inferior efficacy with a pre-specified RR = 2.0); RR = 1.123 (0.749-1.684)

A pre-planned pooled analysis of outcomes from the Einstein DVT and PE studies was conducted (see Table 5).

Table 5. Efficacy and safety assessment results in the pooled analysis of phase III Einstein DVT and Einstein PE studies

A) Rivaroxaban 15 mg twice daily for 3 weeks, then 20 mg once daily.

B) Enoxaparin for at least 5 days with concurrent and subsequent VKA use.

* p < 0.0001 (non-inferior efficacy with a pre-specified RR = 1.75); RR = 0.886 (0.661-1.186)

The pre-specified net clinical benefit – a measure of the drug’s appropriateness which compares its efficacy and safety (primary efficacy endpoint plus major bleeding) in the pooled analysis was recorded with an RR = 0.771 ((95% CI: 0.614-0.967), nominal p = 0.0244).

In the Einstein Extension study (see Table 6), Rivaroxaban was more effective than placebo regarding the primary and secondary efficacy endpoints. For the primary safety endpoint (major bleeding), there was a non-significant, numerically higher incidence of this endpoint in patients receiving Rivaroxaban 20 mg once daily compared to placebo. Secondary safety endpoints (major or clinically relevant non-major bleeding) demonstrated a higher frequency in patients receiving Rivaroxaban 20 mg once daily compared to placebo.

Table 6. Efficacy and safety assessment results in the phase III Einstein Extension study

A) Rivaroxaban 20 mg once daily

* p < 0.0001 (superior efficacy), RR = 0.185 (0.087-0.393)

In the Einstein Choice study (see Table 7), Rivaroxaban 20 mg and 10 mg were more effective than acetylsalicylic acid 100 mg regarding the primary efficacy endpoint. The main safety criterion (major bleeding) was similar in patients receiving Rivaroxaban 20 mg and 10 mg once daily compared to ASA 100 mg.

Table 7. Efficacy and safety assessment results in the phase III Einstein Choice study

* p < 0.001 (superior efficacy) Rivaroxaban 20 mg once daily compared to ASA 100 mg once daily; RR = 0.34 (0.20-0.59)

** p < 0.001 (superior efficacy) Rivaroxaban 10 mg once daily compared to ASA 100 mg once daily; RR=0.26 (0.14-0.47)

⁺Rivaroxaban 20 mg once daily compared to ASA 100 mg once daily; RR = 0.44 (0.27-0.71), p = 0.0009 (nominal)

⁺⁺ Rivaroxaban 10 mg once daily compared to ASA 100 mg once daily; RR = 0.32 (0.18-0.55), p < 0.0001 (nominal)

In addition to the EINSTEIN phase III study program, a prospective, non-interventional, open, cohort study (XALIA) with centralized outcome assessment, including VTE recurrence, major bleeding, and death cases, was conducted. 5142 patients with acute DVT were included in the study to evaluate the long-term safety of rivaroxaban compared to standard anticoagulant therapy in clinical practice. The incidence of major bleeding, VTE recurrence, and overall mortality during rivaroxaban use was 0.7%, 1.4%, and 0.5%, respectively. There were differences in baseline patient characteristics, including age, presence of malignancy, and renal impairment. A pre-defined propensity score stratified analysis was used to account for measured baseline differences, but despite this, residual confounding factors may influence the analysis results. The adjusted RRs for comparing rivaroxaban and standard therapy for the frequency of major bleeding, recurrent VTE, and overall 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 results in clinical practice are consistent with the established safety profile for this indication.

Children

Treatment of VTE and prevention of recurrent VTE in children

Six open multicenter studies involving children were conducted, which included a total of 727 children with confirmed acute venous thromboembolism (VTE), of whom 528 received Rivaroxaban. The dose of rivaroxaban used in children from birth to <18 years was adjusted for body weight and resulted in rivaroxaban exposure similar to that of a 20 mg rivaroxaban once-daily dose in adult patients with DVT, as confirmed in the phase III study (see section “Pharmacological Properties”).

EINSTEIN Junior – a randomized, open, multicenter phase III clinical study with active control involving 500 patients (aged from birth to <18 years) with confirmed acute VTE, of which 276 children were aged 12 to <18 years, 101 children – 6 to <12 years, 69 children – 2 to <6 years and 54 50 children under 2 years of age. VTE was classified as catheter-associated VTE (90/335 patients in the rivaroxaban group, 37/165 patients in the comparator group), cerebral venous and sinus thrombosis (74/335 patients in the rivaroxaban group, 43/165 patients in the comparator group) or as other VTE, including DVT and PE (non-catheter-associated VTE, 171/335 patients in the rivaroxaban group, 85/165 patients in the comparator group). The most common VTE in children aged 12 to <18 years was non-catheter-associated VTE in 211 children (76.4%); in children aged 6 to <12 years and 2 to <6 years – cerebral venous and sinus thrombosis in 48 children (47.5%) and 35 children (50.7%) respectively; in children under 2 years – catheter-associated VTE in 37 children (68.5%). In the rivaroxaban group, there were no children under 6 months with cerebral venous and sinus thrombosis. 22 patients with cerebral venous and sinus thrombosis had a CNS infection (13 patients in the rivaroxaban group and 9 patients in the comparator group). VTE was provoked by persistent or temporary risk factors or their combination in 438 (87.6%) children.

Patients received initial treatment with therapeutic doses of unfractionated heparin, low molecular weight heparin, or fondaparinux for at least 5 days, after which they were randomized in a 2:1 ratio to either the rivaroxaban group at a body weight-adjusted dose or the comparator group (heparins, VKA) for the main treatment period of 3 months (1 month for children under 2 years with catheter-associated VTE). If clinically feasible, repeat vascular imaging was performed at the end of the main treatment period; the primary imaging was performed at the study inclusion stage. After this, the study drug could be discontinued or, at the investigator’s discretion, continued for a total of up to 12 months (for children under 2 years with catheter-associated VTE up to 3 months). The primary efficacy endpoint was the frequency of symptomatic recurrent VTE. The primary safety endpoint was the combined frequency of major and clinically relevant non-major bleeding. All efficacy and safety endpoints were centrally assessed by an independent committee, which was blinded to the patients’ treatment allocation. Recurrent VTE occurred in 4 out of 335 patients in the rivaroxaban group and 5 out of 165 patients in the comparator group.

The combined frequency of major bleeding and clinically relevant non-major bleeding was noted in 10 out of 329 patients (3%) receiving Rivaroxaban and 3 out of 162 patients (1.9%) receiving the comparator drug. Net clinical benefit (combined frequency of symptomatic recurrent VTE and major bleeding) was noted in 4 out of 335 patients in the rivaroxaban group and 7 out of 165 patients in the comparator group. Vein recanalization on repeat imaging was observed in 128 out of 335 patients treated with rivaroxaban and 43 out of 165 patients in the comparator group. These results were generally comparable across children of different age groups. In the rivaroxaban group, there were 119 children (36.2%) with any treatment-emergent bleeding, and in the comparator group – 45 children (27.8%).

Combined endpoint: major bleeding + clinically relevant non-major bleeding (primary safety endpoint) was noted in 10 patients (3.0%, 95% CI: 1.6-5.5%) out of 329 receiving Rivaroxaban and in 3 (1.9%, 95% CI: 0.5-5.3%) out of 162 receiving the comparator drug. Major bleeding was noted in 0 patients (0.0%, 95% CI: 0.0-1.1%) out of 329 receiving Rivaroxaban and in 2 (1.2%, 95% CI: 0.2-4.3%) out of 162 receiving the comparator drug. Any treatment-emergent bleeding was noted in 119 patients (36.2%) out of 329 receiving Rivaroxaban and in 45 (27.8%) out of 162 receiving the comparator drug.

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

* FAS = full analysis set, i.e., all randomized children

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

* SAF = safety analysis population, all children who were randomized and received at least 1 dose of the study drug.

The efficacy and safety profile of rivaroxaban was generally comparable in the pediatric population with VTE and the adult population with DVT/PE, however, the proportion of patients with any bleeding was higher in the pediatric population with VTE compared to the adult population with DVT/PE.

Patients with high-risk triple-positive antiphospholipid syndrome

In an investigator-sponsored randomized open multicenter study with blinded endpoint assessment, Rivaroxaban was studied compared to warfarin in patients with a history of thrombosis, diagnosed with antiphospholipid syndrome at high risk of thromboembolic events (positive for all three antiphospholipid syndrome tests: presence of lupus anticoagulant, anticardiolipin antibodies, and anti-beta-2-glycoprotein I antibodies). After including 120 patients, the study was terminated early due to an increased frequency of events in patients in the rivaroxaban group. The mean follow-up period was 569 days. 59 patients were randomized to the rivaroxaban group at a dose of 20 mg (15 mg for patients with CrCl <50 ml/min) and 61 to the warfarin group (INR 2.0-3.0). Thromboembolic events occurred in 12% of patients randomized to the rivaroxaban group (4 ischemic strokes and 3 myocardial infarctions). No events were recorded in patients randomized to the warfarin group. Major bleeding occurred in 4 patients (7%) from the rivaroxaban group and 2 patients (3%) from the warfarin group.

Pharmacokinetics

Absorption

The information provided below is based on data obtained from the adult population. Rivaroxaban is rapidly absorbed; C_max is reached within 2-4 hours after tablet intake. When rivaroxaban is administered orally as 2.5 mg and 10 mg tablets, the drug is almost completely absorbed, with high bioavailability (80-100%) regardless of food intake. Co-administration of rivaroxaban 2.5 mg and 10 mg doses with food does not affect the AUC and C_max of rivaroxaban. Due to reduced absorption, a bioavailability of 66% was observed when 20 mg tablets were taken on an empty stomach. When 20 mg rivaroxaban tablets were taken with food, a 39% increase in mean AUC was noted compared to taking the tablet on an empty stomach, showing almost complete absorption and high bioavailability. Rivaroxaban 15 mg and 20 mg doses should be taken with food (see section “Dosage Regimen”).

The pharmacokinetics of rivaroxaban are almost linear in doses up to 15 mg once daily when taken on an empty stomach. Under conditions of rivaroxaban intake as 10 mg, 15 mg, and 20 mg tablets with food, dose-dependency is observed. At higher doses, Rivaroxaban demonstrates dissolution-limited absorption, with reduced bioavailability and a decreased absorption rate as the dose increases.

The pharmacokinetics of rivaroxaban are characterized by moderate inter-individual variability (coefficient of variation) in the range of 30 to 40%.

The absorption of rivaroxaban depends on the site of release in the GI tract. A reduction in AUC and C_max by 29% and 56%, respectively, was observed when rivaroxaban granulate was released in the proximal small intestine compared to intake of an intact tablet. Drug exposure is further reduced when rivaroxaban is administered into the distal small intestine or ascending colon. Therefore, administration of rivaroxaban distal to the stomach should be avoided, as it may lead to reduced absorption and, consequently, reduced exposure to rivaroxaban. The bioavailability (AUC and C_max) of rivaroxaban 20 mg when administered orally as a crushed tablet mixed with apple puree or suspended in water, as well as when administered via a gastric tube followed by liquid nutrition, was comparable to the bioavailability of an intact tablet. Given the predictable dose-dependent pharmacokinetic profile of rivaroxaban, the results of this bioavailability study are also applicable to lower doses of rivaroxaban.

Children. Children received Rivaroxaban as tablets or oral suspension during or immediately after feeding or meals, along with a usual amount of fluid to ensure proper dosing in children. As in adults, Rivaroxaban is rapidly absorbed after oral administration in the tablet or granule for oral suspension form. No difference was noted in either the rate or extent of absorption between the tablet and granule for oral suspension forms. Data on pharmacokinetics after intravenous administration in children are lacking, so the absolute bioavailability of rivaroxaban in children is unknown. A 55% reduction in relative bioavailability was found with increasing doses (in mg/kg body weight), suggesting absorption limitations for higher doses, even when taken with food. Rivaroxaban as 15 mg or 20 mg tablets should be taken during feeding or with meals (see section “Dosage Regimen”).

Distribution

Plasma protein binding in adults is high and amounts to approximately 92-95%, with serum albumin being the main binding component. The volume of distribution is moderate, V_ss is approximately 50 L.

Children. There are no child-specific data on the binding of rivaroxaban to plasma proteins. Data on pharmacokinetics after intravenous administration of rivaroxaban in children are lacking. The V_ss in children (age range from 0 to <18 years) after oral administration of rivaroxaban, predicted by population pharmacokinetic modeling, is dependent on body weight and can be described by an allometric function with a mean value of 113 L for a subject with a body weight of 82.8 kg.

Metabolism and Excretion

In adult patients taking rivaroxaban, approximately two-thirds of the dose is metabolized and subsequently excreted in equal parts by the kidneys and via the intestines. The remaining one-third of the administered dose is excreted via direct renal excretion as unchanged active substance, mainly via active renal secretion.

Rivaroxaban is metabolized via the CYP3A4 and CYP2J2 isoenzymes, as well as by mechanisms independent of the cytochrome system. The main sites of biotransformation are oxidation of the morpholine group and hydrolysis of amide bonds. According to in vitro data, Rivaroxaban is a substrate for the transporter proteins Pgp (P-glycoprotein) and BCRP (Breast Cancer Resistance Protein). Unchanged Rivaroxaban is the most important compound in human plasma; no major or active circulating metabolites have been detected in plasma. Rivaroxaban, with a systemic clearance of approximately 10 L/h, can be classified as a low-clearance drug. After intravenous administration of 1 mg rivaroxaban, T_1/2 is about 4.5 hours. After oral administration, elimination becomes limited by the absorption rate. During elimination of rivaroxaban from plasma, the terminal T_1/2 is from 5 to 9 hours in young patients and from 11 to 13 hours in elderly patients.

Children. There are no child-specific data on metabolism. Data on pharmacokinetics after intravenous administration of rivaroxaban in children are lacking. Clearance in children (age range from 0 to <18 years) after oral administration of rivaroxaban, predicted by population pharmacokinetic modeling, is dependent on body weight and can be described by an allometric function with a mean value of 8 L/h for a subject with a body weight of 82.8 kg. The geometric mean T_1/2 values, calculated using population pharmacokinetic modeling, decrease with decreasing age and range from 4.2 hours in adolescents to approximately 3 hours in children aged 2-12 years, to 1.9 and 1.6 hours in children aged 0.5-<2 years and less than 0.5 years, respectively.

Pharmacokinetics in Special Patient Groups

Gender

In adults, there were no clinically relevant differences in pharmacokinetics and pharmacodynamics between men and women. Analysis of the data did not reveal significant differences in rivaroxaban exposure among children of different genders.

Elderly Patients

In elderly patients, rivaroxaban plasma concentrations are higher than in young patients; the mean AUC is approximately 1.5 times higher than the corresponding values in young patients, mainly due to a reduction in (probable) total and renal clearance. Dose adjustment is not required.

Body Weight

In adults, extreme body weight (less than 50 kg and more than 120 kg) only slightly influenced rivaroxaban plasma concentrations (less than 25%). Dose adjustment is not required.

In children, the dose of rivaroxaban depends on body weight. Analysis of data obtained for children did not reveal a significant effect of underweight or obesity on rivaroxaban exposure.

Interethnic Differences

No clinically significant differences in pharmacokinetics and pharmacodynamics were observed in adult patients of Caucasian, African-American, Hispanic, Japanese, or Chinese ethnicity.

Analysis of the data did not reveal significant interethnic differences in rivaroxaban exposure among children of Japanese, Chinese, or Asian ethnicity outside Japan and China compared to the general 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 from the corresponding parameters in the control group of healthy subjects (on average, a 1.2-fold increase in rivaroxaban AUC was noted).

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 unbound AUC increased 2.6-fold. These patients also had reduced renal excretion of rivaroxaban, similar to that in patients with moderate renal impairment. Data for patients with severe impairment are not available.

Inhibition of factor Xa activity in patients with moderate hepatic impairment was 2.6 times more pronounced than in healthy volunteers; the increase in prothrombin time similarly increased 2.1-fold. Patients with moderate hepatic impairment were more sensitive to rivaroxaban, which is a consequence of a closer relationship between pharmacodynamic effects and pharmacokinetic parameters between concentration and prothrombin time. Rivaroxaban is contraindicated in patients with liver disease associated with coagulopathy and a risk of clinically significant bleeding, including patients with Child-Pugh class B and C cirrhosis (see section “Contraindications”).

Clinical data for children with hepatic impairment are not available.

Renal Impairment

In adult patients, an increase in rivaroxaban exposure was observed, correlating with decreased renal function, assessed by measuring CrCl. In patients with mild (CrCl 50-80 ml/min), moderate (CrCl 30-49 ml/min), and severe (CrCl 15-29 ml/min) renal impairment, rivaroxaban plasma concentrations (AUC) were increased 1.4-fold, 1.5-fold, and 1.6-fold, respectively. The corresponding increase in pharmacodynamic effects was more pronounced. In patients with mild, moderate, and severe renal impairment, total inhibition of factor Xa activity increased 1.5-fold, 1.9-fold, and 2.0-fold, respectively, compared to healthy volunteers; prothrombin time also increased 1.3-fold, 2.2-fold, and 2.4-fold, respectively.

Data for patients with CrCl <15 ml/min are not available.

Rivaroxaban is not expected to be dialyzable due to high plasma protein binding.

The use of the drug is not recommended in patients with CrCl <15 ml/min. Caution should be exercised when using the drug in patients with CrCl 15-29 ml/min (see section "Special Instructions").

Data from clinical studies in children aged 1 year and older with moderate or severe renal impairment (GFR <50 ml/min/1.73 m²) are not available.

Pharmacokinetic Data in Patients

In adult patients receiving Rivaroxaban 20 mg once daily for the treatment of acute DVT, the geometric mean concentrations (90% predictive interval) at 2-4 hours and approximately 24 hours after dose administration (which approximately corresponds to C_max and C_min in the dosing interval) were 215 (22-535) μg/L and 32 (6-239) μg/L, respectively.

The geometric mean concentrations (90% interval) at sampling time points approximately corresponding to C_max and C_min in the dosing interval in children with acute VTE receiving Rivaroxaban at a body weight-dependent dose to achieve exposure corresponding to that in adult patients with DVT receiving a 20 mg once daily dose are presented in Table 13-10.

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

N.c. – not calculated

Values below the lower limit of quantification (LLOQ) were replaced by 1/2 LLOQ for statistical calculation (LLOQ = 0.5 μg/L).

Relationship between Pharmacokinetic Parameters and Pharmacodynamic Effects

The relationship between pharmacokinetic parameters and pharmacodynamic effects (PK/PD) between rivaroxaban plasma concentration and several pharmacodynamic endpoints (inhibition of factor Xa, prothrombin time, aPTT, HepTest) was evaluated after administration of a wide range of doses (from 5 to 30 mg twice daily). The relationship between rivaroxaban concentration and factor Xa activity was best demonstrated using an E_max model. For prothrombin time, a linear regression model generally better described the data. The slope varied significantly depending on the 60 reagents used to determine prothrombin time. When using the Neoplastin PT kit, the baseline prothrombin time was about 13 sec with a line slope of about 3-4 sec (100 μg/L). The results of the PK/PD relationship analysis in phase II and III studies were consistent with those in healthy patients.

Children

The safety and efficacy of rivaroxaban in children and adolescents under 18 years of age for the indication of prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation have not been established.

Indications

Adults aged 18 years and older

• Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation;
• Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of recurrent DVT and PE.

Children and adolescents under 18 years of age

Xiltess^®, 15 mg, film-coated tablets

• Treatment of venous thromboembolism (VTE) and prevention of recurrent VTE in children and adolescents under 18 years of age with a body weight from 30 kg to 50 kg after at least 5 days of initial parenteral anticoagulant therapy.

Xiltess^®, 20 mg, film-coated tablets

• Treatment of venous thromboembolism (VTE) and prevention of recurrent VTE in children and adolescents under 18 years of age with a body weight over 50 kg after at least 5 days of initial parenteral anticoagulant therapy.

ICD codes

Dosage Regimen

Tablets

Prevention of stroke and systemic embolism in adults

The recommended dose is 20 mg once daily, which is also the recommended maximum daily dose.

Therapy with Xiltess^® should be considered as long-term treatment provided that the benefit of preventing stroke and systemic embolism outweighs the risk of bleeding (see section “Special Instructions”).

If a dose is missed, the patient should take the Xiltess^® tablet immediately and continue taking the drug once daily as recommended the next day. A double dose should not be taken on the same day to compensate for the missed dose.

Treatment of DVT and PE and prevention of recurrent DVT and PE in adults

The recommended initial dose for the treatment of acute DVT or PE is 15 mg twice daily for the first 3 weeks, followed by a switch to 20 mg once daily for further treatment and prevention of recurrent DVT and PE.

A short duration of treatment (at least 3 months) should be considered for patients with DVT or PE provoked by major reversible risk factors (i.e., recent major surgery or trauma). A longer treatment period should be considered for patients with DVT or PE not associated with major reversible risk factors, with unprovoked DVT or PE, or with a history of DVT or PE.

When extended prevention of recurrent DVT or PE is indicated (after completing at least 6 months of treatment for DVT or PE), the recommended dose is 10 mg once daily. For patients at high risk of recurrent DVT or PE, such as patients with severe comorbidities or those who developed recurrent DVT or PE during extended prophylaxis with Xiltess^® at a dose of 10 mg once daily, the use of Xiltess^® at a dose of 20 mg once daily should be considered. The duration of treatment and choice of dose should be determined individually after careful assessment of the benefit of treatment against the risk of bleeding (see section “Special Instructions”).

Table 11 .

If a dose is missed during the 15 mg twice daily dosing regimen (days 1-21), the patient should take the Xiltess^® tablet immediately to achieve the daily dose of 30 mg of Xiltess^®. In this case, two 15 mg tablets can be taken at one time. The next day, the patient should continue the regular intake of 15 mg twice daily as recommended.

If a dose is missed with a dosing regimen of once daily, the patient should take the Xiltess^® tablet immediately and continue taking the drug once a day as recommended the next day. A double dose should not be taken on the same day to compensate for the missed dose.

Treatment of VTE and prevention of recurrent VTE in children and adolescents

Treatment with Xiltess^® in children and adolescents under 18 years of age should be initiated after at least 5 days of initial parenteral anticoagulant therapy (see the “Pharmacological Action” section).

The dose for children and adolescents is calculated based on body weight:

• body weight from 30 kg to 50 kg recommended dose is 15 mg of rivaroxaban once daily, which is the maximum daily dose;
• body weight 50 kg or more recommended dose is 20 mg of rivaroxaban once daily, which is the maximum daily dose;
• For patients with body weight less than 30 kg, other rivaroxaban drugs available on the market in the form of granules for oral suspension should be used.

Body weight should be monitored regularly and the dose should be reviewed. This is necessary to ensure maintenance of the therapeutic dose. Dose adjustment should be performed only based on changes in body weight.

Treatment in children and adolescents should continue for at least 3 months. The duration of treatment can be extended up to 12 months if clinically necessary. There are no data to support dose reduction in children after 6 months of therapy. The benefit-risk ratio for therapy duration beyond 3 months should be assessed individually, taking into account the risk of thrombosis recurrence and the potential risk of bleeding.

If a dose is missed, the missed dose should be taken as soon as possible after it is noticed, but only on the same day. If this is not possible, the patient should skip that dose and continue with the next dose as prescribed by the doctor. The patient should not take a double dose to compensate for the missed dose.

Transition from Vitamin K Antagonists (VKAs) to Xiltess^®

For stroke prevention and systemic embolism VKA treatment should be discontinued and treatment with Xiltess^® should be initiated when the INR value is ≤ 3.0.

For treatment of DVT, PE and prevention of recurrence in adults, as well as for treatment of VTE and prevention of recurrence in children: VKA treatment should be discontinued and treatment with Xiltess^® should be initiated when the INR value is ≤ 2.5. When transitioning patients from VKAs to Xiltess^®, INR values will be falsely elevated after taking Xiltess^®. INR is not suitable for determining the anticoagulant activity of Xiltess^® and therefore should not be used for this purpose (see the “Drug Interactions” section).

Transition from Xiltess^® to Vitamin K Antagonists (VKAs)

There is a possibility of insufficient anticoagulant effect when transitioning from Xiltess^® to VKAs. Continuous adequate anticoagulant effect must be ensured during the transition to an alternative anticoagulant. It should be noted that Xiltess^® may contribute to an increase in INR.

Patients transitioning from Xiltess^® to VKAs should take VKAs concomitantly until the INR reaches ≥ 2.0. During the first two days of the transition period, the standard initial dose of VKA should be used, followed by a VKA dose determined based on the INR value. During concomitant use of Xiltess^® and VKAs, the INR value should be determined no earlier than 24 hours after the previous dose, but before taking the next dose of Xiltess^®. After discontinuation of Xiltess^®, the INR value can be reliably determined 24 hours after the last dose (see the “Pharmacokinetics” and “Drug Interactions” sections).

Children. Children transitioning from Xiltess^® to VKAs should continue taking Xiltess^® for 48 hours after the first VKA dose. After two days of concomitant use, INR should be measured before taking the next scheduled dose of Xiltess^®. Concomitant use of Xiltess^® and VKAs is recommended to continue until the INR reaches ≥2.0. After discontinuation of Xiltess^®, the INR value can be reliably determined 24 hours after the last dose (see above and the “Drug Interactions” section).

Transition from parenteral anticoagulants to Xiltess^®

In adults and children receiving parenteral anticoagulants, the parenteral anticoagulant should be discontinued and Xiltess^® should be initiated 0-2 hours before the time of the next scheduled administration of the parenteral drug (e.g., low molecular weight heparin) or at the time of discontinuation of continuous parenteral drug administration (e.g., intravenous unfractionated heparin (UFH)).

Transition from Xiltess^® to parenteral anticoagulants

Xiltess^® should be discontinued and the first dose of the parenteral anticoagulant should be administered at the time when the next dose of Xiltess^® was due.

Special patient groups

Patients with renal impairment

• Adults

Available limited clinical data demonstrate a significant increase in rivaroxaban plasma concentrations in patients with severe renal impairment (CrCl 15-29 ml/min). Consequently, Xiltess^® should be used with caution in this category of patients. Use is not recommended in patients with CrCl <15 ml/min (see the “Pharmacokinetics” and “Special Instructions” sections). In patients with moderate (CrCl 30-49 ml/min) or severe (CrCl 15-29 ml/min) renal impairment, the recommendations below should be followed.

For stroke prevention and systemic embolism in patients with non-valvular atrial fibrillation the recommended dose is 15 mg once daily (see the “Pharmacokinetics” section).

For treatment of DVT and PE and prevention of recurrent DVT and PE patients should take 15 mg twice daily for the first three weeks. Subsequently, when the recommended dose of Xiltess^® is 20 mg once daily, a dose reduction from 20 mg to 15 mg once daily should be considered if the patient’s risk of bleeding is higher than the risk of recurrent DVT and PE. The recommendation for the 15 mg dose is based on pharmacokinetic modeling and has not been studied in clinical trials (see the “Pharmacokinetics” and “Special Instructions” sections). When the recommended dose is 10 mg once daily, no dose adjustment compared to the recommended dose is required.

In patients with mild renal impairment (CrCl 50-80 ml/min) no dose adjustment is required (see the “Pharmacokinetics” section).

• Children

Children and adolescents with mild renal impairment (GFR 50-80 ml/min/1.73 m² ) no dose adjustment is required based on data in the adult population and limited data in the pediatric population (see the “Pharmacokinetics” section).

Children and adolescents with moderate or severe renal impairment (GFR <50 ml/min/1.73 m² ) Xiltess^® is not recommended due to lack of clinical data.

Patients with hepatic impairment

Xiltess^® is contraindicated in patients with liver disease associated with coagulopathy and clinically significant bleeding risk, including patients with Child-Pugh class B and C cirrhosis. For children with hepatic impairment, clinical data are lacking.

Elderly patients

No dose adjustment is required (see the “Special Instructions” section).

Body weight

No dose adjustment is required for adults (see the “Pharmacokinetics” section). The dose for children is determined based on body weight.

Gender

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

Patients undergoing cardioversion

Treatment with Xiltess^® may be initiated or continued in patients who may require cardioversion.

For cardioversion under transesophageal echocardiography (TEE) control in patients who have not previously received anticoagulant therapy, to ensure adequate anticoagulation, treatment with Xiltess^® should be initiated at least 4 hours before cardioversion. For all patients, confirmation should be obtained before cardioversion that the patient has taken Xiltess^® as prescribed by the doctor. When making decisions on initiation and duration of treatment, current guidelines and recommendations for anticoagulant therapy in patients undergoing cardioversion should be taken into account.

Patients with non-valvular atrial fibrillation who have undergone PCI (percutaneous coronary intervention) with stenting

There is limited experience with Xiltess^® at a reduced dose of 15 mg once daily (or 10 mg once daily for patients with moderate renal impairment (CrCl 30-49 ml/min)) in combination with a P2Y12 receptor inhibitor for up to 12 months in patients with non-valvular atrial fibrillation requiring oral anticoagulants who have undergone PCI with stenting (see the “Pharmacological Action” and “Special Instructions” sections).

Children

The safety and efficacy of Xiltess^® in children aged 0 to <18 years for the indication stroke prevention and systemic embolism in patients with non-valvular atrial fibrillation have not been established. Data are lacking. Therefore, Xiltess^® is not recommended for use in children under 18 years of age for indications other than treatment of VTE and prevention of recurrent VTE.

Method of administration

Adults. Xiltess^® is intended for oral administration. The tablets should be taken with food (see the “Pharmacokinetics” section).

Crushed tablets

If the patient is unable to swallow the tablet whole, the Xiltess^® tablet may be crushed and mixed with water or apple puree immediately before use and administered orally. After administration of the crushed 15 mg or 20 mg Xiltess^® tablet, a meal should be taken immediately. The crushed tablet can also be administered via a nasogastric or gastric tube.

Children with body weight of at least 30 kg. Xiltess^® is intended for oral administration. The patient should be advised to swallow the tablet with liquid. It should also be taken with food. Tablets should be taken at intervals of approximately 24 hours. If the patient regurgitates the administered dose immediately or vomits within 30 minutes after taking the dose, a new dose should be taken. However, if the patient vomits later than 30 minutes after taking the dose, a repeat dose is not required, and the next dose should be taken as scheduled.

The tablet should not be split to obtain a partial dose from the tablet.

Crushing tablets

If the patient is unable to swallow the tablet whole, other drugs available on the market in the form of granules for oral suspension should be used. If an oral suspension is not immediately available when a 15 mg or 20 mg Rivaroxaban dose is prescribed, these doses can be obtained by crushing a 15 mg or 20 mg tablet and mixing it with water or apple puree immediately before use and oral administration.

The crushed tablet can also be administered via a nasogastric or gastric tube.

Rivaroxaban tablets can be crushed, suspended in 50 ml of water, and administered via a nasogastric or gastric tube after confirming the tube’s position in the stomach. The tube should then be flushed with water. Because the absorption of rivaroxaban depends on the site of release of the active substance, administration of rivaroxaban distal to the stomach should be avoided, otherwise it may lead to reduced absorption and consequently reduced exposure to the active substance. After administration of the crushed 15 mg or 20 mg rivaroxaban tablet, enteral nutrition should be initiated immediately.

All remaining medicinal product and waste should be disposed of in accordance with established procedures.

Adverse Reactions

The safety of rivaroxaban was evaluated in thirteen phase III studies (see Table 12). A total of 69,608 adult patients in nineteen phase III studies and 488 children in two phase II studies and two phase III studies received Rivaroxaban.

Table 12. Number of patients participating in studies, and total daily dose and maximum duration of treatment in phase III clinical studies involving adult and pediatric patients

* Patients who received at least one dose of rivaroxaban.

** From the VOYAGER PAD study.

The most frequently reported adverse reactions in patients receiving Rivaroxaban were bleeding (Table 13). The most frequently reported bleedings were epistaxis (4.5%) and gastrointestinal bleeding (3.8%).

Table 13. Frequency of bleeding* and anemia in patients treated with rivaroxaban in completed phase III clinical studies involving adult and pediatric patients

* In all rivaroxaban clinical studies, all bleeding events are collected, recorded, and assessed.

** In the COMPASS study, the incidence of anemia is low due to a selective approach to collecting adverse event data.

The frequency of adverse reactions reported in children and adults with rivaroxaban use is presented in Table 14 below, categorized by system organ class (MedDRA) and by frequency. Frequency is defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data).

Table 14. All adverse reactions reported in adult patients in phase III clinical studies or during post-marketing use*, as well as in pediatric patients in two phase II studies and two phase III studies

^A observed during VTE prophylaxis in adult patients undergoing elective hip or knee replacement surgery;

^B observed during treatment of DVT, PE and recurrence prevention as very common in women under 55 years of age;

^C observed as uncommon in the context of prevention of atherothrombotic events in patients after ACS (after percutaneous coronary intervention).

* A predefined selective approach to collecting adverse event data was used in individual Phase III studies. Based on the analysis of data from these studies, the frequency of adverse reactions did not increase, and no new adverse drug reactions were identified.

Description of selected adverse reactions

Given the pharmacological mechanism of action, the use of rivaroxaban may be associated with an increased risk of occult or overt bleeding from any tissues and organs, which may lead to post-hemorrhagic anemia.

Signs, symptoms and severity (including possible fatal outcome) will vary depending on the location, intensity or duration of bleeding and/or anemia.

In clinical studies, mucosal bleeding (namely, epistaxis, gingival, gastrointestinal, genitourinary bleeding, including abnormal vaginal or increased menstrual bleeding) and anemia were observed more frequently during long-term treatment with rivaroxaban compared to VKA treatment.

Thus, in addition to proper clinical monitoring, laboratory testing of hemoglobin/hematocrit may be useful for detecting occult bleeding and quantifying the clinical significance of overt bleeding where applicable.

The risk of bleeding may be increased in certain patient groups, for example, in patients with severe uncontrolled arterial hypertension and/or when used concomitantly with drugs affecting hemostasis. Menstrual bleeding may be heavier and/or prolonged.

Hemorrhagic complications may manifest as weakness, pallor, dizziness, headache, or unexplained swelling, shortness of breath, or unexplained shock. In some cases, symptoms of myocardial ischemia, such as chest pain or angina, have been observed due to anemia.

Known complications secondary to severe bleeding, such as compartment syndrome and renal failure due to hypoperfusion, have been reported with rivaroxaban use.

Therefore, the possibility of bleeding should be considered when assessing the condition of any patient receiving anticoagulants.

Children

Treatment of VTE and prevention of recurrent VTE

The safety assessment in children and adolescents is based on safety data from active-controlled open-label studies (two Phase II and one Phase III study) involving patients from birth to <18 years of age. Safety data were generally comparable between the rivaroxaban and comparator groups across different age groups of children. Overall, the safety profile in 412 children and adolescents receiving Rivaroxaban was similar to the safety profile observed in the adult population and was consistent across age groups, although the assessment is limited by the small number of 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 concentration (common, 1.5%) and increased conjugated bilirubin concentration (uncommon, 0.7%) were reported more frequently in pediatric patients than in adults. As in the adult population, menorrhagia was observed in 6.6% (common) of post-menarche adolescent girls. Thrombocytopenia, observed in post-marketing surveillance in the adult population, was observed commonly (4.6%) in clinical studies in the pediatric population.

Adverse drug reactions in children were mostly of mild to moderate severity.

Contraindications

• Hypersensitivity to rivaroxaban or to any of the excipients;
• Clinically significant active bleeding;
• Lesion or condition associated with an increased risk of major bleeding, e.g., current or recent gastrointestinal ulcer, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal cord injury, recent brain, spinal cord or eye surgery, recent intracranial hemorrhage, diagnosed or suspected esophageal varices, arteriovenous malformations, vascular aneurysms or major abnormalities of the brain or spinal cord vessels;
• Concomitant therapy with any other anticoagulants, e.g., unfractionated heparin (UFH), low molecular weight heparins (including enoxaparin, dalteparin), heparin derivatives (including fondaparinux), oral anticoagulants (including warfarin, dabigatran etexilate, apixaban), except when switching to or from Rivaroxaban, or when using unfractionated heparin (UFH) at doses necessary to maintain the patency of a central venous or arterial catheter;
• Liver disease associated with coagulopathy and clinically significant bleeding risk, including patients with Child-Pugh class B and C cirrhosis;
• Pregnancy;
• Breastfeeding period.

Use in Pregnancy and Lactation

Pregnancy

The safety and efficacy of rivaroxaban in pregnant women have not been established. Data from animal studies have shown reproductive toxicity. Due to the potential reproductive toxicity, risk of bleeding, and data on the ability of rivaroxaban to cross the placenta, Xiltess^® is contraindicated during pregnancy. Women of childbearing potential should avoid becoming pregnant during rivaroxaban therapy.

Breastfeeding period

The safety and efficacy of rivaroxaban in women during breastfeeding have not been established. Data from animals indicate that Rivaroxaban is excreted in breast milk. Therefore, Xiltess^® is contraindicated during breastfeeding. A decision must be made to discontinue breastfeeding or to discontinue/interrupt therapy.

Fertility

No specific studies have been conducted to evaluate the effect of rivaroxaban on human fertility. Studies have shown that Rivaroxaban does not affect male or female fertility in rats.

Use in Hepatic Impairment

Xiltess^® is contraindicated in patients with liver disease associated with coagulopathy and clinically significant bleeding risk, including patients with Child-Pugh class B and C cirrhosis.

For children with hepatic impairment, clinical data are lacking.

Use in Renal Impairment

Available limited clinical data demonstrate a significant increase in rivaroxaban plasma concentrations in patients with severe renal impairment (CrCl 15-29 ml/min). Therefore, Xiltess^® should be used with caution in this category of patients. Use is not recommended in patients with CrCl <15 ml/min. In patients with moderate (CrCl 30-49 ml/min) or severe (CrCl 15-29 ml/min) renal impairment, dose adjustment is required according to recommendations.

Pediatric Use

The safety and efficacy of Xiltess^® in children aged 0 to <18 years for the indication **prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation** have not been established. No data are available. Therefore, Xiltess^® is not recommended for use in children under 18 years of age for indications other than treatment of VTE and prevention of recurrent VTE.

Geriatric Use

No dose adjustment is required.

Special Precautions

Clinical monitoring in accordance with the clinical practice of anticoagulant use is recommended throughout the treatment period.

Bleeding risk

As with other anticoagulants, patients taking Xiltess^® should be carefully observed for signs of bleeding. The drug should be used with caution in conditions associated with an increased risk of bleeding. In case of severe bleeding, Xiltess^® should be discontinued.

In clinical studies, mucosal bleeding (namely, epistaxis, gingival, gastrointestinal, genitourinary bleeding, including abnormal vaginal or increased menstrual bleeding) and anemia were observed more frequently during long-term treatment with rivaroxaban compared to VKA treatment.

Thus, in addition to proper clinical monitoring, laboratory testing of hemoglobin/hematocrit may be useful for detecting occult bleeding and quantifying the clinical significance of overt bleeding where applicable.

Several patient subgroups listed below have an increased risk of bleeding. Such patients should be carefully monitored after initiation of treatment for signs and symptoms of bleeding complications and anemia.

Any unexplained decrease in hemoglobin or blood pressure should prompt a search for a bleeding source.

Routine monitoring of rivaroxaban exposure is not required during therapy. However, measurement of rivaroxaban concentration using a calibrated quantitative anti-Xa activity assay may be helpful in exceptional situations where information on rivaroxaban exposure may be used in making clinically relevant decisions, such as in cases of overdose or emergency surgery.

Use in pediatrics

There are limited data on use in children with cerebral venous sinus thrombosis who have a CNS infection. The risk of bleeding should be carefully assessed before prescribing and during rivaroxaban therapy.

Patients with renal impairment

In patients with severe renal impairment (CrCl <30 ml/min), rivaroxaban plasma concentrations may be significantly increased (on average 1.6-fold), which may lead to an increased risk of bleeding. Xiltess^® should be used with caution in patients with CrCl 15-29 ml/min. Use of the drug in patients with CrCl <15 ml/min is not recommended.

Xiltess^® should be used with caution in patients with renal impairment receiving concomitant drugs that increase rivaroxaban plasma concentrations.

Xiltess^® is not recommended for use in children and adolescents with moderate or severe renal impairment (eGFR <50 ml/min/1.73 m² ) due to lack of clinical data.

Drug interactions

Use of Xiltess^® is not recommended in patients receiving concomitant systemic treatment with azole antifungal agents (such as ketoconazole, itraconazole, voriconazole and posaconazole) or HIV protease inhibitors (e.g., ritonavir). These drugs are potent inhibitors of both CYP3A4 and P-glycoprotein. Thus, these drugs may increase rivaroxaban plasma concentrations to clinically significant levels (on average 2.6-fold), which may lead to an increased risk of bleeding. Clinical data on concomitant systemic treatment of children with potent inhibitors of both CYP3A4 and P-glycoprotein are lacking.

Caution should be exercised if the patient is concomitantly receiving drugs affecting hemostasis, such as NSAIDs, acetylsalicylic acid (ASA) and platelet aggregation inhibitors or selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs). Patients at risk of gastrointestinal ulceration may be prescribed appropriate prophylactic treatment.

Other risk factors for bleeding

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

• Congenital or acquired bleeding diathesis;
• Uncontrolled severe arterial hypertension;
• Other gastrointestinal diseases without active ulceration that may potentially lead to bleeding complications (e.g., inflammatory bowel disease, esophagitis, gastritis and gastroesophageal reflux disease);
• Vascular retinopathy;
• Bronchiectasis or history of pulmonary hemorrhage.

Patients with cancer

Patients with a malignant disease may simultaneously be at higher 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 tumor location, anticancer therapy and disease stage. Tumors located in the gastrointestinal or genitourinary tract were associated with an increased risk of bleeding during rivaroxaban therapy. In patients with malignant neoplasms at high risk of bleeding, the use of rivaroxaban is contraindicated.

Patients with prosthetic heart valves

Rivaroxaban should not be used for thrombosis prophylaxis in patients who have undergone recent transcatheter aortic valve replacement. The safety and efficacy of Xiltess^® have not been studied in patients with prosthetic heart valves; therefore, there are no data to support that the use of Xiltess^® provides adequate anticoagulation in this category of patients. Use of Xiltess^® is not recommended in this category of patients.

Patients with antiphospholipid syndrome

The use of direct oral anticoagulants, including Rivaroxaban, is not recommended in patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome. In particular, in patients with triple-positive antiphospholipid syndrome (presence of lupus anticoagulant, anticardiolipin antibodies and anti-beta-2-glycoprotein I antibodies), therapy with direct oral anticoagulants may be associated with an increased frequency of recurrent thrombotic events compared with vitamin K antagonist therapy.

Patients with non-valvular atrial fibrillation who have undergone PCI with stenting

There are data from an interventional clinical study whose primary objective was to evaluate the safety profile in patients with non-valvular atrial fibrillation who underwent PCI with stenting. Efficacy data in this population are limited. There are no data on such patients with a history of stroke/transient ischemic attack.

Patients with hemodynamically unstable pulmonary embolism (PE) or patients requiring thrombolysis or pulmonary embolectomy

Xiltess^® is not recommended as an alternative to unfractionated heparin in patients with pulmonary embolism who are hemodynamically unstable or may require thrombolysis or pulmonary embolectomy, since the safety and efficacy of Xiltess^® in such clinical situations have not been established.

Spinal/epidural anesthesia or puncture

When performing neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural puncture in patients receiving antithrombotic drugs for the prevention of thromboembolic complications, there is a risk of developing an epidural or spinal hematoma, which may lead to long-term or permanent paralysis.

The risk of these events may be increased with postoperative use of indwelling epidural catheters or concomitant therapy with drugs affecting hemostasis. Traumatic or repeated epidural or spinal puncture may also increase the risk. Patients should be monitored for signs and symptoms of neurological impairment (e.g., numbness or weakness in the legs, bowel or bladder dysfunction). If neurological disorders are detected, urgent diagnosis and treatment are necessary. The physician should weigh the potential benefit and risk before performing neuraxial intervention in patients receiving anticoagulants, or in whom anticoagulants are planned for thrombosis prophylaxis.

There is no clinical experience with rivaroxaban at doses of 15 mg and 20 mg in the described situations. To reduce the potential risk of bleeding associated with the simultaneous use of rivaroxaban and performance of neuraxial (epidural/spinal) anesthesia or spinal puncture, the pharmacokinetic profile of rivaroxaban should be taken into account. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of rivaroxaban is estimated to be low. However, the exact timing to achieve a sufficiently low anticoagulant effect in each patient is unknown and should be assessed against the urgency of the diagnostic procedure.

Based on general pharmacokinetic characteristics, the epidural catheter is removed after at least twice the half-life, i.e., no earlier than 18 hours after the last dose of rivaroxaban for young adult patients and no earlier than 26 hours for elderly patients. At least 6 hours should elapse after removal of the epidural catheter before the next dose of rivaroxaban is taken. In case of traumatic puncture, rivaroxaban administration should be delayed for 24 hours.

There are no data on the timing of placement or removal of a neuraxial catheter in children taking Xiltess^®. In such cases, rivaroxaban should be discontinued and consideration given to using a short-acting parenteral anticoagulant.

Dosing Recommendations Before and After Invasive Procedures and Surgical Interventions

If an invasive procedure or surgical intervention is necessary, based on the physician’s assessment, administration of Xiltess^® 15 mg and 20 mg should be discontinued at least 24 hours prior to the intervention, if possible.

If the procedure cannot be postponed, the increased risk of bleeding should be weighed against the urgency of the intervention.

Administration of Xiltess^® should be resumed as soon as possible after the invasive procedure or surgical intervention, provided the treating physician determines that the clinical situation allows it and adequate hemostasis has been achieved.

Elderly Patients

The risk of bleeding may increase with advancing age.

Dermatological Reactions

During post-marketing surveillance, cases of serious skin reactions, including Stevens-Johnson syndrome/toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported with the use of rivaroxaban. Patients appear to be at the highest risk of developing these reactions early in treatment: the onset of the reaction occurs in most cases within the first weeks of treatment. At the first appearance of a severe skin rash (e.g., spreading, intensifying and/or blistering) or any other symptoms of hypersensitivity associated with mucosal lesions, therapy with rivaroxaban should be discontinued.

Excipients

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Effect on Ability to Drive and Use Machines

Xiltess^® has a minor influence on the ability to drive and use machines. Adverse reactions such as syncope (frequency: uncommon) and dizziness (frequency: common) have been reported. Patients experiencing such adverse reactions should not drive or operate machinery.

Overdose

Symptoms

Rare cases of overdose up to 1960 mg have been reported in adults.

Data in children are limited. Due to limited absorption, a plateau in drug concentration is expected without further increase in its mean plasma concentration at supratherapeutic doses equal to 50 mg of rivaroxaban or higher in adults; however, data on supratherapeutic doses are lacking in children.

Treatment

In case of overdose, patients should be carefully observed for the development of bleeding or other adverse reactions (see “Treatment of Bleeding”). For adults, a specific antidote (andexanet alfa) that blocks the pharmacodynamic effect of rivaroxaban exists, but it is not approved for use in children. In case of rivaroxaban overdose, activated charcoal may be used to reduce absorption.

Treatment of Bleeding

If a patient develops bleeding complications while receiving Rivaroxaban, the next dose of rivaroxaban should be postponed or, if necessary, treatment should be discontinued. The T_1/2 of rivaroxaban in adults is approximately 5-13 hours. The T_1/2 in children, predicted by population pharmacokinetic modeling, is shorter (see section “Pharmacokinetics”). Treatment should be individualized depending on the severity and location of the bleeding. Appropriate symptomatic treatment, such as mechanical compression (e.g., for severe epistaxis), surgical hemostasis with bleeding control procedures, fluid replacement and hemodynamic support, administration of blood products (packed red blood cells or fresh frozen plasma, depending on whether anemia or coagulopathy has occurred) or platelets, may be used if necessary.

If the measures listed above do not lead to bleeding cessation, a specific Factor Xa inhibitor antidote (andexanet alfa), which blocks the pharmacodynamic effect of rivaroxaban, or specific procoagulant agents, for example, prothrombin complex concentrate, activated prothrombin complex concentrate, or recombinant factor VIIa (r-FVIIa), may be administered. However, current experience with these medicinal products in adults and children receiving Rivaroxaban is very limited. These recommendations are also based on limited non-clinical data. The possibility of recombinant factor VIIa re-administration and dose titration should be considered based on the reduction in bleeding activity. Depending on local availability, consultation with a coagulation specialist should be considered in case of major bleeding.

Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is limited experience with tranexamic acid and no experience with aminocaproic acid and aprotinin in adults receiving Rivaroxaban. There is no experience with these agents in children receiving Rivaroxaban. There is no scientific rationale or experience for the use of the systemic hemostatic agent desmopressin in patients receiving Rivaroxaban. Given the high plasma protein binding, Rivaroxaban is not expected to be dialyzable.

Drug Interactions

The extent of drug interactions in children is unknown. The interaction data provided below, obtained in adult patients, and the warnings in section 4.4 should be taken into account for the pediatric population.

CYP3A4 and P-glycoprotein Inhibitors

Concomitant use of rivaroxaban and ketoconazole (400 mg once daily) or ritonavir (600 mg twice daily) led to a 2.6-fold/2.5-fold increase in rivaroxaban AUC and a 1.7-fold/1.6-fold increase in mean rivaroxaban C_max with a significant enhancement of pharmacodynamic effects, which may lead to an increased risk of bleeding. Therefore, the use of Xiltess^® is not recommended in patients receiving concomitant systemic treatment with azole antifungal agents such as ketoconazole, itraconazole, voriconazole and posaconazole, or HIV protease inhibitors. These active substances are potent inhibitors of both CYP3A4 and P-glycoprotein.

Active substances that strongly inhibit only one of the elimination pathways of rivaroxaban, either CYP3A4 or P-glycoprotein, are expected to increase rivaroxaban plasma concentrations to a lesser extent. For example, clarithromycin (500 mg twice daily), considered a potent CYP3A4 inhibitor and a moderate P-glycoprotein inhibitor, caused a 1.5-fold increase in mean rivaroxaban AUC and a 1.4-fold increase in C_max. The interaction with clarithromycin is considered clinically insignificant for most patients but may be potentially significant for high-risk patients (for patients with renal impairment).

Erythromycin (500 mg three times daily), a moderate inhibitor of CYP3A4 and P-glycoprotein, caused a 1.3-fold increase in mean rivaroxaban AUC and C_max values. The interaction with erythromycin is considered clinically insignificant for most patients but may be potentially significant for high-risk patients.

In patients with mild renal impairment, erythromycin (500 mg three times daily) caused a 1.8-fold increase in mean rivaroxaban AUC and a 1.6-fold increase in C_max compared to patients with normal renal function. In patients with moderate renal impairment, erythromycin caused a 2.0-fold increase in mean rivaroxaban AUC and a 1.6-fold increase in C_max compared to patients with normal renal function. The effect of erythromycin is additive to renal impairment.

Fluconazole (400 mg once daily), considered a moderate CYP3A4 inhibitor, caused a 1.4-fold increase in mean rivaroxaban AUC and a 1.3-fold increase in mean C_max. The interaction with fluconazole is considered clinically insignificant for most patients but may be potentially significant for high-risk patients (for patients with renal impairment). Based on the available limited clinical data, concomitant use of rivaroxaban with dronedarone should be avoided.

Anticoagulants

After simultaneous administration of enoxaparin sodium (single dose 40 mg) and rivaroxaban (single dose 10 mg), an additive effect on anti-Xa activity was observed, without additional effects on coagulation tests (prothrombin time (PT), aPTT). Enoxaparin did not affect the pharmacokinetics of rivaroxaban.

Due to the increased risk of bleeding, caution should be exercised when co-administering with any other anticoagulants.

NSAIDs/Platelet Aggregation Inhibitors

After concomitant use of rivaroxaban (15 mg) and naproxen at a dose of 500 mg, no clinically significant increase in bleeding time was observed. However, a more pronounced pharmacodynamic response may be possible in some individuals.

No clinically significant pharmacokinetic or pharmacodynamic interactions were observed with the concomitant use of rivaroxaban and 500 mg acetylsalicylic acid.

No pharmacokinetic interaction was found between rivaroxaban (15 mg) and clopidogrel (loading dose of 300 mg, followed by a maintenance dose of 75 mg), but in a subgroup of patients, a significant increase in bleeding time was observed, which did not correlate with the extent of platelet aggregation and the content of P-selectin or GP?b/IIIa receptor. Caution should be exercised when co-administering with NSAIDs (including acetylsalicylic acid) and platelet aggregation inhibitors, as the use of these drugs usually increases the risk of bleeding.

SSRIs / SNRIs

As with other anticoagulants, the risk of bleeding may be increased in patients with concomitant use of selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs), due to the effect of these drugs on platelets. Results from clinical studies of rivaroxaban demonstrated a numerical increase in major and minor clinically relevant bleeding across all treatment groups with concomitant use of these drugs.

Warfarin

Transitioning patients from the vitamin K antagonist warfarin (INR 2.0 to 3.0) to Rivaroxaban (20 mg) or from rivaroxaban (20 mg) to warfarin (INR 2.0 to 3.0) increased prothrombin time/INR (Neoplastin) to a greater extent than the simple summation of effects (individual INR values may reach 12), while the effects on aPTT, Factor Xa activity inhibition, and endogenous thrombin potential (ETP) were additive.

If investigation of the pharmacodynamic effects of rivaroxaban is necessary during the transition period, anti-Xa activity, PiCT, and HepTest can be used as tests not affected by warfarin. Starting from the 4th day after the last dose of warfarin, all laboratory parameters (including PT, aPTT, Factor Xa activity inhibition, and ETP) reflected only the effect of rivaroxaban. If investigation of the pharmacodynamic effects of warfarin is necessary during the transition period, INR measurement at the rivaroxaban C_trough (24 hours after the previous rivaroxaban intake) may be used, since Rivaroxaban has a minimal effect on this parameter at that time.

No pharmacokinetic interaction was observed between warfarin and rivaroxaban.

CYP3A4 Inducers

Concomitant use of rivaroxaban and rifampicin, a potent CYP3A4 inducer, led to a decrease in mean rivaroxaban AUC by approximately 50% and a simultaneous reduction in its pharmacodynamic effects. Concomitant use of rivaroxaban with other potent CYP3A4 inducers (e.g., phenytoin, carbamazepine, phenobarbital, or St. John’s wort (Hypericum perforatum) preparations) may also lead to decreased rivaroxaban plasma concentrations. Therefore, concomitant use of potent CYP3A4 inducers should be avoided unless the patient is closely monitored for signs and symptoms of thrombosis.

Other Concomitant Therapy

No clinically significant pharmacokinetic or pharmacodynamic interactions were observed with the concomitant use of rivaroxaban with midazolam (CYP3A4 substrate), digoxin (P-glycoprotein substrate), atorvastatin (CYP3A4 and P-glycoprotein substrate), or omeprazole (proton pump inhibitor). Rivaroxaban does not inhibit or induce CYP3A4.

Effect on Laboratory Parameters

Rivaroxaban affects coagulation parameters (PT, aPTT, HepTest) due to its mechanism of action.

Storage Conditions

The medicine should be stored out of the reach of children, at a temperature not exceeding 25°C (77°F), in the original packaging (blister in a cardboard carton) to protect from moisture.

Shelf Life

The shelf life is 3 years.

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

Dispensing Status

The medicine is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.