Zinacoren (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

In humans, dose-dependent inhibition of factor Xa activity is observed.

Rivaroxaban has a dose-dependent effect on prothrombin time, which correlates well with rivaroxaban plasma concentrations (r=0.98) when the Neoplastin reagent is used for the assay.

When other reagents are used, the results will differ.

Prothrombin time should be measured in seconds, as INR 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 recurrence of 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 when taking 15 mg rivaroxaban twice daily, and from 15 to 30 seconds when taking 20 mg rivaroxaban once daily.

In the interval 8-16 hours after tablet intake, the 5th/95th percentiles ranged from 14 to 24 seconds when taking 15 mg twice daily, and 18-30 hours after tablet intake – from 13 to 20 seconds when taking 20 mg once daily.

In patients with non-valvular atrial fibrillation taking Rivaroxaban for stroke prevention and systemic embolism, 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), the effect of single doses (50 IU/kg) of two different types of prothrombin complex concentrate was investigated: 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 sec over 30 minutes compared to a reduction of approximately 3.5 sec 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.

Rivaroxaban also dose-dependently increases aPTT and HepTest results; however, these parameters are not recommended for assessing the pharmacodynamic effect 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 test (see the “Pharmacokinetics” section).

Clinical efficacy and safety

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

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

In the pivotal double-blind ROCKET AF study, 14264 patients were randomized to receive 20 mg rivaroxaban once daily (15 mg once daily for patients with CrCl 30-49 ml/min) or warfarin, dose-titrated to a target INR of 2.5 (therapeutic range 2.0 to 3.0).

The median treatment duration was 19 months, and the total treatment duration was up to 41 months.

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

Rivaroxaban was non-inferior to warfarin for the primary composite endpoint of stroke and non-CNS systemic embolism.

In the per-protocol population, stroke or systemic embolism occurred in 188 patients receiving Rivaroxaban (1.71% per year) and in 241 patients receiving warfarin (2.16% per year) (hazard ratio (HR) 0.79; 95% CI, 0.66-0.96; p<0.001 for non-inferiority).

Among all randomized patients analyzed according to the intention-to-treat principle (ITT), primary events occurred in 269 patients receiving Rivaroxaban (2.12% per year) and in 306 patients receiving warfarin (2.42% per year) (HR 0.88; 95% CI, 0.74-1.03; p<0.001 for non-inferiority; p=0.117 for superiority).

Results for secondary endpoints, tested hierarchically in the intention-to-treat analysis, are shown 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 effect of rivaroxaban did not differ across quartiles of equal size based on center TTR (time in therapeutic INR range 2.0 to 3.0) (p=0.74 for interaction).

Within the highest quartile relative to the center, the hazard ratio (HR) for rivaroxaban compared to warfarin was 0.74 (95% CI, 0.49-1.12).

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

Table 1. Efficacy profile data from the phase III ROCKET AF clinical trial

Table 2. Safety profile data from the phase III ROCKET AF clinical trial

^a) safety population, on-treatment period

* nominally significant

In addition to the phase III ROCKET AF study, a prospective, non-controlled, post-marketing, non-interventional, open cohort study (XANTUS) with central adjudication of endpoints, including thromboembolic events and major bleeding, was conducted.

6704 patients with non-valvular atrial fibrillation were included in this clinical practice study investigating the prevention of stroke and non-CNS systemic embolism.

The mean CHADS₂ and HAS-BLED scores in the XANTUS study were 1.9 and 2.0 compared to mean CHADS₂ and HAS-BLED scores of 3.5 and 2.8 in the ROCKET AF study, respectively.

Major bleeding occurred in 2.1 cases per 100 patient-years.

Fatal bleeding was reported in 0.2 cases per 100 patient-years, and intracranial hemorrhage in 0.4 cases per 100 patient-years.

Stroke or non-CNS systemic embolism was reported in 0.8 cases per 100 patient-years.

These observations in clinical practice are consistent with the established safety profile for this indication.

In a post-marketing non-interventional study of over 162,000 patients with non-valvular atrial fibrillation from four countries receiving Rivaroxaban for stroke prevention and systemic embolism, the rate of ischemic stroke was 0.70 (95% CI 0.44-1.13) per 100 patient-years.

Bleeding leading to hospitalization occurred at the following rates per 100 patient-years: 0.43 (95% CI 0.31-0.59) for intracranial hemorrhage, 1.04 (95% CI 0.65-1.66) for gastrointestinal bleeding, 0.41 (95% CI 0.31-0.53) for urogenital bleeding, and 0.40 (95% CI 0.25-0.65) for other bleeding.

Patients undergoing cardioversion

A prospective, randomized, open-label, multicenter, exploratory study with blinded endpoint adjudication (X-VERT) was conducted in 1504 patients (both those newly prescribed oral anticoagulants and those previously treated) with non-valvular atrial fibrillation who were scheduled for cardioversion, to compare rivaroxaban and dose-adjusted vitamin K antagonist (VKA) (randomized in a 2:1 ratio) for the prevention of cardiovascular events.

The following strategies were used: transesophageal echocardiography after 1-5 days of pre-treatment anticoagulant therapy or a conventional approach to cardioversion (at least 3 weeks of pre-treatment).

The primary efficacy endpoint (all cases of stroke, transient ischemic attack, non-CNS systemic embolism, myocardial infarction, and cardiovascular death) occurred in 5 (0.5%) patients in the rivaroxaban group (n=978) and in 5 (1.0%) patients in the VKA group (n=492; HR 0.50; 95% CI 0.15-1.73; modified ITT population).

The primary safety endpoint (major bleeding) occurred in 6 (0.6%) and 4 (0.8%) patients in the rivaroxaban (n=988) and VKA (n=499) groups, respectively (HR 0.76; 95% CI 0.21-2.67; safety population).

This exploratory study demonstrated comparable efficacy and safety for rivaroxaban and VKA treatment groups during cardioversion.

Patients with non-valvular atrial fibrillation undergoing PCI with stenting

A randomized, open-label, multicenter study (PIONEER AF-PCI) was conducted to compare the safety of two rivaroxaban dosing regimens versus one VKA dosing regimen in 2124 patients with non-valvular atrial fibrillation who underwent PCI with stenting for atherosclerotic disease.

Patients were randomized in a 1:1:1 ratio to 12 months of therapy.

Patients with a history of stroke or transient ischemic attack (TIA) were not included in the study.

Group 1 received 15 mg rivaroxaban once daily (10 mg once daily in patients with CrCl 30-49 ml/min) and a P2Y12 receptor inhibitor.

Group 2 received 2.5 mg rivaroxaban twice daily and dual antiplatelet therapy (i.e., 75 mg clopidogrel (or an alternative P2Y12 receptor inhibitor) and low-dose acetylsalicylic acid) for 1, 6, or 12 months, followed by a switch to 15 mg rivaroxaban (10 mg once daily in patients with CrCl 30-49 ml/min) once daily with low-dose acetylsalicylic acid.

Group 3 received dose-adjusted VKA and dual antiplatelet therapy for 1, 6, or 12 months, followed by a switch to dose-adjusted VKA with low-dose acetylsalicylic acid.

The primary safety endpoint, cases of clinically significant bleeding, was recorded in 109 (15.7%), 117 (16.6%), and 167 (24.0%) patients in Group 1, Group 2, and Group 3, respectively (hazard ratio [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 (composite rate of cardiovascular events: cardiovascular death, myocardial infarction, or stroke) occurred in 41 (5.9%), 36 (5.1%), and 36 (5.2%) patients in Group 1, Group 2, and Group 3, respectively.

Each of the rivaroxaban regimens showed a significant reduction in the incidence of clinically significant bleeding compared to VKA therapy in patients with non-valvular atrial fibrillation undergoing PCI with stenting.

The primary objective of the PIONEER AF-PCI study was to assess safety.

Data on efficacy (including thromboembolic events) in this population are limited.

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

The rivaroxaban clinical development program was designed to demonstrate the efficacy of rivaroxaban in the initial treatment of acute DVT and PE, continued therapy, and prevention of recurrence of DVT and PE.

More than 12800 patients participated in four randomized controlled phase III clinical trials (EINSTEIN DVT, EINSTEIN PE, EINSTEIN Extension and EINSTEIN Choice); in addition, a pre-planned pooled analysis of the EINSTEIN DVT and EINSTEIN PE studies was conducted.

The maximum duration of treatment in all studies was 21 months.

The EINSTEIN DVT study was conducted in 3449 patients with acute DVT to investigate the use of rivaroxaban for the treatment of DVT and prevention of recurrence of DVT and PE (patients with symptomatic PE were excluded from this study).

Treatment duration was 3, 6, or 12 months based on the investigator’s clinical assessment.

During the first three weeks of treatment for acute DVT, Rivaroxaban 15 mg twice daily was used, followed by a switch to Rivaroxaban 20 mg once daily.

The EINSTEIN PE study was conducted in 4832 patients with acute PE to investigate the treatment of PE and prevention of recurrence of DVT and PE.

Treatment duration was 3, 6, or 12 months based on the investigator’s clinical assessment.

During the first 3 weeks of initial treatment for acute PE, Rivaroxaban 15 mg twice daily was used, followed by a switch to Rivaroxaban 20 mg once daily.

In both the EINSTEIN DVT and EINSTEIN PE studies, the comparator regimen included enoxaparin administration for at least 5 days in combination with vitamin K antagonist therapy until a therapeutic PT/INR level (≥2.0) was achieved.

Treatment was then continued with a vitamin K antagonist, the dose of which was adjusted to maintain PT/INR values within the therapeutic range of 2.0 to 3.0.

The EINSTEIN Extension study was conducted in 1197 patients with DVT or PE to investigate the prevention of recurrence of DVT and PE.

Treatment duration for patients who had completed 6 to 12 months of venous thromboembolism treatment was an additional 6 to 12 months based on the investigator’s clinical assessment.

Rivaroxaban 20 mg once daily was compared with placebo.

The EINSTEIN DVT, PE, and EINSTEIN Extension studies used identical pre-defined primary and secondary efficacy endpoints.

The primary efficacy endpoint was symptomatic recurrent VTE, defined as a composite of recurrent DVT or fatal or nonfatal PE.

The secondary endpoint was defined as a composite of recurrent DVT, nonfatal PE, and death from any cause.

In the EINSTEIN Choice study, 3396 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 nonfatal symptomatic recurrence of DVT or PE.

Patients who required continued therapeutic-dose anticoagulant therapy were excluded from 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 acetylsalicylic acid 100 mg once daily.

The primary efficacy endpoint was symptomatic recurrent VTE, defined as a composite of recurrent DVT or fatal or nonfatal PE.

In the EINSTEIN DVT study (see Table 3), Rivaroxaban was demonstrated to be non-inferior to enoxaparin/VKA for the primary efficacy endpoint (p<0.0001 (non-inferiority test); HR: 0.680 (0.443-1.042), p=0.076 (superiority test)).

The pre-defined net clinical benefit (primary efficacy endpoint and major bleeding events) was recorded 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 for a mean treatment duration of 189 days and 55.4%, 60.1%, and 62.8% of the time in the groups extended to 3, 6, and 12 months of treatment, respectively.

In the enoxaparin/VKA group, there was no clear association between the level of mean center TTR (time in therapeutic INR range 2.0-3.0) in tertiles of equal size and the rate of recurrent VTE (p=0.932 for interaction).

Within the highest tertile relative to the center, the HR for rivaroxaban compared to warfarin was 0.69 (95% CI: 0.35-1.35).

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

Table 3. Efficacy and safety profile data in the phase III EINSTEIN DVT study

^a) Rivaroxaban 15 mg twice daily for 3 weeks, followed by 20 mg once daily

^b) Enoxaparin for at least 5 days, with concurrent and subsequent VKA administration

* p<0.0001 (non-inferiority for the predefined HR of 2.0); HR: 0.680 (0.443-1.042), p=0.076 (superiority).

The EINSTEIN PE study (see Table 4) demonstrated that Rivaroxaban was non-inferior to enoxaparin/VKA for the primary efficacy endpoint (p=0.0026 (non-inferiority test); HR: 1.123 (0.749-1.684)). The predefined net clinical benefit (primary efficacy endpoint and major bleeding events) was recorded with an HR of 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 for a mean treatment duration of 215 days and 57%, 62%, and 65% of the time in the groups extended to 3, 6, and 12 months of treatment, respectively. In the enoxaparin/VKA group, there was no clear association between the level of mean center TTR (time in therapeutic INR range 2.0-3.0) in equally sized tertiles and the rate of recurrent VTE (p = 0.082 for interaction). Within the highest tertile relative to the center, the HR for rivaroxaban compared to warfarin was 0.642 (95% CI: 0.277-1.484).

The incidence of the primary safety endpoint (major or clinically relevant non-major bleeding events) was somewhat lower in the rivaroxaban treatment group (10.3% (249/2412)) than in the enoxaparin/VKA treatment group (11.4% (274/2405)). The incidence of the secondary safety endpoint (major bleeding events) was lower in the rivaroxaban group (1.1% (26/2412)) than in the enoxaparin/VKA group (2.2% (52/2405)) with an HR of 0.493 (95% CI: 0.308-0.789).

Table 4. Efficacy and safety profile data in the phase III EINSTEIN PE study

^a) Rivaroxaban 15 mg twice daily for 3 weeks, followed by 20 mg once daily

^b) Enoxaparin for at least 5 days, with concurrent and subsequent VKA administration

* p<0.0026 (non-inferiority for the predefined HR of 2.0); HR: 1.123 (0.749-1.684)

A prespecified pooled analysis of endpoints from the EINSTEIN DVT and PE studies was conducted (see Table 5).

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

^a) Rivaroxaban 15 mg twice daily for 3 weeks, followed by 20 mg once daily

^b) Enoxaparin for at least 5 days, with concurrent and subsequent VKA administration

* p<0.0001 (non-inferiority for the predefined HR of 1.75); HR: 0.886 (0.661-1.186)

The predefined net clinical benefit (primary efficacy endpoint plus major bleeding events) of the pooled analysis was recorded with an HR of 0.771 ((95% CI: 0.614-0.967), nominal p=0.0244).

In the EINSTEIN Extension study (see Table 6), Rivaroxaban was superior to placebo for the primary and secondary efficacy endpoints. The incidence of the primary safety endpoint (major bleeding events) was numerically slightly higher in patients receiving rivaroxaban therapy at a dose of 20 mg once daily compared to placebo. The secondary safety endpoint (major or clinically relevant non-major bleeding) showed a higher frequency in patients receiving rivaroxaban therapy at a dose of 20 mg once daily compared to placebo.

Table 6. Efficacy and safety profile data in the phase III EINSTEIN Extension study

^a) Rivaroxaban 20 mg once daily

* p<0.0001 (superiority), HR: 0.185 (0.087-0.393)

In the EINSTEIN Choice study (see Table 7), Rivaroxaban at doses of 20 mg and 10 mg was superior to acetylsalicylic acid (ASA) at a dose of 100 mg for the primary efficacy endpoint. The primary safety endpoint (major bleeding events) was similar in patients receiving Rivaroxaban at doses of 20 mg and 10 mg once daily compared to 100 mg acetylsalicylic acid.

Table 7. Efficacy and safety profile data in the phase III EINSTEIN Choice study

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

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

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

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

In addition to the EINSTEIN phase III program, a prospective, non-interventional, open cohort study (XALIA) with central adjudication of endpoints, including recurrent VTE, major bleeding, and death, was conducted. This clinical practice study included 5142 patients with acute DVT to investigate the long-term safety of rivaroxaban compared to standard 43 anticoagulant therapy. The rates of major bleeding, recurrent VTE, and all-cause mortality for rivaroxaban were 0.7%, 1.4%, and 0.5%, respectively. There were differences in baseline patient characteristics, including age, cancer, and renal impairment. A prespecified propensity score-stratified analysis was used to adjust for baseline intergroup differences. Despite this, residual confounding may have influenced the results. The adjusted HRs comparing Rivaroxaban and standard of care regarding major bleeding, recurrent VTE, and all-cause mortality were 0.77 (9% 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 from clinical practice are consistent with the established safety profile for this indication.

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

Children

Pharmacodynamic effects

Prothrombin time (Neoplastin), aPTT, and anti-Xa activity measured by a calibrated quantitative assay 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 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 assays (see Table 10 in the “Pharmacokinetics” section for the ranges of observed rivaroxaban plasma concentrations in children). When using an anti-Xa activity assay 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

Treatment of VTE and prevention of recurrent VTE in pediatric patients

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

EINSTEIN Junior – a randomized, open-label, multicenter, active-controlled phase III clinical study 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 were aged 6 to <12 years, 69 children were aged 2 to <6 years, and 54 children were 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, it was cerebral venous and sinus thrombosis in 48 children (47.5%) and 35 children (50.7%), respectively; in children under 2 years, it was catheter-associated VTE in 37 children (68.5%). There were no children under 6 months of age with cerebral venous and sinus thrombosis in the rivaroxaban group. Twenty-two 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 transient 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 conducted 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 incidence of symptomatic recurrent VTE. The primary safety endpoint was the combined incidence of major and clinically relevant non-major bleeding. All efficacy and safety endpoints were centrally adjudicated by an independent committee, which was blinded to the treatment group assignment. Efficacy and safety results are presented in Tables 8 and 9 below.

Recurrent VTE occurred in 4 of 335 patients in the rivaroxaban group and in 5 of 165 patients in the comparator group. The combined rate of major bleeding and clinically relevant non-major bleeding was noted in 10 of 329 patients (3%) receiving Rivaroxaban and in 3 of 162 patients (1.9%) receiving the comparator. Net clinical benefit (combined incidence of symptomatic recurrent VTE and major bleeding) was noted in 4 of 335 patients in the rivaroxaban group and in 7 of 165 patients in the comparator group. Venous recanalization on repeat imaging was observed in 128 of 335 patients treated with rivaroxaban and in 43 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 bleeding occurring during therapy, and in the comparator group, there were 45 children (27.8%).

Table 8. Efficacy profile data for rivaroxaban and comparator at the end of the main treatment period

* full analysis set, i.e., all children who were randomized

CI = confidence interval

Table 9. Safety profile data for rivaroxaban and comparator at the end of the main treatment period

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

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.

High-risk triple-positive antiphospholipid syndrome patients

In an investigator-sponsored, randomized, open-label, multicenter study with blinded endpoint evaluation, Rivaroxaban was studied compared to warfarin in patients with a history of thrombosis who were 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-beta₂-glycoprotein I antibodies). After enrolling 120 patients, the study was terminated early due to an increased frequency of events in patients in the rivaroxaban group. The mean observation period duration was 569 days. 59 patients were randomized to the rivaroxaban 20 mg group (15 mg for patients with creatinine clearance <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 below is based on data obtained in the adult population. Rivaroxaban is rapidly absorbed; C_max is reached within 2-4 hours after tablet intake. When taken orally as 2.5 mg and 10 mg tablets, Rivaroxaban is almost completely absorbed, with high bioavailability (80-100%) regardless of food intake. Concomitant administration of rivaroxaban 2.5 mg and 10 mg with food does not affect the AUC and C_max of rivaroxaban.

Due to reduced absorption extent, a bioavailability of 66% was observed when 20 mg tablets were taken fasting. When 20 mg rivaroxaban tablets were taken with food, a 39% increase in mean AUC was noted compared to taking the tablet fasting, showing almost complete absorption and high bioavailability. Zinacoren 15 mg and 20 mg should be taken with food (see section “Dosage and Administration”).

The pharmacokinetics of rivaroxaban are almost linear in doses up to 15 mg once daily when taken fasting. Under conditions of taking rivaroxaban 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 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 taking a whole 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 this may lead to reduced absorption and, consequently, reduced rivaroxaban exposure.

The bioavailability (AUC and C_max) of rivaroxaban 20 mg when taken orally as a crushed tablet mixed with apple puree or suspended in water, and when administered via a gastric tube followed by liquid nutrition, was comparable to the bioavailability of a whole 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 a meal, along with a usual amount of fluid to ensure proper dosing in children. As in adults, Rivaroxaban is rapidly absorbed after oral administration of the drug in the tablet or granule for oral suspension dosage form. No difference was noted in either the rate or extent of absorption between the tablet and granule for oral suspension dosage forms. Data on pharmacokinetics in children after IV administration are lacking, so the absolute bioavailability of rivaroxaban in children is unknown. A decrease in relative bioavailability was found with increasing doses (in mg/kg body weight), suggesting absorption limitations for higher doses, even when taken with food. Zinacoren as 15 mg or 20 mg tablets should be taken during feeding or with a meal (see section “Dosage and Administration”).

Distribution

Plasma protein binding in adults is high, 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 plasma protein binding of rivaroxaban. Data on the pharmacokinetics of rivaroxaban after IV administration 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 body weight-dependent and can be described by an allometric function with a mean value of 113 L for a subject weighing 82.8 kg.

Metabolism and 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 intestine. 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 CYP3A4, 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 IV administration of 1 mg rivaroxaban, the half-life is about 4.5 hours. After oral administration, elimination becomes absorption rate-limited. During the elimination of rivaroxaban from plasma, the terminal T_1/2 ranges 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 the pharmacokinetics of rivaroxaban after IV administration 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 body weight-dependent and can be described by an allometric function with a mean value of 8 L/h for a subject weighing 82.8 kg. 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.

Pharmacokinetic-pharmacodynamic relationship

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 in 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 reduced (presumed) 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 relevant 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 in children of Japanese, Chinese, or Asian ethnicity outside Japan and China compared to the overall pediatric population.

Hepatic impairment

In adult patients with liver cirrhosis and mild hepatic impairment (Child-Pugh class A), the pharmacokinetics of rivaroxaban differed only slightly from those in the control group of healthy subjects (a mean increase in rivaroxaban AUC of 1.2-fold 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 hepatic 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. Zinacoren 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 declining 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 by 1.4, 1.5, and 1.6-fold, respectively. The corresponding increase in pharmacodynamic effects was more pronounced. In patients with mild, moderate, and severe renal impairment, overall inhibition of factor Xa activity increased by 1.5, 1.9, and 2.0-fold, respectively, compared to healthy volunteers; prothrombin time also increased by 1.3, 2.2, 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 warnings and precautions for use”).

Clinical study data 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 intake (which approximately corresponds to the maximum and minimum concentrations 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 the maximum and minimum concentration in the dosing interval in children with acute VTE receiving Rivaroxaban in a body weight-dependent dose to achieve exposure corresponding to that in adult DVT patients receiving a 20 mg once daily dose are presented in Table 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 dose range (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 described the data better. The slope factor varied significantly depending on the 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 stroke prevention and systemic embolism in patients with non-valvular atrial fibrillation have not been established.

Indications

Adults

• 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

15 mg 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.

20 mg 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.

Treatment with Zinacoren should be considered as long-term therapy provided that the benefit of stroke and systemic embolism prevention outweighs the risk of bleeding (see section “Adverse Reactions”).

If a dose is missed, the patient should take the Zinacoren tablet immediately and continue the next day with the once-daily intake as recommended. A double dose should not be taken on the same day to compensate for a 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 transition to a dose of 20 mg once daily for further treatment and prevention of recurrent DVT and PE.

A short duration of treatment course (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 (after completion of at least 6 months of treatment for DVT or PE) is indicated, 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 who developed recurrent DVT or PE during extended prophylaxis with Zinacoren at a dose of 10 mg once daily, the use of Zinacoren 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 treatment benefit against the risk of bleeding (see the “Adverse Reactions” section).

Table 11 .

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

If a dose is missed during the once-daily regimen, the patient should immediately take the Zinacoren tablet and continue the once-daily intake 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 Zinacoren 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 – the recommended dose is 15 mg of rivaroxaban once daily, which is the maximum daily dose;
• body weight 50 kg or more – the 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 drugs available on the market in the form of granules for the preparation of an oral suspension should be used.

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

Therapy in children and adolescents should continue for at least 3 months. The duration of treatment may be extended up to 12 months in case of clinical necessity. There are no data to support dose reduction in children after 6 months of therapy. The benefit-risk ratio for therapy duration exceeding 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 physician. The patient should not take a double dose to compensate for the missed dose.

Transition from vitamin K antagonists (VKAs) to Zinacoren

For stroke and systemic thromboembolism prevention, VKA treatment should be discontinued and treatment with Zinacoren should be initiated when the INR 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 Zinacoren should be initiated when the INR is ≤2.5.

When transitioning patients from VKAs to Zinacoren, INR values will be falsely elevated after taking Zinacoren. INR is not suitable for determining the anticoagulant activity of Zinacoren and therefore should not be used for this purpose (see the “Drug Interactions” section).

Transition from Zinacoren to vitamin K antagonists (VKAs)

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

Patients transitioning from Zinacoren to a VKA should take the VKA concomitantly until the INR reaches ≥2.0. During the first two days of the transition period, the standard initial dose of the VKA should be used, followed by the VKA dose determined based on the INR value. During concomitant use of Zinacoren and a VKA, the INR should be measured no earlier than 24 hours after the previous dose but before taking the next dose of Zinacoren. After discontinuation of Zinacoren, the INR can be reliably determined 24 hours after the last dose.

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

Transition from parenteral anticoagulants to Zinacoren

In adults and children receiving parenteral anticoagulants, the parenteral anticoagulant should be discontinued and Zinacoren 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 administration of the parenteral drug (e.g., intravenous unfractionated heparin).

Transition from Zinacoren to parenteral anticoagulants

Zinacoren should be discontinued and the first dose of the parenteral anticoagulant should be administered at the time when the next dose of Zinacoren 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, Zinacoren should be used with caution in this category of patients. Use is not recommended in patients with CrCl <15 ml/min (see sections “Pharmacokinetics” and “Special Instructions”).

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 and systemic thromboembolism prevention 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 3 weeks. Subsequently, when the recommended dose of Zinacoren 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 sections “Pharmacokinetics” and “Special Instructions”). 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 ) Zinacoren is not recommended due to lack of clinical data (see the “Special Instructions” section).

Patients with hepatic impairment

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

For children with hepatic impairment, clinical data are lacking.

Elderly patients

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

Body weight

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

Gender

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

Patients undergoing cardioversion

Treatment with Zinacoren 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 Zinacoren should be initiated at least 4 hours before cardioversion. For all patients, confirmation should be obtained before cardioversion that the patient has taken Zinacoren as prescribed. 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 Zinacoren 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 a maximum of 12 months in patients with non-valvular atrial fibrillation who require oral anticoagulants and have undergone PCI with stenting (see sections “Pharmacological Action” and “Special Instructions”).

Children

The safety and efficacy of Zinacoren in children aged 0 to <18 years for the indication of stroke and systemic thromboembolism prevention in patients with non-valvular atrial fibrillation have not been established. Data are lacking. Therefore, Zinacoren 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

Zinacoren is intended for oral administration.

The tablets should be taken with food (see the “Pharmacokinetics” section).

Crushing tablets

If a patient is unable to swallow the tablet whole, the Zinacoren tablet may be crushed and mixed with water or apple puree immediately before use and administered orally. After administration of the crushed Zinacoren 15 mg or 20 mg tablet, food intake should be initiated immediately. The crushed tablet can also be administered via a gastric tube (see the “Pharmacokinetics” section).

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 rivaroxaban 15 mg or 20 mg tablet, enteral feeding should be initiated immediately.

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

Children with body weight of at least 30 kg

Zinacoren is intended for oral administration.

The patient should be advised to swallow the tablet with liquid. It should also be taken with food (see the “Pharmacokinetics” section). 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 administered. 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

Crushing the tablet is possible.

If the patient is unable to swallow the tablet whole, other drugs available on the market in the form of granules for the preparation of an oral suspension should be used. If an oral suspension is not immediately available when Rivaroxaban in a dosage of 15 mg or 20 mg is prescribed, these dosages 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 be administered via a nasogastric or gastric tube.

Adverse Reactions

The safety of rivaroxaban was evaluated in thirteen main phase III studies (see Table 12).

In total, 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, total daily dose and maximum duration of treatment in phase III clinical studies involving adult and pediatric patients

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

** In the COMPASS study, the incidence of anemia is low because a selective approach was used for collecting adverse event data.

*** A selective approach was used for collecting adverse event data.

^# From the VOYAGER PAD study.

The incidence of adverse reactions reported in children and adults with the use of Zinacoren is presented in Table 14, categorized by system organ class (MedDRA) and by frequency. Definition of adverse reaction frequency: 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 in the prevention of VTE in adult patients undergoing elective hip or knee replacement surgery.

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

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

* A predefined selective approach to collecting adverse event data was used in specific Phase III studies. Based on the analysis of these study data, 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 Zinacoren may be associated with an increased risk of occult or overt bleeding from any tissue and organ, which may lead to posthemorrhagic anemia. The signs, symptoms, and severity (including fatal outcome) will vary depending on the location, intensity, or duration of the bleeding and/or anemia (see the “Overdosage” section). In clinical studies, mucosal bleeding (namely, epistaxis, gingival, gastrointestinal, urogenital, 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 significant 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 (see the “Special Precautions” section). 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 pectoris, 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 the use of Zinacoren. Therefore, the possibility of bleeding should be considered when evaluating 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 open-label, active-controlled studies (two Phase II and one Phase III) involving children from birth to <18 years of age. Safety data were generally comparable for rivaroxaban and the comparator drug 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 remained 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 blood bilirubin (common, 1.5%), and increased conjugated bilirubin (rare, 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 postmenarche 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, known or suspected esophageal varices, arteriovenous malformations, vascular aneurysms, or major intraspinal or intracerebral vascular abnormalities;
• Concomitant therapy with any other anticoagulants, e.g., unfractionated heparin, 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 at doses necessary to maintain patency of a central venous or arterial catheter;
• Hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including patients with Child-Pugh class B and C cirrhosis;
• Pregnancy;
• Breast-feeding period.

Use in Pregnancy and Lactation

Pregnancy

The safety and efficacy of Zinacoren in pregnant women have not been established. Data from animal studies have shown reproductive toxicity. Due to potential reproductive toxicity, risk of bleeding, and data on the ability of rivaroxaban to cross the placenta, Zinacoren is contraindicated during pregnancy.

Women of childbearing potential should avoid pregnancy during rivaroxaban therapy.

Breast-feeding

The safety and efficacy of Zinacoren in women during breast-feeding have not been established. Data from animals indicate that Rivaroxaban is excreted in breast milk. Therefore, Zinacoren is contraindicated during breast-feeding. A decision must be made to discontinue breast-feeding or to discontinue/abstain from 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

Contraindication: hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including patients with Child-Pugh class B and C cirrhosis.

Zinacoren is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including patients with Child-Pugh class B and C cirrhosis.

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, Zinacoren should be used with caution in this patient category. Use is not recommended in patients with CrCl <15 ml/min.

Dosage adjustment is required in patients with moderate (CrCl 30-49 ml/min) or severe (CrCl 15-29 ml/min) renal impairment.

No dose adjustment is required in patients with mild renal impairment (CrCl 50-80 ml/min).

Pediatric Use

Zinacoren is not recommended for use in children and adolescents under 18 years of age with moderate or severe renal impairment (GFR <50 ml/min/1.73 m² ) due to lack of clinical data.

No clinical data are available for children with hepatic impairment.

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.

Risk of bleeding

As with other anticoagulants, patients taking Zinacoren 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, Zinacoren should be discontinued (see the “Overdosage” section).

In clinical studies, mucosal bleeding (namely, epistaxis, gingival, gastrointestinal, urogenital, 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 significant 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 (see the “Adverse Reactions” section).

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 cases where information on rivaroxaban exposure may be used in making clinically significant decisions, e.g., in case of overdose or emergency surgery (see the “Pharmacokinetics” section).

Children

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

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. Zinacoren should be used with caution in patients with CrCl 15-29 ml/min. Use in patients with CrCl <15 ml/min is not recommended (see the "Pharmacokinetics" and "Dosage and Administration" sections).

Zinacoren should be used with caution in patients with renal impairment receiving concomitant drugs that increase rivaroxaban plasma concentrations (see the “Drug Interactions” section).

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

Drug interactions

The use of Zinacoren 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 (see the “Drug Interactions” section).

Caution should be exercised if the patient is concomitantly receiving medicinal products affecting hemostasis, such as NSAIDs, acetylsalicylic acid 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 (see the “Drug Interactions” section).

Other risk factors for bleeding

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

• Congenital or acquired bleeding tendency;
• 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 malignant diseases

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 urogenital tract were associated with an increased risk of bleeding during rivaroxaban therapy. In patients with malignant neoplasms and a high risk of bleeding, the use of rivaroxaban is contraindicated (see the “Contraindications” section).

Patients with prosthetic heart valves

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

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-β₂-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 undergoing PCI with stenting

There are data from an interventional clinical study whose primary objective was to assess the safety profile in patients with non-valvular atrial fibrillation undergoing PCI with stenting. Efficacy data in this population are limited (see the “Pharmacodynamics” and “Dosage and Administration” sections). Data are lacking for such patients with a history of stroke/transient ischemic attack.

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

Zinacoren 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 Zinacoren 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 agents for the prevention of thromboembolic complications, there is a risk of epidural or spinal hematoma, which may lead to long-term or permanent paralysis.

The risk of these events may be increased with the postoperative use of indwelling epidural catheters or concomitant therapy with medicinal products affecting hemostasis. Traumatic or repeated epidural or spinal punctures 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 who are planned to receive anticoagulants 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 the 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 weighed against the urgency of the diagnostic procedure.

Based on general pharmacokinetic characteristics, the epidural catheter should be removed after at least twice the T_1/2, 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 (see the “Pharmacokinetics” section). At least 6 hours should elapse after the removal of the epidural catheter before the next dose of rivaroxaban is taken.

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

There are no data on the timing of insertion or removal of a neuraxial catheter in children receiving Zinacoren. In such cases, rivaroxaban administration should be discontinued and the possibility of using a short-acting parenteral anticoagulant should be considered.

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 Zinacoren 15 mg and 20 mg should be discontinued at least 24 hours before 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 Zinacoren 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.

Dermatological reactions

Post-marketing surveillance has reported cases of serious skin reactions, including Stevens-Johnson syndrome/toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), associated with the use of rivaroxaban (see the “Adverse Reactions” section). 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 involvement, rivaroxaban therapy should be discontinued.

Elderly age

The risk of bleeding may increase with advancing age.

Excipients

Zinacoren contains lactose monohydrate. Patients with rare hereditary galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medication.

Effect on ability to drive and operate machinery

Zinacoren has a minor influence on the ability to drive and operate machinery. Adverse reactions such as syncope (frequency: uncommon) and dizziness (frequency: common) have been reported (see the “Adverse Reactions” section). Patients who experience such adverse reactions should not drive vehicles or operate other machinery.

Overdose

Rare cases of overdose up to 1960 mg have been reported in adults. Due to limited absorption, a plateau in drug concentration is expected without a further increase in its mean plasma concentration at doses exceeding therapeutic levels, equal to 50 mg of rivaroxaban or higher in adults; however, there are no data on supratherapeutic doses in children.

Symptoms bleeding or other adverse reactions.

Treatment in case of overdose, the patient should be carefully monitored for the development of bleeding or other adverse reactions. Data in children are limited. 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.

If a patient receiving Rivaroxaban develops a bleeding complication, 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 the “Pharmacokinetics” section). Treatment should be individualized depending on the severity and location of the bleeding. If necessary, appropriate symptomatic treatment can be applied, such as mechanical compression (e.g., for severe nosebleeds), surgical hemostasis with bleeding control procedures, fluid replacement therapy 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.

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

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 drugs in children receiving Rivaroxaban.

There is no scientific rationale or experience for the use of the systemic hemostatic drug desmopressin in patients receiving Rivaroxaban.

Given the intensive binding to plasma proteins, Rivaroxaban is not expected to be eliminated by dialysis.

Drug Interactions

The extent of drug interactions in children is unknown. The following interaction data obtained in adult patients and the warnings in the “Special Instructions” section 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 an increase in the mean AUC of rivaroxaban by 2.6-fold/2.5-fold and an increase in the mean C_max of rivaroxaban by 1.7-fold/1.6-fold with a significant enhancement of pharmacodynamic effects, which may lead to an increased risk of bleeding. Therefore, the use of Zinacoren 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 (see the “Special Instructions” section). 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), which is considered a potent CYP3A4 inhibitor and a moderate P-glycoprotein inhibitor, caused a 1.5-fold increase in the mean AUC of rivaroxaban 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, see the “Special Instructions” section).

Erythromycin (500 mg three times daily), a moderate inhibitor of CYP3A4 and P-glycoprotein, caused a 1.3-fold increase in the mean AUC and C_max values of rivaroxaban. 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 the mean AUC of rivaroxaban 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 the mean AUC of rivaroxaban 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 (see the “Special Instructions” section).

Fluconazole (400 mg once daily), which is considered a moderate CYP3A4 inhibitor, caused a 1.4-fold increase in the mean AUC of rivaroxaban and a 1.3-fold increase in the 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, see the “Special Instructions” section).

Based on available limited clinical data, concomitant use of rivaroxaban with dronedarone should be avoided.

Anticoagulants

After simultaneous administration of enoxaparin (a single 40 mg dose) and rivaroxaban (a single 10 mg dose), 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 an increased risk of bleeding, caution should be exercised when co-administering with any other anticoagulants (see “Contraindications”, “Special Instructions” sections).

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 is possible in some individuals.

No clinically significant pharmacokinetic or pharmacodynamic interaction was observed with the concomitant use of rivaroxaban and 500 mg of 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 a significant increase in bleeding time was observed in a subgroup of patients, which did not correlate with the degree of platelet aggregation and the content of P-selectin or GPIIb/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 (see the “Special Instructions” section).

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 trials of rivaroxaban demonstrated a numerical increase in major and minor clinically significant bleeding across all treatment groups with the concomitant use of these drugs.

Warfarin

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

If it is necessary to investigate the pharmacodynamic effects of rivaroxaban 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 it is necessary to investigate the pharmacodynamic effects of warfarin during the transition period, the INR value can be measured at the C_trough of rivaroxaban (24 hours after the previous dose of rivaroxaban), 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 an approximately 50% decrease in the mean AUC of rivaroxaban and a simultaneous reduction in its pharmacodynamic effects. Concomitant use of rivaroxaban with other potent CYP3A4 inducers (e.g., phenytoin, carbamazepine, phenobarbital, or preparations of St. John’s wort (Hypericum perforatum)) may also lead to decreased rivaroxaban plasma concentrations. Therefore, concomitant use of potent CYP3A4 inducers should be avoided, except when the patient is under close observation for signs and symptoms of thrombosis.

Other concomitant therapies

No clinically significant pharmacokinetic or pharmacodynamic interaction was observed with the concomitant use of rivaroxaban with midazolam (a CYP3A4 substrate), digoxin (a P-glycoprotein substrate), atorvastatin (a CYP3A4 and P-glycoprotein substrate), or omeprazole (a proton pump inhibitor).

Zinacoren does not inhibit or induce CYP3A4.

Effect on laboratory parameters

Zinacoren affects coagulation parameters (PT, aPTT, HepTest) due to its mechanism of action (see the “Pharmacological Action” section).

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2 years.

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

Dispensing Status

The drug 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.