Rivaxored^® (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 interrupts the intrinsic and extrinsic pathways of the coagulation cascade, inhibiting thrombin formation and thrombus development.

Rivaroxaban does not inhibit thrombin (activated factor II) and has not been shown to affect 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 rivaroxaban plasma concentrations (r=0.98) when the Neoplastin kit is used for the analysis.

Results will differ when other reagents are used.

Prothrombin time should be measured in seconds, since 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 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) range 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 range 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 and systemic embolism prevention, the 5th/95th percentiles for prothrombin time (Neoplastin) 1-4 hours after tablet intake (i.e., at peak effect) range 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 range 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 result; however, these parameters are not recommended for assessing the pharmacodynamic effect of rivaroxaban.

Monitoring of coagulation parameters is not required during rivaroxaban treatment in routine clinical practice.

However, if clinically justified, rivaroxaban concentration can be measured using a calibrated quantitative anti-Xa activity test (see the “Pharmacokinetics” section).

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 corresponding plasma concentrations may occur.

Monitoring of coagulation parameters is not required during rivaroxaban treatment.

However, if clinically justified, rivaroxaban concentrations can be measured in μg/L using calibrated quantitative anti-Xa activity tests (see Table 6 in section 5.2. for the ranges of observed rivaroxaban plasma concentrations in children).

When using the anti-Xa activity test to quantify rivaroxaban plasma concentrations in children, the lower limit of quantification must be considered.

Thresholds 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 dose of rivaroxaban used in children from birth to <18 years was adjusted for body weight and resulted in a rivaroxaban exposure similar to the 20 mg rivaroxaban once daily dose in adult patients with DVT, as confirmed in a phase III study (see the "Pharmacokinetics" section).

EINSTEIN Junior was a randomized, open-label, active-controlled multicenter phase III clinical trial 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 - 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%).

There were no children under 6 months of age with cerebral venous and sinus thrombosis in the rivaroxaban group.

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 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 assessed by an independent committee, for which treatment group assignment was blinded.

Efficacy and safety results are shown in Tables 1 and 2 below.

Recurrent VTE occurred in 4 of 335 patients in the rivaroxaban group and 5 of 165 patients in the comparator group.

The combined incidence of major bleeding and clinically relevant non-major bleeding was noted in 10 of 329 patients (3%) receiving Rivaroxaban and 3 of 162 patients (1.9%) receiving the comparator drug.

Net clinical benefit (combined incidence of symptomatic recurrent VTE and major bleeding) was noted in 4 of 335 patients in the rivaroxaban group and 7 of 165 patients in the comparator group.

Venous recanalization on repeat imaging was observed in 128 of 335 patients treated with rivaroxaban and 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 on-treatment bleeding, and in the comparator group – 45 children (27.8%).

Table 1. Efficacy profile results at the end of the main treatment period

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

CI = confidence interval

Table 2. Safety profile results 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 study drug

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

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 1:1:1 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, clinically significant bleeding events, 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 of cardiovascular events: death from cardiovascular causes, 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 safety assessment.

Efficacy data (including thromboembolic events) in this population are limited.

Patients with high-risk triple-positive antiphospholipid syndrome

In an investigator-sponsored randomized open-label multicenter study with blinded endpoint evaluation, Rivaroxaban was studied versus 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-β₂-glycoprotein I antibodies).

After enrolling 120 patients, the study was terminated early due to an increased frequency of events in the rivaroxaban group.

The mean follow-up duration was 569 days.

59 patients were randomized to the rivaroxaban 20 mg group (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 below is based on data obtained from the adult population.

Rivaroxaban is rapidly absorbed; C_max is reached 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.

Co-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 taking 20 mg tablets on an empty stomach.

When taking 20 mg rivaroxaban tablets with food, an increase in mean AUC of 39% was noted compared to taking the tablet on an empty stomach, showing almost complete absorption and high bioavailability.

Rivaroxaban in 15 mg and 20 mg doses should be taken with food (see the “Dosage and Administration” section).

The pharmacokinetics of rivaroxaban are almost linear in doses up to 15 mg once daily when taken on an empty stomach.

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 of 29% and 56%, respectively, was observed when rivaroxaban granules were released in the proximal small intestine compared to taking a whole tablet.

Drug exposure is further reduced when rivaroxaban is administered to 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 applesauce or suspended in water, as well as 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 meals, together with a usual portion 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.

Rivaroxaban as 15 mg or 20 mg tablets should be taken during feeding or with meals (see the “Dosage and Administration” section).

Distribution

Plasma protein binding in adults is high and is 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 in children after IV administration of rivaroxaban 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, approximately two-thirds of the rivaroxaban dose is metabolized and then 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, primarily through active renal secretion.

Rivaroxaban is metabolized via the CYP3A4 and CYP2J2 isoenzymes, as well as through mechanisms independent of the cytochrome system. The main sites of biotransformation are the oxidation of the morpholine group and the 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 identified in plasma.

Rivaroxaban, which has a systemic clearance of approximately 10 L/h, can be classified as a drug with low clearance. After intravenous administration of 1 mg rivaroxaban, the half-life is about 4.5 hours. After oral administration, elimination becomes absorption rate-limited. For the elimination of rivaroxaban from plasma, the terminal T_1/2 is between 5 and 9 hours in young patients and between 11 and 13 hours in elderly patients.

Children. There are no specific data on metabolism in children. Data on the pharmacokinetics of rivaroxaban in children after intravenous administration are not available. The 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 using 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.

Special Patient Populations

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 a reduction in (probable) total and renal clearance. Dose adjustment is not required.

Varying 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 is dependent on body weight. Analysis of data from 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 of Japan and China compared to the general pediatric population.

Patients with 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 (on average, a 1.2-fold increase in rivaroxaban AUC was observed).

In patients with liver cirrhosis and moderate hepatic impairment (Child-Pugh class B), the mean rivaroxaban AUC 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 increased to a similar extent by 2.1 times. 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.

Patients with Renal Impairment

In adult patients, an increase in rivaroxaban exposure was observed, correlating with the decline in 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 times, respectively. The corresponding increase in pharmacodynamic effects was more pronounced. In patients with mild, moderate, and severe renal impairment, the overall inhibition of factor Xa activity increased by 1.5, 1.9, and 2.0 times, respectively, compared to healthy volunteers; prothrombin time also increased by 1.3, 2.2, and 2.4 times, respectively.

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

Rivaroxaban is not expected to be dialyzable due to its 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").

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 administration (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 times 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 patients with DVT receiving a dose of 20 mg once daily are presented in Table 3.

Table 3. 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 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 seconds with a line slope of about 3-4 seconds (100 μg/L). The results of the PK/PD relationship analysis in phase II and III studies were consistent with those in healthy patients.

Indications

Adults over 18 years

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

Children and adolescents under 18 years

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 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.

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

If a dose is missed, the patient should take the rivaroxaban 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 switch to a dose of 20 mg once daily for continued 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 (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 rivaroxaban at a dose of 10 mg once daily, consideration should be given to prescribing rivaroxaban at a dose of 20 mg once daily.

The duration of treatment and the choice of dose should be determined individually after careful assessment of the benefit of treatment against the risk of bleeding (see section “Adverse Reactions”).

Table 4.

If a dose is missed during the 15 mg twice-daily dosing regimen (day 1-21), the patient should take Rivaroxaban immediately to achieve the daily dose of 30 mg of rivaroxaban. 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 dosing regimen, the patient should take the rivaroxaban 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 VTE and prevention of recurrent VTE in children and adolescents

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

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

• body weight from 30 kg to 50 kg – recommended dose 15 mg rivaroxaban once daily, which is the maximum daily dose;
• body weight 50 kg or more – recommended dose 20 mg rivaroxaban once daily, which is the maximum daily dose;
• For patients with body weight less than 30 kg, please refer to the summary of product characteristics for rivaroxaban in the pharmaceutical form of granules for oral suspension.

The child’s body weight should be monitored regularly and the dose 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 may 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 recurrent thrombosis 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 make up for a missed dose.

Switching from Vitamin K Antagonists (VKAs) to Rivaxored^®

For prevention of stroke and systemic embolism discontinue VKA treatment and initiate rivaroxaban treatment when the INR is ≤3.0.

For treatment of DVT, PE and prevention of recurrence in adults, and for treatment of VTE and prevention of recurrence in children: discontinue VKA treatment and initiate rivaroxaban treatment when the INR is ≤2.5.

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

Switching from Rivaxored^® to Vitamin K Antagonists (VKAs)

There is a possibility of insufficient anticoagulant effect when switching from rivaroxaban to VKAs. Continuous adequate anticoagulant effect must be ensured during the transition to an alternative anticoagulant. It should be noted that Rivaroxaban may contribute to an increased INR.

Patients transitioning from rivaroxaban 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 subsequent VKA dosing based on the INR value. During concurrent use of rivaroxaban and a VKA, the INR should be determined no earlier than 24 hours after the previous dose, but before taking the next dose of rivaroxaban.

After discontinuation of rivaroxaban, the INR can be reliably determined 24 hours after the last dose.

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

Switching from parenteral anticoagulants to Rivaxored^®

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

Switching from Rivaxored^® to parenteral anticoagulants

Rivaroxaban should be discontinued and the first dose of the parenteral anticoagulant should be administered at the time the next dose of rivaroxaban would have been taken.

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, Rivaroxaban 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 prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation, the recommended dose is 15 mg once daily (see sections “Pharmacological Properties” and “Pharmacokinetics”).

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 rivaroxaban 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 “Pharmacological Properties”, “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 section “Pharmacokinetics”).

• 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 section “Pharmacokinetics”).

Children and adolescents with moderate or severe renal impairment (GFR <50 ml/min/1.73 m² ) Rivaroxaban is not recommended due to lack of clinical data (see section “Special Instructions”).

Patients with hepatic impairment

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

For children with hepatic impairment, clinical data are lacking.

Elderly patients

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

Body weight

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

Gender

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

Patients undergoing cardioversion

Treatment with rivaroxaban may be initiated or continued in patients who may require cardioversion.

For transesophageal echocardiography (TEE)-guided cardioversion in patients not previously receiving anticoagulant therapy, to ensure adequate anticoagulation, rivaroxaban treatment should be initiated at least 4 hours before cardioversion. For all patients, confirmation should be obtained prior to cardioversion that the patient has taken Rivaroxaban as prescribed. Decisions regarding initiation and duration of treatment should take into account current guidelines and recommendations for anticoagulant therapy in patients undergoing cardioversion.

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

There is limited experience with rivaroxaban 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 sections “Pharmacological Properties” and “Special Instructions”).

Children

The safety and efficacy of rivaroxaban in children aged 0 to <18 years for the indication of prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation have not been established. No data are available. Therefore, Rivaroxaban 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

Rivaxored^® is intended for oral administration.

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

Children weighing at least 30 kg

Rivaxored^® is intended for oral administration.

The patient should be advised to swallow the tablet with liquid. It should also be taken with food (see section “Pharmacokinetics”). Tablets should be taken at intervals of approximately 24 hours.

If the patient regurgitates the dose immediately, or vomits within 30 minutes of taking the dose, a new dose should be taken. However, if the patient vomits more than 30 minutes after taking the dose, a repeat dose is not required, and the next dose should be taken as scheduled.

The tablet must not be split to obtain a partial dose.

Adverse Reactions

The safety of rivaroxaban was evaluated in thirteen main phase III studies (see Table 5). 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 5. Number of patients 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 events are collected, recorded, and assessed.

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

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

# From the VOYAGER PAD study.

The incidence of adverse reactions reported in children and adults with rivaroxaban is presented in the table below by system organ class (MedDRA) and by frequency. Within each frequency group, adverse reactions are presented in order of decreasing severity. Incidence 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 7. 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 pre-specified selective approach to collecting adverse event data was used in certain 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 Rivaxored^® 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 fatal outcome) will vary depending on the location, intensity or duration of bleeding and/or anemia (see section “Overdose”). 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 treatment with VKAs. Therefore, 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, e.g., patients with severe uncontrolled arterial hypertension and/or when used concomitantly with drugs affecting hemostasis (see section “Special Instructions”). 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 rivaroxaban use. 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 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 (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 adolescent girls after menarche. 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 mild to moderate in severity.

Contraindications

• Hypersensitivity to rivaroxaban or to any of the excipients of the drug;
• Active clinically significant bleeding;
• Lesion or condition associated with an increased risk of major bleeding, e.g., current or recently past gastrointestinal ulcer, presence of malignant neoplasms with a high risk of bleeding, recent trauma to the brain or spinal cord, recent surgery on the brain, spinal cord or eyes, recent intracranial hemorrhage, diagnosed or suspected esophageal varices, arteriovenous malformations, vascular aneurysms, or major vascular abnormalities of the brain or spinal cord;
• 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 the patency of a central venous or arterial catheter;
• Liver disease associated with coagulopathy and a clinically significant risk of bleeding, 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 for reproductive toxicity, risk of bleeding, and data on the ability of rivaroxaban to cross the placenta, Rivaroxaban is contraindicated during pregnancy.

Women of childbearing potential should avoid pregnancy during therapy with rivaroxaban.

Breastfeeding

The safety and efficacy of rivaroxaban in women during breastfeeding have not been established. Data from animals show that Rivaroxaban is excreted in breast milk. Therefore, Rivaxored^® 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

Contraindication: liver disease accompanied by coagulopathy and risk of clinically significant bleeding, including patients with Child-Pugh class B and C liver cirrhosis.

For children with hepatic impairment, clinical data are lacking.

Use in Renal Impairment

Use with caution in patients with moderate (CrCl 30-49 ml/min) and severe renal impairment (CrCl 15-29 ml/min). In patients with mild renal impairment (CrCl 50-80 ml/min), dose adjustment is not required.

Pediatric Use

Children and adolescents with mild renal impairment (GFR 50-80 ml/min/1.73 m² ): dose adjustment is not required based on data in the adult population and limited data in the pediatric population.

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

Geriatric Use

Dose adjustment is not required.

Special Precautions

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

Risk of bleeding

As with other anticoagulants, patients taking Rivaxored^® should be carefully observed for signs of bleeding. The drug should be used with caution in conditions with an increased risk of bleeding. In case of severe bleeding, administration of Rivaxored^® should be discontinued (see section “Overdose”).

In clinical trials, 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 treatment with VKAs. Therefore, 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 (see section “Adverse Reactions”).

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-Factor Xa activity assay may be helpful in exceptional situations where information on rivaroxaban exposure could be used in making clinically relevant decisions, for example, in case of overdose or emergency surgery (see section “Pharmacokinetics”).

Children

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

Renal impairment

In patients with severe renal impairment (CrCl <30 ml/min), the plasma concentration of rivaroxaban may be significantly increased (on average 1.6-fold), which may lead to an increased risk of bleeding. Rivaroxaban 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 (see sections “Pharmacokinetics” and “Dosage and Administration”).

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

Rivaroxaban 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.

Interactions with other medicinal products

Use of rivaroxaban 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 the plasma concentration of rivaroxaban 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 section “Drug Interactions”).

Caution should be exercised if the patient is simultaneously 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 ulcer formation may be prescribed appropriate prophylactic treatment (see section “Drug Interactions”).

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 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 genitourinary 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 section “Contraindications”).

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 rivaroxaban have not been studied in patients with prosthetic heart valves; therefore, there are no data to support that the use of rivaroxaban provides adequate anticoagulant effect in this category of patients. Use of rivaroxaban is not recommended in this category of patients.

Patients with antiphospholipid syndrome

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 to therapy with vitamin K antagonists.

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

There are data from an international clinical trial whose primary objective was to assess the safety profile in patients with non-valvular atrial fibrillation who have undergone PCI with stenting. Efficacy data in this population are limited (see sections “Pharmacological Properties” and “Dosage and Administration”). Data on such patients with a history of stroke/transient ischemic attack are lacking.

Patients with hemodynamically unstable PE or patients requiring thrombolysis or pulmonary embolectomy

Rivaroxaban 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, as the safety and efficacy of rivaroxaban 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 prolonged or permanent paralysis.

The risk of these events may be increased with 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 in whom anticoagulants are planned to be prescribed 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 assessed as 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 is 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 section “Pharmacokinetics”). 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 receiving Rivaroxaban. 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 judgment, administration of Rivaxored^® 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 need for urgent intervention.

Administration of Rivaxored^® 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

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 (see section “Adverse Reactions”). Patients appear to be at greatest risk of developing these reactions early in treatment: 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 in the presence of any other hypersensitivity symptoms associated with mucosal involvement, rivaroxaban therapy should be discontinued.

Elderly age

The risk of bleeding may increase with advancing age.

Excipients

Rivaxored^® contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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

Effect on ability to drive and use machines

Rivaroxaban 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 (see section “Adverse Reactions”). Patients experiencing such adverse reactions should not drive vehicles or operate machinery.

Overdose

Symptoms

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

Bleeding or other adverse reactions were observed.

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, there is a specific antidote (andexanet alfa) that blocks the pharmacodynamic effect of rivaroxaban, 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 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 section “Pharmacokinetics”). 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 epistaxis), surgical hemostasis with bleeding control procedures, fluid replacement and hemodynamic support, use 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 cessation of bleeding, a specific Factor Xa inhibitor antidote (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, experience with these medicinal products in adults and children receiving Rivaroxaban is currently 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 depending on the reduction in bleeding activity. Depending on local availability, in case of major bleeding, consultation with a coagulation specialist should be considered (see section “Pharmacological Properties”).

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 plasma protein binding, Rivaroxaban is not expected to be eliminated by dialysis.

Drug Interactions

The extent of drug interactions in children is not known. The following interaction data obtained in adult patients and the warnings in the “Special Precautions” section should be taken into account for the pediatric population.

Inhibitors of CYP3A4 and P-glycoprotein

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, use of rivaroxaban 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 section “Special Precautions”). Active substances that strongly inhibit only one of the elimination pathways of rivaroxaban, either CYP3A4 or P-glycoprotein, are expected to increase the plasma concentration of rivaroxaban to a lesser extent. For example, clarithromycin (500 mg twice daily), which is considered a potent inhibitor of CYP3A4 and a moderate inhibitor of P-glycoprotein, caused an increase in the mean AUC of rivaroxaban by 1.5-fold and an increase in C_max by 1.4-fold. 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 section “Special Precautions”).

Erythromycin (500 mg three times daily), a moderate inhibitor of CYP3A4 and P-glycoprotein, caused an increase in the mean AUC and C_max values of rivaroxaban by 1.3-fold. 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 an increase in the mean AUC of rivaroxaban by 1.8-fold and C_max by 1.6-fold compared to patients with normal renal function. In patients with moderate renal impairment, erythromycin caused an increase in the mean AUC of rivaroxaban by 2.0-fold and C_max by 1.6-fold compared to patients with normal renal function. The effect of erythromycin is additive to renal impairment (see section “Special Precautions”).

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 (single dose of 40 mg) and rivaroxaban (single dose of 10 mg), an additive effect on anti-Xa activity was observed, which was not accompanied by 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 used concomitantly 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 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 used concomitantly 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 the use of other anticoagulants, an increased risk of bleeding is possible 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 significant bleeding across all treatment groups with concomitant use of these drugs.

Warfarin

Transitioning patients from 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 summation of effects (individual INR values could reach 12), while the effects on aPTT, inhibition of factor Xa activity, and endogenous thrombin potential (ETP) were additive.

If it is necessary to study 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, inhibition of factor Xa activity, and ETP) reflected only the effect of rivaroxaban.

If it is necessary to study 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 rivaroxaban dose), since Rivaroxaban has a minimal effect on this parameter at that time.

No pharmacokinetic interaction between warfarin and rivaroxaban was observed.

CYP3A4 Inducers

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

Other Concomitant Therapy

No clinically significant pharmacokinetic or pharmacodynamic interaction was observed with 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 (see “Pharmacological Action” section).

Storage Conditions

The drug should be stored at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 years.

Crushed rivaroxaban tablets are stable in water and in apple puree 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.