Kruoksaban (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.

Activation of factor X to form factor Xa via the intrinsic and extrinsic coagulation pathways plays a central role in the coagulation cascade. Factor Xa is a component of the forming prothrombinase complex, whose action leads to the direct conversion of prothrombin to thrombin. As a result, these reactions lead to the formation of a fibrin thrombus and the activation of platelets by thrombin. One molecule of factor Xa catalyzes the formation of more than 1000 thrombin molecules, a phenomenon known as the “thrombin burst”. The reaction rate of factor Xa bound in prothrombinase is increased 300,000-fold compared to that of free factor Xa, providing a sharp surge in thrombin levels. Selective factor Xa inhibitors can stop the “thrombin burst”. Thus, Rivaroxaban affects the results of some specific or general laboratory tests used to assess the coagulation system.

Pharmacodynamic effects

In humans, dose-dependent inhibition of factor Xa activity is observed. Rivaroxaban has a dose-dependent effect on prothrombin time and closely correlates with plasma concentrations (correlation coefficient r=0.98) when the Neoplastin kit is used for analysis. When using other reagents, the results will differ. Prothrombin time should be measured in seconds, since INR is calibrated and certified only for coumarin derivatives and cannot be used for other anticoagulants.

In a clinical pharmacology study of changes in the pharmacodynamics of rivaroxaban in healthy adult volunteers (n=22), an effect of single doses (50 IU/kg) of two different types of prothrombin complex concentrate was identified: 3-factor (factors II, IX and X) and 4-factor (factors II, VII, IX and X). The 3-factor prothrombin complex concentrate reduced mean prothrombin time (Neoplastin) values by approximately 1.0 second over 30 minutes compared to a reduction of approximately 3.5 seconds observed with the 4-factor prothrombin complex concentrate. In contrast, the 3-factor prothrombin complex concentrate had a stronger and faster overall effect on the reversibility of changes in endogenous thrombin generation than the 4-factor prothrombin complex concentrate (see section “Overdose”).

In patients undergoing major orthopedic surgery, the 5th/95th percentiles for prothrombin time (Neoplastin) 2-4 hours after tablet intake (i.e., at peak effect) ranged from 13 to 25 seconds.

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 in patients taking 15 mg twice daily, and from 15 to 30 seconds in patients taking 20 mg once daily.

Rivaroxaban also dose-dependently increases activated partial thromboplastin time (aPTT) and the HepTest result; however, these parameters are not recommended for assessing the pharmacodynamic effects of rivaroxaban.

Monitoring of coagulation parameters is not required during treatment with rivaroxaban. However, if clinically justified (e.g., in case of drug overdose or the need for emergency surgery), the concentration of rivaroxaban can be measured using a calibrated quantitative anti-factor Xa test (e.g., STA- Liquid Anti-Xa, manufacturer Diagnostica Stago SAS, France or similar) (see section “Pharmacokinetics”).

Children

Prothrombin time (Neoplastin), aPTT and anti-Xa activity measured by a calibrated quantitative test closely correlate with plasma concentrations in children. The correlation between anti-Xa activity and plasma concentration is linear with a slope close to 1. Individual discrepancies of higher or lower anti-Xa activity values compared to the corresponding plasma concentrations may occur. Monitoring of coagulation parameters is not required during treatment with rivaroxaban. However, if clinically justified, rivaroxaban concentrations can be measured in μg/L using calibrated quantitative anti-Xa activity tests (see Table 3 in the “Pharmacokinetics” section for the ranges of observed rivaroxaban plasma concentrations in children). When using an anti-Xa activity test to quantify rivaroxaban plasma concentrations in children, the lower limit of quantification must be considered. Threshold values for efficacy or safety criteria have not been established.

Clinical efficacy and safety

Treatment of VTE and prevention of VTE recurrence in children

Six open-label multicenter studies involving children were conducted, 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 that of a 20 mg rivaroxaban once daily dose in adult patients with DVT, as confirmed in a phase III study (see section "Pharmacokinetics").

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 whom 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 permanent or temporary risk factors or a combination thereof 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, which was blinded to the patients’ treatment assignment. Efficacy and safety results are presented in Tables 1 and 2 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 incidence of major bleeding and clinically relevant non-major bleeding was observed in 10 of 329 patients (3%) receiving Rivaroxaban and in 3 of 162 patients (1.9%) receiving the comparator drug. Net clinical benefit (combined incidence of symptomatic recurrent VTE and major bleeding) was observed 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 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 profile of rivaroxaban was 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 who have undergone 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 for 12 months of therapy. Patients with a history of stroke or 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 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 who underwent PCI with stenting.

The primary objective of the PIONEER AF-PCI study was to evaluate safety. Efficacy data (including thromboembolic events) in this population are limited.

Patients with high-risk triple-positive antiphospholipid syndrome

In a randomized open-label multicenter study with blinded endpoint evaluation, Rivaroxaban was studied compared to warfarin in patients with a history of thrombosis and at high risk of thromboembolic events, diagnosed with antiphospholipid syndrome (positive for all three antiphospholipid syndrome tests: presence of lupus anticoagulant, anticardiolipin antibodies and anti-β₂-glycoprotein I antibodies). After including 120 patients, the study was terminated early due to an increased frequency of thromboembolic events in patients in the rivaroxaban group compared to warfarin therapy. The mean duration of the observation period 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 in 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. 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, a bioavailability of 66% was observed when 20 mg tablets were taken on an empty stomach. When 20 mg rivaroxaban tablets were taken with food, 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 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 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 reduced 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, accordingly, reduced exposure to rivaroxaban.

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, 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 a meal, together 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. Rivaroxaban 15 mg or 20 mg tablets should be taken during feeding or with a meal (see section “Dosage and Administration”).

Distribution

In the human body, the majority of rivaroxaban (92-95%) is bound to plasma proteins, with serum albumin being the main binding component. V_d is moderate, V_ss (volume of distribution at steady state) is approximately 50 L.

Children. There are no specific data on the binding of rivaroxaban to plasma proteins in children. There are no data on the pharmacokinetics in children after intravenous administration of rivaroxaban. 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 using an allometric function with a mean value of 113 L for a subject with a body weight of 82.8 kg.

Metabolism and Excretion

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

Rivaroxaban is metabolized via the 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 P-gp (P-glycoprotein) and BCRP (Breast Cancer Resistance Protein). Unchanged Rivaroxaban is the only active compound in human plasma; no significant or active circulating metabolites were detected in plasma. Rivaroxaban, with a systemic clearance of approximately 10 L/h, can be classified as a low-clearance drug. After intravenous administration of 1 mg rivaroxaban, the T_1/2 is about 4.5 hours. After oral administration, elimination is limited by the absorption rate. During the elimination of rivaroxaban from plasma, the terminal T_1/2 is from 5 to 9 hours in young patients and from 11 to 13 hours in elderly patients.

Children. There are no specific data on metabolism in children. There are no data on the pharmacokinetics in children after intravenous administration of rivaroxaban. 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 significant 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, plasma concentrations of rivaroxaban 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 an apparent reduction in total and renal clearance. No dose adjustment is required for elderly patients.

Body weight. Very low or high body weight (less than 50 kg and more than 120 kg) only slightly affected the plasma concentration of rivaroxaban (the difference is less than 25%) (see section “Dosage Regimen”). No dose adjustment of the drug based on patient body weight is required.

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

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

Analysis of the obtained 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 general pediatric population.

Impaired hepatic function. In adult patients with liver cirrhosis and mild hepatic impairment (Child-Pugh class A), the pharmacokinetics of rivaroxaban differed only slightly from the corresponding parameters in the control group of healthy subjects (on average, a 1.2-fold increase in the AUC of rivaroxaban 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 values were increased 2.6-fold. The rate of renal excretion of rivaroxaban in these patients was reduced, similar to 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 (Child-Pugh class B) was more pronounced (2.6-fold) than in healthy volunteers; PT was also 2.1 times higher than in healthy volunteers. Patients with moderate hepatic impairment are more sensitive to rivaroxaban, which is a consequence of a closer relationship between pharmacodynamic effects and pharmacokinetic parameters, especially between concentration and prothrombin time.

The use of the drug Kruoksaban is contraindicated in patients with liver disease accompanied by coagulopathy and a clinically significant risk of bleeding, including patients with Child-Pugh class B and C liver cirrhosis (see section “Contraindications”).

Patients with impaired renal function. In adult patients with impaired renal function, an increase in the AUC of rivaroxaban was observed, inversely proportional to the degree of reduction in renal function, assessed by CrCl.

In patients with mild (CrCl 50-80 mL/min), moderate (CrCl 30-49 mL/min), or severe (CrCl 15-29 mL/min) renal impairment, a 1.4-fold, 1.5-fold, and 1.6-fold increase in rivaroxaban plasma concentrations (AUC) was observed, respectively, compared to healthy volunteers. 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 times compared to healthy volunteers; prothrombin time also increased by 1.3, 2.2, and 2.4 times, respectively.

Data on the use of rivaroxaban in patients with CrCl <15 mL/min are not available.

Due to significant binding to plasma proteins, Rivaroxaban is not expected to be eliminated by hemodialysis.

The use of the drug Kruoksaban is not recommended in patients with CrCl <15 mL/min.

The drug Kruoksaban should be used with caution in patients with CrCl 15-29 mL/min (see section “Special Instructions”).

Pharmacokinetic data in patients

In adult patients receiving Rivaroxaban at a dose of 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 time points approximately corresponding to the maximum and minimum concentration in the dosing interval in children with acute VTE receiving Rivaroxaban at a body weight-dependent dose to achieve exposure corresponding to that in adult patients with DVT receiving a 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).

Pharmacokinetic-pharmacodynamic relationship

The relationship between pharmacokinetic parameters and pharmacodynamic effects (PK/PD) between rivaroxaban plasma concentration and pharmacodynamic endpoints (inhibition of factor Xa, prothrombin time, aPTT, and HepTest result) was evaluated when taking rivaroxaban over 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. A linear regression model better demonstrates the relationship between rivaroxaban concentration and prothrombin time value. The slope varied significantly depending on the reagents used to determine prothrombin time. When using the Neoplastin 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.

The baseline level of factor Xa and prothrombin time in patients was influenced by surgery, leading to a difference in the concentration-prothrombin time slope between the day after surgery and the steady state.

Children and adolescents

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

Indications

Adults

• 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 VTE and prevention of recurrent VTE in children and adolescents under 18 years of age with a body weight of 50 kg or more 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 the drug Kruoksaban should be considered as long-term therapy provided that the benefit of preventing stroke and systemic embolism outweighs the risk of bleeding (see section “Special Instructions”).

Missed dose

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

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

The recommended initial dose for the treatment of acute DVT or PE is 15 mg twice daily for the first 3 weeks, followed by a switch to 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 is indicated (after completing at least 6 months of treatment for DVT or PE), the recommended dose is 10 mg once daily. For patients at high risk of recurrent DVT or PE, such as those with severe comorbidities or who developed recurrent DVT or PE during extended prophylaxis with Kruoksaban at a dose of 10 mg once daily, the use of Kruoksaban at a dose of 20 mg once daily should be considered.

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 “Special Instructions”).

Table 4

Missed dose

If a dose is missed during the 15 mg twice daily dosing regimen (day 1-21), the patient should take Kruoksaban immediately to achieve the daily dose of 30 mg of Kruoksaban. 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 Kruoksaban tablet immediately and continue taking the drug once daily as recommended the next day. A double dose should not be taken on the same day to compensate for the missed dose.

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

Treatment with the drug Kruoksaban in children and adolescents under 18 years of age should be started 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 is 15 mg of rivaroxaban once daily, which is the maximum daily dose;
• body weight 50 kg or more – recommended dose is 20 mg of rivaroxaban once daily, which is the maximum daily dose;
• For patients with body weight less than 30 kg, please refer to the summary of product characteristics of rivaroxaban in the pharmaceutical form of granules for oral suspension.

The child’s 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 thrombosis recurrence and the potential risk of bleeding.

Missed dose

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

Switching from vitamin K antagonists (VKAs) to the drug Kruoksaban

Prevention of stroke and systemic embolism

VKA treatment should be discontinued and treatment with Kruoksaban started when the INR is ≤3.0.

Treatment of DVT, PE and prevention of recurrence in adults, and in the treatment of VTE and prevention of recurrence in children

VKA treatment should be discontinued and treatment with Kruoksaban started when the INR is ≤2.5. When switching patients from VKAs to Kruoksaban, INR values will be falsely elevated after taking Kruoksaban. INR is not suitable for determining the anticoagulant activity of Kruoksaban and therefore should not be used for this purpose (see section “Drug Interactions”).

Switching from the drug Kruoksaban to vitamin K antagonists (VKAs)

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

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

Children

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

Transition from parenteral anticoagulants to Kruoksaban

In adults and children receiving parenteral anticoagulants, the parenteral anticoagulant should be discontinued and Kruoksaban 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 infusion (e.g., intravenous unfractionated heparin).

Transition from Kruoksaban to parenteral anticoagulants

Kruoksaban should be discontinued and the first dose of the parenteral anticoagulant should be administered at the time the next dose of Kruoksaban was due.

Special patient groups

Patients with renal impairment

Adults

Available limited clinical data show a significant increase in rivaroxaban plasma concentrations in patients with severe renal impairment CrCl 15-29 ml/min. Consequently, Kruoksaban should be used with caution in this patient category. 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 section “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 Kruoksaban 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 “Pharmacodynamics”, “Pharmacokinetics” and “Special Instructions”). When the recommended dose is 10 mg once daily, no dose adjustment from 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 ): Kruoksaban is not recommended due to lack of clinical data (see section “Special Instructions”).

Patients with hepatic impairment

Kruoksaban is contraindicated in patients with hepatic disease associated with coagulopathy and clinically significant bleeding risk, including 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 Kruoksaban may be initiated or continued in patients who may require cardioversion.

For cardioversion under transesophageal echocardiography (TEE) guidance in patients not previously receiving anticoagulant therapy, to ensure adequate anticoagulation, treatment with Kruoksaban should be initiated at least 4 hours before cardioversion. For all patients, confirmation should be obtained before cardioversion that the patient has taken Kruoksaban 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 percutaneous coronary intervention (PCI) with stenting

There is limited experience with Kruoksaban 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 “Pharmacodynamics” and “Special Instructions”).

Children

The efficacy and safety of Kruoksaban in children aged 0 to <18 years for the indication “Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation” have not been established. Due to the lack of clinical data, Kruoksaban is not recommended for use in children under 18 years of age, except for use for the indication “Treatment of VTE and prevention of recurrent VTE” .

Method of administration

Orally.

Crushing tablets

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

Adults

Tablets should be taken with food (see section “Pharmacokinetics”). If the patient is unable to swallow the tablet whole, the Kruoksaban tablet can be crushed and mixed with water or apple puree immediately before intake. After intake of a crushed 15 mg or 20 mg Kruoksaban tablet, a meal should be taken immediately. The crushed tablet can also be administered via a gastric tube (see “Crushing tablets” and section “Pharmacokinetics”).

Children weighing 30 to 50 kg

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 tablet immediately or vomits within 30 minutes of taking the drug, a new dose should be taken. However, if the patient vomits more than 30 minutes after taking the tablet, 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 contained in one tablet. If the patient is unable to swallow a 15 mg tablet whole, administration of a 15 mg rivaroxaban tablet, crushed and mixed with water or apple puree immediately before intake, should be prescribed. The crushed tablet can be administered via a nasogastric or gastric tube (see “Crushing tablets” and section “Pharmacokinetics”).

Children weighing more than 50 kg

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 tablet immediately or vomits within 30 minutes of taking the drug, a new dose should be taken. However, if the patient vomits more than 30 minutes after taking the tablet, 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 contained in one tablet. If the patient is unable to swallow a 20 mg tablet whole, administration of a 20 mg rivaroxaban tablet, crushed and mixed with water or apple puree immediately before intake, should be prescribed. The crushed tablet can be administered via a nasogastric or gastric tube (see “Crushing tablets” and section “Pharmacokinetics”).

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

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

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

# From the VOYAGER PAD study.

Tabulated summary of adverse reactions

The frequency of adverse reactions reported in children and adults taking rivaroxaban is presented in Table 7 below, categorized by system organ class (MedDRA) and frequency.

Frequency is defined as: very common (≥1/10), common (≥1/100, but <1/10), uncommon (≥1/1000, but <1/100), rare (≥1/10000, but <1/1000), very rare (<1/10000), 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

^AObserved 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.

^CObserved as uncommon in the prevention of atherothrombotic events in patients after ACS (after PCI).

* 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 rivaroxaban may be associated with an increased risk of occult or overt bleeding from any organ and tissue, which may lead to post-hemorrhagic anemia. Signs, symptoms and severity (including possible fatal outcome) vary depending on the location, severity or duration of bleeding and/or anemia (see section “Overdose”).

In clinical studies, mucosal bleeding (namely: epistaxis, gingival, gastrointestinal, genitourinary, including abnormal vaginal or increased menstrual bleeding) and anemia were observed more frequently during long-term treatment with rivaroxaban compared to treatment with VKAs. Thus, in addition to proper clinical monitoring, laboratory testing of hemoglobin/hematocrit may be useful for detecting occult bleeding and quantifying the clinical significance of overt bleeding that is deemed acceptable. The risk of bleeding may be increased in certain patient groups, e.g., patients with uncontrolled severe arterial hypertension and/or when used concomitantly with drugs affecting hemostasis (see section “Special Instructions”). Menstrual bleeding may be more intense and/or prolonged.

Hemorrhagic complications may manifest as weakness, pallor, dizziness, headache, or unexplained swelling, shortness of breath, or shock that cannot be explained by other causes. In some cases, symptoms of myocardial ischemia, such as chest pain and angina, have developed due to anemia.

Such known complications secondary to severe bleeding as compartment syndrome, renal failure due to hypoperfusion or anticoagulant-associated nephropathy have also been reported with rivaroxaban use. Therefore, the possibility of bleeding should be considered when assessing the condition of any patient receiving anticoagulants.

Children

Treatment of VTE and prevention of recurrent VTE

The safety assessment in children and adolescents is based on safety data from open-label, active-controlled studies (two phase II and one phase III) involving children from birth to <18 years. 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 concentration (common, 1.5%) and increased conjugated bilirubin concentration (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 the context of post-marketing surveillance in the adult population, was observed frequently (4.6%) in clinical studies in the pediatric population. Adverse drug reactions in children were mainly of mild to moderate severity.

Contraindications

• Hypersensitivity to rivaroxaban or to any of the excipients;
• Clinically significant active bleeding (e.g., intracranial hemorrhage, gastrointestinal bleeding);
• Injury or pathological condition associated with an increased risk of major bleeding (e.g., existing or recently experienced 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 pathologies of the blood vessels of the brain or spinal cord);
• Concomitant therapy with any other anticoagulants, for example, unfractionated heparin, low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, apixaban, dabigatran etexilate, etc.), except when switching from or to Rivaroxaban (see section “Dosage Regimen”) or when using unfractionated heparin in doses necessary to maintain the function of a central venous or arterial catheter (see section “Drug Interactions”);
• Liver disease accompanied by coagulopathy and risk of clinically significant bleeding, including patients with liver cirrhosis (Child-Pugh class B and C) (see section “Pharmacokinetics”);
• Pregnancy;
• Breastfeeding period.

Use in Pregnancy and Lactation

Origin has not been established.

Pregnancy

The safety and efficacy of rivaroxaban in pregnant women have not been established. Data obtained from experimental animals have shown significant reproductive toxicity. Due to possible reproductive toxicity, risk of bleeding and ability to cross the placenta, Rivaroxaban is contraindicated during pregnancy (see section “Contraindications”).

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

Breastfeeding period

The efficacy and safety of rivaroxaban in women during breastfeeding have not been established. Data from experimental animals show that Rivaroxaban is excreted in breast milk. The drug is contraindicated during breastfeeding (see section “Contraindications”). A decision must be made to discontinue breastfeeding or to discontinue therapy.

Fertility

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

Use in Hepatic Impairment

Kruoksaban is contraindicated in patients with liver disease accompanied by coagulopathy and risk of clinically significant bleeding, including those with liver cirrhosis class B and C according to the Child-Pugh classification.

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

In patients with moderate (CrCl 30-49 ml/min) or severe (CrCl 15-29 ml/min) renal impairment, adjustment of the dosage regimen is required.

In patients with mild renal impairment (CrCl 50-80 ml/min), no dose adjustment is required.

Pediatric Use

The efficacy and safety of Kruoksaban in children aged 0 to <18 years for the indication “Prevention of stroke and systemic thromboembolism in patients with non-valvular atrial fibrillation” have not been established. Due to the lack of clinical data, Kruoksaban is not recommended for use in children under 18 years of age, except for use for the indication “Treatment of VTE and prevention of recurrent VTE”.

In 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.

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

For children with hepatic impairment, clinical data are lacking.

Geriatric Use

In elderly patients, no dose adjustment is required.

Special Precautions

The practice of using anticoagulant therapy shows that patients should be monitored throughout the entire treatment period.

Risk of bleeding

As with other anticoagulants, patients taking Rivaroxaban should be carefully monitored for signs of bleeding. The drug is recommended to be taken with caution in conditions with an increased risk of bleeding. In case of severe bleeding, administration of Kruoksaban should be discontinued (see section “Overdose”).

In clinical studies, mucosal bleeding (namely: epistaxis, gingival bleeding, gastrointestinal bleeding, genitourinary bleeding, including abnormal vaginal or increased menstrual bleeding) and anemia were observed more frequently during long-term treatment with rivaroxaban compared with VKA treatment. Thus, in addition to proper clinical monitoring, laboratory testing of hemoglobin/hematocrit may be useful for detecting occult bleeding and quantifying the clinical significance of overt bleeding where applicable.

Some patient subgroups listed below are at 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.

Rivaroxaban therapy does not require routine monitoring of its exposure. However, measurement of rivaroxaban concentration using a calibrated test for quantitative determination of anti-Xa activity may be useful in exceptional cases where information on rivaroxaban exposure can be used in making clinically significant decisions, for example, in case of overdose or emergency surgery (see sections “Pharmacodynamics” and “Pharmacokinetics”).

Children

There is limited data on the use of rivaroxaban in children with cerebral venous sinus thrombosis who have a CNS infection (see section “Pharmacodynamics”). 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. Kruoksaban should be used with caution in patients with CrCl 15-29 ml/min. The use of Kruoksaban is not recommended in patients with CrCl <15 ml/min (see sections “Pharmacokinetics” and “Dosage Regimen”).

Kruoksaban should be used with caution in patients with moderate renal impairment (CrCl 30-49 ml/min) receiving concomitant drugs that may lead to an increase in rivaroxaban plasma concentration (see section “Drug Interactions”).

Kruoksaban 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 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 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 (see section “Drug Interactions”).

There are no clinical data on concomitant systemic treatment of children with potent inhibitors of both CYP3A4 and P-glycoprotein (see section “Drug Interactions”).

Caution should be exercised if the patient is simultaneously receiving drugs that affect hemostasis, such as NSAIDs, acetylsalicylic acid and platelet aggregation inhibitors or selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs).

In patients at risk of GI ulceration, appropriate prophylactic treatment may be prescribed (see section “Drug Interactions”).

Other risk factors for bleeding

Rivaroxaban, like other antithrombotic agents, should be used with caution when treating patients with an increased risk of bleeding, including:

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

Patients with cancer

Patients with a malignant disease may simultaneously be at higher risk of both bleeding and thrombosis. The individual benefit of antithrombotic therapy should be weighed against the risk of bleeding in patients with active cancer depending on tumor location, anticancer therapy and disease stage. Tumors located in the gastrointestinal or genitourinary tract were associated with an increased risk of bleeding during rivaroxaban therapy. The use of rivaroxaban in patients with malignant neoplasms and a high risk of bleeding is contraindicated (see section “Contraindications”).

Patients with prosthetic heart valves

Rivaroxaban is not recommended 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 confirm that the use of rivaroxaban provides adequate anticoagulant effect in this patient population. Treatment of such patients with Kruoksaban is not recommended.

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 (VKA) therapy.

Surgical interventions for hip fracture

The use of rivaroxaban in surgical interventions for hip fracture has not been studied in interventional clinical trials to evaluate efficacy and safety. There are limited clinical data from observational studies in patients undergoing surgery for lower limb fractures, including proximal femur fractures.

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

There are data from an interventional clinical trial whose primary objective was to assess the safety profile in patients with non-valvular atrial fibrillation who underwent PCI with stenting. Efficacy data in this population are limited (see sections “Pharmacodynamics” and “Dosage Regimen”). There are no data on such patients with a history of stroke/transient ischemic attack. Patients with hemodynamically unstable pulmonary embolism (PE) and patients requiring thrombolysis or thrombectomy Rivaroxaban is not recommended as an alternative to unfractionated heparin in patients with hemodynamically unstable pulmonary embolism, as well as in patients who may require thrombolysis or thrombectomy, since the safety and efficacy of rivaroxaban in such clinical situations have not been established.

Epidural/spinal anesthesia or puncture

When performing neuraxial (epidural/spinal) 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 can lead to prolonged or permanent paralysis. The risk of these events is further increased with the use of indwelling catheters or concomitant use of drugs that affect hemostasis. Traumatic performance of epidural or spinal puncture or repeated puncture may also increase the risk.

Patients should be monitored for signs or 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 a spinal intervention in patients receiving anticoagulants or 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 spinal puncture is best performed when the anticoagulant effect of rivaroxaban is assessed as weak (see section “Pharmacokinetics”).

The epidural catheter is removed no earlier than 18 hours after the last dose of rivaroxaban. The next dose of rivaroxaban should be taken no earlier than 6 hours after removal of the epidural catheter. In case of traumatic puncture, rivaroxaban administration should be delayed for 24 hours.

There are no data on the timing of placement or removal of a neuraxial catheter in children taking 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, administration of Kruoksaban 15 mg and 20 mg should be discontinued at least 24 hours before the intervention, if possible, and based on the physician’s judgment.

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

Administration of Kruoksaban should be resumed after an invasive procedure or surgical intervention, provided that appropriate clinical indicators and adequate hemostasis are present, as determined by the attending physician (see section “Pharmacokinetics”).

Elderly age

The risk of bleeding may increase with age (see section “Pharmacokinetics”).

Dermatological reactions

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 during post-marketing surveillance with the use of rivaroxaban (see section “Adverse Reactions”). Patients appear to be at greatest risk of 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 any other symptoms of hypersensitivity associated with mucosal involvement, therapy with Kruoksaban should be discontinued.

Excipients

Lactose

Patients with rare hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this drug.

Effect on ability to drive vehicles and operate machinery

Cases of syncope and dizziness have been observed with the use of rivaroxaban, which may affect the ability to drive vehicles or operate machinery (see section “Adverse Reactions”). Patients experiencing these adverse reactions should not drive vehicles or operate machinery.

Overdose

Rare cases of overdose up to 1960 mg have been reported. In case of overdose, the patient should be carefully monitored for bleeding complications or other adverse reactions (see subsection “Treatment of Bleeding”). Data in children are limited. Due to limited absorption, a saturation effect is expected without further increase in the mean rivaroxaban plasma concentration at hypertherapeutic doses of 50 mg or higher.

For adults, the specific antidote that suppresses the pharmacodynamic effect of rivaroxaban is andexanet alfa. However, it is contraindicated for use in children.

In case of overdose, activated charcoal can be used to reduce the absorption of rivaroxaban.

Treatment of bleeding

If a complication in the form of bleeding occurs in a patient taking Rivaroxaban, the next dose of the drug should be postponed or the treatment should be discontinued, depending on the situation. The T_1/2 of rivaroxaban is approximately 5-13 hours. The T_1/2 in children, predicted using population pharmacokinetic modeling, is shorter (see the “Pharmacokinetics” section).

Treatment should be individualized according to the severity and location of the bleeding. If necessary, appropriate symptomatic treatment may be used, for example, mechanical compression (e.g., in case of severe epistaxis), surgical hemostasis with bleeding control procedures, fluid replacement and hemodynamic support, administration of blood products (packed red blood cells or fresh frozen plasma, depending on concomitant anemia or coagulopathy) or platelets.

If the measures listed above do not lead to the cessation of bleeding, a specific antidote for Factor Xa inhibitors (andexanet alfa), which suppresses the pharmacodynamic effect of rivaroxaban, or a specific procoagulant drug, for example, prothrombin complex concentrate, activated prothrombin complex concentrate, recombinant factor VIIa (r-FVIIa), may be prescribed. However, to date, experience with these drugs in the treatment of patients receiving Rivaroxaban is very limited. These recommendations are also based on limited preclinical data. Dose adjustment of recombinant factor VIIa and titration based on the reduction in bleeding activity should be considered. 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 patients receiving Rivaroxaban. There is no experience with these drugs in children receiving Rivaroxaban.

There is no scientific rationale or experience for 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 not known. The interaction data provided below, 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 the pharmacodynamic effect of the drug, which may lead to an increased risk of bleeding. Therefore, Rivaroxaban is not recommended for use in patients receiving 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).

Other medicinal products that strongly inhibit only one of the elimination pathways of rivaroxaban – involving CYP3A4 or P-glycoprotein – are expected to increase rivaroxaban plasma concentrations to less significant values.

Clarithromycin (500 mg twice daily), a potent inhibitor of the CYP3A4 isoenzyme and a moderate inhibitor of P-glycoprotein, caused an increase in the mean AUC of rivaroxaban by 1.5-fold and 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 the “Special Instructions” section).

Erythromycin (500 mg three times daily), which moderately suppresses the CYP3A4 isoenzyme and P-glycoprotein, caused an increase in the mean AUC and C_max 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 due to renal impairment (see the “Special Instructions” section).

Fluconazole (400 mg once daily), a moderate inhibitor of the CYP3A4 isoenzyme, caused an increase in the mean AUC of rivaroxaban by 1.4-fold and C_max by 1.3-fold. 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).

Concomitant use of rivaroxaban with dronedarone should be avoided due to limited clinical data on co-administration.

Anticoagulants

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

Due to the 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 co-administration of rivaroxaban 15 mg and naproxen 500 mg, no clinically significant prolongation of bleeding time was observed. However, a more pronounced pharmacodynamic response is possible in some individuals.

No clinically significant pharmacokinetic or pharmacodynamic interactions were observed with the co-administration 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 found in some patients, which did not correlate with platelet aggregation and P-selectin or glycoprotein IIb/IIIa receptor content.

Caution should be exercised when co-administering rivaroxaban 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, an increased risk of bleeding may occur in patients concomitantly taking Rivaroxaban with selective serotonin reuptake inhibitors (SSRIs) and 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 co-administration of these drugs.

Warfarin

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

To assess the pharmacodynamic effects of rivaroxaban during the transition period, anti-Factor Xa activity, PiCT, and HepTest, which are tests not affected by warfarin, can be used as necessary tests. Starting from day 4 after the last dose of warfarin, all tests (including PT, aPTT, Factor Xa activity inhibition, and ETP) reflected exclusively the effect of rivaroxaban.

To assess the pharmacodynamic effects of warfarin during the transition period, the INR value measured at the time of the C_trough of rivaroxaban (24 hours after the previous rivaroxaban dose) can be used, because at this time the influence of rivaroxaban on the test results is minimal.

No pharmacokinetic interaction was found between warfarin and rivaroxaban.

CYP3A4 inducers

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

Concomitant use of other drugs

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

No clinically significant interactions with food were observed (see the “Dosage Regimen” section).

Effect on laboratory parameters

The effect on the results of coagulation parameter tests (PT, aPTT, HepTest) corresponds to that expected based on the mechanism of action of rivaroxaban (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 3 years.

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.