Rivaroxaban-SZ (Tablets) Instructions for Use

ATC Code

B01AF01 (Rivaroxaban)

Active Substance

Rivaroxaban (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Anticoagulant – direct factor Xa inhibitor

Pharmacotherapeutic Group

Antithrombotic agents; direct factor Xa inhibitors

Pharmacological Action

Mechanism of action

Rivaroxaban is a highly selective direct factor Xa inhibitor with high oral bioavailability.

Inhibition of factor Xa disrupts the intrinsic and extrinsic pathways of the coagulation cascade, inhibiting thrombin formation and thrombus formation.

Rivaroxaban does not inhibit thrombin (activated factor II) and has not been shown to affect platelets.

Pharmacodynamic effects

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

Rivaroxaban has a dose-dependent effect on prothrombin time, which correlates well with rivaroxaban plasma concentrations (r=0.98) when the Neoplastin 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 pharmacological study of rivaroxaban pharmacodynamics changes in healthy adult volunteers (n=22), the effect of single doses (50 IU/kg) of two different types of prothrombin complex concentrate was studied: 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 reversing changes in endogenous thrombin generation than the 4-factor prothrombin complex concentrate (see the “Overdose” section).

Rivaroxaban also dose-dependently increases 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, the concentration of rivaroxaban can be measured using a calibrated quantitative anti-Xa activity test (see the “Pharmacokinetics” section).

Clinical efficacy and safety

Acute coronary syndrome (ACS)

The rivaroxaban clinical program was designed to demonstrate the efficacy of rivaroxaban for the prevention of death from cardiovascular causes, myocardial infarction, or stroke in patients with recent ACS (ST-segment elevation myocardial infarction, non-ST-segment elevation myocardial infarction, or unstable angina).

In the pivotal double-blind study ATLAS ACS 2 TIMI 51, 15526 patients were randomly assigned in a 1:1:1 ratio to one of three treatment groups: Rivaroxaban 2.5 mg orally twice daily, 5 mg orally twice daily, or placebo twice daily, in combination with either aspirin monotherapy or dual antiplatelet therapy (aspirin and a thienopyridine (clopidogrel or ticlopidine)).

Patients with ACS under 55 years of age were required to have either diabetes mellitus or a prior myocardial infarction.

The mean treatment duration was 13 months, and the maximum treatment duration reached almost 3 years.

93.2% of patients received treatment with aspirin concurrently with a thienopyridine and 6.8% received only aspirin.

Among patients receiving dual antiplatelet therapy, 98.8% received clopidogrel, 0.9% received ticlopidine, and 0.3% received prasugrel.

Patients received the first dose of rivaroxaban at least 24 hours and up to 7 days (mean 4.7 days) after hospital admission, but as soon as possible after the patient was stabilized during the current ACS (including revascularization procedures) and when parenteral anticoagulant therapy was typically discontinued.

Both the rivaroxaban 2.5 mg twice daily and 5 mg rivaroxaban twice daily regimens were effective in further reducing the incidence of cardiovascular events on top of standard antiplatelet therapy.

When taking 2.5 mg twice daily, mortality was reduced, and it was proven that the lower dose has a lower risk of bleeding, therefore it is recommended to prescribe Rivaroxaban at a dose of 2.5 mg twice daily in combination with aspirin monotherapy or dual antiplatelet therapy (aspirin and clopidogrel or ticlopidine) for the prevention of atherothrombotic events in adult patients after ACS with elevated cardiac biomarkers.

Compared to placebo, Rivaroxaban significantly reduced the primary composite endpoint, including death from cardiovascular causes, myocardial infarction, or stroke.

The treatment benefit, due to a reduction in death from cardiovascular events and myocardial infarction, appeared early and persisted throughout the treatment period (see Table 1 and Figure 1).

The first secondary endpoint, including death from any cause, myocardial infarction, or stroke, was also significantly reduced.

An additional retrospective analysis showed a nominally significant reduction in the incidence of stent thrombosis compared to placebo (see Table 1).

The incidence of the primary safety endpoint (non-coronary artery bypass graft (CABG) related major bleeding according to the TIMI scale) was higher in patients receiving Rivaroxaban than in patients receiving placebo (see Table 3).

However, the incidence of fatal bleeding, arterial hypotension requiring treatment with intravenous inotropic agents, and surgery for ongoing bleeding was the same for rivaroxaban and placebo.

Table 2 presents efficacy results in patients who underwent percutaneous coronary intervention (PCI).

Safety results in the subgroup of patients who underwent PCI were comparable to the overall safety results.

Patients with elevated biomarkers (troponin or CK-MB) and without prior stroke/TIA constituted 80% of the study population.

The results in this patient population were also consistent with the overall efficacy and safety results.

Table 1. Efficacy results from the phase III study ATLAS ACS 2 TIMI 51

^a modified approach to analysis set handling (full analysis set approach for stent thrombosis)

^b compared to placebo; log-rank p-value

* statistically superior

** nominally significant

Table 2. Efficacy results from the phase III study ATLAS ACS 2 TIMI 51 in patients who underwent PCI

^a modified approach to analysis set handling (full analysis set approach for stent thrombosis)

^b compared to placebo; log-rank p-value

** nominally significant

Table 3. Safety results from the phase III study ATLASACS2 TIMI 51

^a safety population, treated

^bcompared to placebo; log-rank p-value

* statistically superior

Figure 1. Time to first occurrence of the primary efficacy endpoint (death from cardiovascular causes, myocardial infarction, or stroke)

Coronary artery disease (CAD)/peripheral artery disease (PAD)

The phase III COMPASS study (27395 patients, 78.0% men, 22.0% women) demonstrated the efficacy and safety of rivaroxaban for the prevention of adverse events, including death from cardiovascular causes, myocardial infarction, stroke in patients with CAD or symptomatic PAD at high risk of ischemic events.

Patients were followed for a mean of 23 months and a maximum of 3.9 years.

Patients not requiring continuous proton pump inhibitor therapy were randomized to receive pantoprazole or placebo.

Then all patients were randomized in a 1:1:1 ratio to receive rivaroxaban 2.5 mg twice daily/aspirin 100 mg once daily, rivaroxaban 5 mg twice daily, or aspirin 100 mg once daily alone and their corresponding placebos.

Patients with CAD had multivessel CAD and/or a prior myocardial infarction.

For patients aged <65 years, the presence of atherosclerosis affecting at least 2 vascular beds or at least 2 additional cardiovascular risk factors was required.

Patients with PAD had previously undergone interventions such as bypass or percutaneous transluminal angioplasty, or amputation of a limb or foot due to arterial vascular disease, or had intermittent claudication with an ankle/brachial blood pressure ratio <0.90 and/or significant peripheral artery stenosis, or prior carotid artery revascularization, or asymptomatic carotid artery stenosis ≥50%.

Patients who required dual antiplatelet or other antiplatelet therapy not related to aspirin, or oral anticoagulant use, as well as patients with a high risk of bleeding, heart failure with an ejection fraction <30%, or New York Heart Association class III or IV, any ischemic non-lacunar stroke within 1 month, or any history of hemorrhagic or lacunar stroke were excluded from the study.

Rivaroxaban at a dose of 2.5 mg twice daily in combination with aspirin at a dose of 100 mg once daily was superior to aspirin at a dose of 100 mg in reducing the primary composite endpoint, including death from cardiovascular causes, myocardial infarction, and stroke (see Table 4 and Figure 2).

In patients receiving Rivaroxaban at a dose of 2.5 mg twice daily in combination with aspirin at a dose of 100 mg once daily, there was a significant increase in events of the primary safety endpoint (major bleeding according to modified ISTH criteria) compared to patients receiving aspirin monotherapy at a dose of 100 mg (see Table 5).

For the primary efficacy endpoint, the observed benefit of rivaroxaban 2.5 mg twice daily in combination with aspirin 100 mg once daily compared to aspirin 100 mg once daily was HR=0.89 (95% CI 0.7-1.1) in patients ≥75 years (incidence: 6.3% vs. 7.0%) and HR=0.70 (95% CI 0.6-0.8) in patients <75 years (3.6% vs. 5.0%).

The incidence of major bleeding according to modified ISTH criteria was HR=2.12 (95% CI 1.5-3.0) in patients ≥75 years (5.2% vs. 2.5%) and HR=1.53 (95% CI 1.2-1.9) in patients <75 years (2.6% vs. 1.7%).

The use of pantoprazole 40 mg once daily in addition to the investigational antithrombotic drug by patients without a clinical need for a proton pump inhibitor showed no benefit in preventing upper gastrointestinal complications (i.e., a combination of upper gastrointestinal bleeding, upper gastrointestinal ulcers, upper gastrointestinal obstruction or perforation); the incidence of upper gastrointestinal complications was 0.39 per 100 patient-years in the group receiving pantoprazole 40 mg once daily and 0.44 per 100 patient-years in the group receiving placebo once daily.

Table 4. Efficacy results from the phase III COMPASS study

^aanalysis of the population as treated, primary analysis

^bcompared to Aspirin 100 mg; log-rank p-value

* reduction in the primary efficacy endpoint was statistically significantly greater

CI: confidence interval

KM %: Kaplan-Meier cumulative incidence risk estimates, calculated at 900 days

Table 5. Safety results from the phase III COMPASS study

^a analysis of the intention-to-treat patient population, primary analysis

^b compared to Aspirin 100 mg; log-rank p-value

CI: confidence interval

Cum. risk: Cumulative incidence risk (Kaplan-Meier estimates) at 30 months

ISTH: International Society on Thrombosis and Haemostasis

Figure 2. Time to first occurrence of the primary efficacy endpoint (stroke, myocardial infarction, death from cardiovascular causes) in the COMPASS study

CI: confidence interval

Patients after a recent lower extremity revascularization procedure due to symptomatic PAD

In the pivotal double-blind phase III VOYAGER PAD study, 6564 patients after a recent successful lower extremity revascularization procedure (surgical or endovascular, including hybrid procedures) due to symptomatic PAD were randomly assigned in a 1:1 ratio to one of two antithrombotic treatment groups: Rivaroxaban 2.5 mg twice daily in combination with aspirin 100 mg once daily or aspirin 100 mg once daily.

Patients were allowed to additionally receive a standard dose of clopidogrel once daily for up to 6 months.

The aim of the study was to demonstrate the efficacy and safety of rivaroxaban in combination with aspirin for the prevention of myocardial infarction, ischemic stroke, death from cardiovascular causes, acute limb ischemia, or major amputation of vascular etiology in patients after recent successful lower extremity revascularization procedures due to symptomatic PAD.

Patients aged ≥50 years with documented moderate or severe symptomatic atherosclerotic PAD of the lower extremities, confirmed by all of the following, were included: clinically (i.e., by functional limitations), anatomically (i.e., by imaging confirming the presence of PAD distal to the external iliac artery), and hemodynamically (ankle-brachial index (ABI) ≤0.80 or toe-brachial index (TBI) ≤0.60 for patients with no history of limb revascularization or ABI ≤0.85 or TBI ≤0.65 for patients with a history of limb revascularization). Patients who required dual antiplatelet therapy for more than 6 months or any additional antiplatelet therapy other than ASA and clopidogrel, or oral anticoagulant therapy, as well as patients with a history of intracranial hemorrhage, stroke, or TIA, or patients with eGFR <15 ml/min were excluded.

The median follow-up duration was 24 months, and the maximum follow-up period was 4.1 years. The mean age of the patients included in the study was 67 years, and 17% of patients were older than 75 years. The mean time from the index revascularization procedure to the start of the study treatment in the overall population was 5 days (6 days after surgical and 4 days after endovascular revascularization, including hybrid procedures). Overall, 53.0% of patients received short-term background clopidogrel therapy with a median duration of 31 days. According to the study protocol, treatment may be initiated as soon as possible, but no later than 10 days after a successful appropriate revascularization procedure and achievement of hemostasis. Rivaroxaban 2.5 mg twice daily in combination with ASA 100 mg once daily was more effective in reducing the primary composite endpoint, including myocardial infarction, ischemic stroke, death from cardiovascular causes, acute limb ischemia, and major amputation of vascular etiology, compared with ASA alone (see Table 6). The primary safety endpoint of TIMI major bleeding was higher in patients receiving Rivaroxaban and ASA, without an increase in fatal or intracranial bleeding (see Table 7).

Secondary efficacy endpoints were tested in a predefined hierarchical order (see Table 6).

Table 6. Efficacy Results from the Phase III VOYAGER PAD Study

^aIntent-to-treat population analysis, primary analysis; adjudicated by the Independent Clinical Adjudication Committee (ICAC)

^bComposite of myocardial infarction, ischemic stroke, death from cardiovascular causes (death from cardiovascular causes and death from unknown cause), acute limb ischemia, and major amputation of vascular etiology

^cThe analysis only considers the first occurrence of an endpoint event within the subject’s data volume

^dHR (95% CI) based on a Cox proportional hazards model, stratified by procedure type, and with clopidogrel use as the sole covariate

^eHomogeneous p-value based on the log-rank test, stratified by procedure type and clopidogrel use, with treatment as a factor

^fAcute limb ischemia is defined as a sudden, significant worsening of limb perfusion, either with a new pulse deficit or requiring therapeutic intervention (e.g., thrombolysis, thrombectomy, or urgent revascularization) and leading to hospitalization

*The efficacy reduction was statistically significantly greater

CI: confidence interval

Table 7. Safety Results from the Phase III VOYAGER PAD Study

^aSafety population analysis (all randomized subjects who received at least one dose of the study drug)

^bn = number of subjects with events, N = number of subjects at risk, % = 100*n/N, n/100 pt-yrs – ratio of the number of subjects with incident events/cumulative time at risk

^cHR (95% CI) based on a Cox proportional hazards model, stratified by procedure type, and with clopidogrel use as the sole covariate

^dTwo-sided p-value based on the log-rank test, stratified by procedure type and clopidogrel use, with treatment as a factor

CAD with Heart Failure

The COMMANDER HF study included 5022 patients with heart failure and established CAD following hospitalization for decompensated heart failure, who were randomly assigned to one of 2 treatment groups: Rivaroxaban 2.5 mg twice daily (N=2507) or placebo (N=2515), respectively. The overall median treatment duration in the study was 504 days.

Patients were required to have symptomatic heart failure for at least 3 months and a left ventricular ejection fraction (LVEF ≤40% within 1 year of enrollment. At baseline, the median ejection fraction was 34% (IQR: 28-38%), and 53% of participants were in NYHA class III or IV.

The primary efficacy analysis (i.e., the composite of all-cause mortality, myocardial infarction, or stroke) did not show a statistically significant difference between the group receiving Rivaroxaban 2.5 mg twice daily and the placebo group with HR=0.94 (95% CI 0.84-1.05), p=0.270. Regarding all-cause mortality, there was no difference in the number of events between rivaroxaban and placebo (event rate per 100 patient-years; 11.41 vs. 11.63 (HR: 0.98; 95% CI: 0.87-1.10; p=0.743). The incidence of myocardial infarction per 100 patient-years (Rivaroxaban compared with placebo) was 2.08 vs. 2.52 (HR 0.83; 95% CI: 0.63-1.08; p=0.165), and the incidence of stroke per 100 patient-years was 1.08 vs. 1.62 (HR: 0.66; 95% CI: 0.47-0.95; p=0.023). The primary safety endpoint (i.e., the combination of fatal bleeding or bleeding into a critical area with potential permanent disability) was observed in 18 (0.7%) patients in the rivaroxaban 2.5 mg twice daily group and in 23 (0.9%) patients in the placebo group, respectively (HR=0.80; 95% CI 0.43-1.49; p=0.484). A statistically significant increase in the incidence of ISTH major bleeding was observed in the rivaroxaban group compared with placebo (event rate per 100 patient-years: 2.04 vs. 1.21, HR 1.68; 95% CI: 1.18-2.39; p=0.003).

In patients with mild to moderate heart failure, the treatment effects in the COMPASS study subgroup were similar to the treatment effects in the overall study population (see subsection “CAD/PAD”).

High-Risk Patients with Triple-Positive Antiphospholipid Syndrome

In an investigator-sponsored, randomized, open-label, multicenter study with blinded endpoint evaluation, Rivaroxaban was studied compared with warfarin in patients with a history of thrombosis and at high risk of thromboembolic events, who were diagnosed with antiphospholipid syndrome (positive for all 3 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 patients in the rivaroxaban group. The mean duration of the observation period was 569 days. 59 patients were randomized to the rivaroxaban group at a dose of 20 mg (15 mg for patients with CrCl <50 ml/min) and 61 to the warfarin group (INR 2.0-3.0). Thromboembolic events occurred in 12% of patients randomized to the rivaroxaban group (4 ischemic strokes and 3 myocardial infarctions). No events were recorded in patients randomized to the warfarin group. Major bleeding occurred in 4 patients (7%) in the rivaroxaban group and 2 patients (3%) in the warfarin group.

Pharmacokinetics

Absorption

Rivaroxaban is rapidly absorbed; C_max is reached within 2-4 hours after tablet intake. Following oral administration of Rivaroxaban as 2.5 mg and 10 mg tablets, the drug is almost completely absorbed, with high bioavailability (80-100%) regardless of food intake. Concomitant administration of food with rivaroxaban 2.5 mg and 10 mg doses does not affect the AUC and C_max of rivaroxaban. Rivaroxaban 2.5 mg and 10 mg tablets can be taken with or without food.

The pharmacokinetics of rivaroxaban are nearly linear at doses up to 15 mg once daily. At higher doses, Rivaroxaban exhibits dissolution-limited absorption, with reduced bioavailability and a decreased absorption rate as the dose increases. This is more pronounced when taken on an empty stomach than when taken with food. The pharmacokinetics of rivaroxaban are characterized by moderate interindividual variability in the range (coefficient of variation) of 30 to 40%.

The absorption of rivaroxaban depends on the site of release in the GI tract. A reduction in AUC and C_max by 29% and 56%, respectively, was observed when rivaroxaban granulate was administered into the proximal small intestine compared with the intake of a whole tablet. Drug exposure also decreases when administered into the distal small intestine or ascending colon. Administration of rivaroxaban into the GI tract distal to the stomach should be avoided, as this may lead to reduced absorption and, consequently, reduced exposure to rivaroxaban.

The bioavailability (AUC and C_max) of rivaroxaban 20 mg when taken as a whole tablet is comparable to the bioavailability of the drug taken orally as a crushed tablet (mixed with apple sauce or suspended in water), as well as to the bioavailability of the drug when administered via a gastric tube followed by liquid nutrition. Given the predictable dose-dependent pharmacokinetic profile of rivaroxaban, the results of this bioavailability study are also applicable to lower doses.

Distribution

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

Metabolism and Excretion

After oral administration, approximately two-thirds of the administered rivaroxaban dose is metabolized and subsequently excreted in equal parts in the urine and via the intestine. The remaining one-third of the administered dose is excreted via direct renal excretion in unchanged form, mainly via active renal secretion. Rivaroxaban is metabolized via CYP3A4, CYP2J2 isoenzymes, as well as by mechanisms independent of the cytochrome system. The main sites of biotransformation are oxidation of the morpholine group and hydrolysis of amide bonds. According to in vitro data, Rivaroxaban is a substrate for the transporter proteins Pgp (P-glycoprotein) and BCRP (breast cancer resistance protein). Unchanged Rivaroxaban is the most significant compound in human plasma; no major or active circulating metabolites have been detected. Rivaroxaban, which has a systemic clearance of approximately 10 L/h, can be classified as a low-clearance drug. T_1/2 after IV administration of a 1 mg dose is approximately 4.5 hours. After oral administration, elimination becomes rate-limited by absorption. 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.

Special Patient Populations

Gender. No clinically significant differences in pharmacokinetics and pharmacodynamics were found between men and women.

Elderly Age. In elderly patients, the plasma concentration of rivaroxaban is higher than in young patients; the mean AUC is approximately 1.5 times higher than the corresponding values in young patients, mainly due to reduced (presumed) total and renal clearance. Dose adjustment is not required.

Body Weight. Very low or high body weight (<50 kg and >120 kg) only slightly affects the plasma concentration of rivaroxaban (difference <25%). Dose adjustment is not required.

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

Hepatic Impairment. In 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 volunteers (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 with 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 in 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 PT 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 PT. 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”).

Renal Impairment. The increase in rivaroxaban exposure correlated with the decline in renal function, as assessed by creatinine clearance. In patients with mild renal impairment (CrCl 50-80 ml/min), moderate renal impairment (CrCl 30-49 ml/min), or severe renal impairment (CrCl 15—29 ml/min), a 1.4-fold, 1.5-fold, and 1.6-fold increase in the plasma AUC of rivaroxaban was observed, 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-fold, 1.9-fold, and 2.0-fold, respectively, compared with healthy volunteers; PT was also prolonged by 1.3-fold, 2.2-fold, and 2.4-fold, respectively. Data on the use of rivaroxaban in patients with CrCl <15 ml/min are not available. 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”).

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

Pharmacokinetic Data in Patients

In patients with ACS receiving Rivaroxaban 2.5 mg twice daily for the prevention of atherothrombotic events in combination with ASA, the geometric mean concentrations (90% predictive interval) at 2-4 hours and approximately 12 hours after dose administration (which approximately corresponds to the maximum and minimum concentrations in the dosing interval) were 47 (13-123) μg/L and 9.2 (4.4-18) μg/L, respectively.

Pharmacokinetic-Pharmacodynamic Relationship

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

Children

The safety and efficacy of rivaroxaban in children and adolescents under 18 years of age for the indications of ACS and CAD/PAD have not been established.

Indications

Adults

• Prevention of death due to cardiovascular causes, myocardial infarction, and stent thrombosis in patients after an acute coronary syndrome (ACS) accompanied by elevated cardiospecific biomarkers, in combination therapy with acetylsalicylic acid (ASA) or with ASA and thienopyridines – clopidogrel or ticlopidine;
• Prevention of stroke, myocardial infarction, and death due to cardiovascular causes, as well as prevention of acute limb ischemia and overall mortality in patients with coronary artery disease (CAD) or peripheral artery disease (PAD) in combination therapy with ASA.

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.

For patients with moderate renal impairment (CrCl 30-49 ml/min) the recommended dose is 15 mg once daily.

Duration of treatment: therapy with Rivaroxaban-SZ should be considered as long-term treatment, continued as long as the benefit of treatment outweighs the risk of bleeding (see section “Special Instructions”).

Missed dose

If a dose is missed, the patient should take the Rivaroxaban-SZ tablet immediately and continue the regular intake the next day according to the recommended regimen. The dose should not be doubled to compensate for a missed dose.

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

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

A minimum treatment course (at least 3 months) should be considered for patients with DVT or PE provoked by major reversible risk factors (i.e., prior 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 extending therapy for the prevention of recurrent DVT or PE (after at least 6 months of treatment for deep vein thrombosis or pulmonary embolism) the recommended dose of rivaroxaban is 10 mg* once daily. For patients at high risk of recurrent DVT and PE, such as patients with severe comorbidities or those who developed recurrent DVT or PE during long-term use of rivaroxaban as secondary prevention at a dose of 10 mg once daily, Rivaroxaban-SZ should be prescribed at a dose of 20 mg once daily.

The duration of treatment is determined individually after careful assessment of the treatment benefit against the risk of bleeding (see section “Special Instructions”).

Table 4

* if it is necessary to take the drug at a dose of 10 mg, Rivaroxaban manufactured in the appropriate dosage should be taken

The maximum recommended daily dose is 30 mg (15 mg twice daily) during the first 3 weeks of treatment and a maximum of 20 mg with further use of the drug.

Missed dose

If a dose is missed during the 15 mg twice daily dosing regimen (days 1 – 21), the patient should take a Rivaroxaban-SZ tablet immediately to achieve the daily dose of 30 mg. Thus, two 15 mg tablets can be taken at one time. The next day, the patient should continue regular intake of the drug according to the recommended regimen.

If a dose is missed during the once-daily dosing regimen, the patient should take a Rivaroxaban-SZ tablet immediately and continue regular intake the next day according to the recommended regimen. The dose should not be doubled in one day to compensate for a missed dose.

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

Initiation of therapy

Treatment with Rivaroxaban-SZ 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 Action”).

Appropriate dose

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

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

The child’s weight should be monitored regularly and the dose should be reviewed. This is necessary to ensure the optimal therapeutic dose. Dose increase should occur only based on changes in body weight.

Duration of treatment

Treatment with Rivaroxaban-SZ in children and adolescents should continue for at least 3 months. The duration of treatment can be extended up to 12 months if clinically necessary. There are no data supporting 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

A missed dose should be taken as soon as the missed dose is identified, but only if this happens on the same day. If this is not possible, the patient should skip that dose and continue intake the next day as prescribed by the physician. The patient should not take a double dose to compensate for a missed dose.

Transition from treatment with vitamin K antagonists (VKAs) to Rivaroxaban-SZ

For prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation, VKA treatment should be discontinued and treatment with Rivaroxaban-SZ should be started when the INR is ≤3.0.

For treatment of DVT and PE and prevention of recurrent DVT and PE in adults, as well as for treatment of VTE and prevention of recurrent VTE in children, VKA treatment should be discontinued and treatment with Rivaroxaban-SZ should be started when the INR is ≤2.5.

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

Transition from Rivaroxaban-SZ to treatment with vitamin K antagonists (VKAs)

There is a possibility of insufficient anticoagulant effect when transitioning from Rivaroxaban-SZ to VKAs. Therefore, continuous adequate anticoagulation must be ensured during the transition from Rivaroxaban-SZ to an alternative anticoagulant. It should be noted that Rivaroxaban-SZ may contribute to an increase in INR.

Adult patients transitioning from Rivaroxaban-SZ 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 a VKA dose determined based on the INR value. During concomitant use of Rivaroxaban-SZ and a VKA, the INR should be measured no earlier than 24 hours after the previous dose, but before taking the next dose of Rivaroxaban-SZ. After discontinuation of Rivaroxaban-SZ, the INR value can be reliably determined 24 hours after the last dose (see sections “Pharmacokinetics” and “Drug Interactions”).

Children

Children transitioning from Rivaroxaban-SZ to a VKA should continue taking Rivaroxaban-SZ for 48 hours after the first dose of the VKA. After 2 days of concomitant use, the INR value should be measured before the next scheduled dose of Rivaroxaban-SZ. Concomitant use of Rivaroxaban-SZ and the VKA is recommended to continue until the INR reaches ≥2.0. After discontinuation of Rivaroxaban-SZ, the INR value can be reliably determined 24 hours after the last dose (see section “Drug Interactions”).

Transition from parenteral anticoagulants to Rivaroxaban-SZ

In adults and children receiving parenteral anticoagulants, Rivaroxaban-SZ should be started 0-2 hours before the time of the next scheduled parenteral administration (e.g., low molecular weight heparin) or at the time of discontinuation of continuous parenteral administration (e.g., intravenous unfractionated heparin).

Transition from Rivaroxaban-SZ to parenteral anticoagulants

Rivaroxaban-SZ should be discontinued and the first dose of the parenteral anticoagulant should be administered at the time when the next dose of Rivaroxaban-SZ was due.

Special patient groups

Patients with hepatic impairment

Rivaroxaban-SZ is contraindicated in patients with liver disease associated with coagulopathy and clinically significant bleeding risk, including cirrhosis and hepatic impairment class B and C according to Child-Pugh classification (see sections “Pharmacokinetics” and “Special Instructions”).

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. For this category of patients, Rivaroxaban-SZ should be used with caution. Use is not recommended in patients with CrCl <15 ml/min (see sections “Pharmacokinetics” and “Special Instructions”).

When prescribing Rivaroxaban-SZ to patients with moderate (CrCl 30-49 ml/min) or severe (CrCl 15-29 ml/min) renal impairment, the following recommendations 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, the recommended dose of Rivaroxaban-SZ is 15 mg twice daily during the first three weeks. Subsequently, when the recommended dose of Rivaroxaban-SZ is 20 mg once daily, a dose reduction to 15 mg once daily should be considered if the risk of bleeding is higher than the risk of recurrent DVT and PE. Recommendations for the use of Rivaroxaban-SZ at a dose of 15 mg are based on pharmacokinetic modeling and have not been studied in clinical trials (see sections “Pharmacological Action”, “Pharmacokinetics” and “Special Instructions”). If the recommended dose is 10 mg once daily, no dose adjustment is required.

When prescribing Rivaroxaban-SZ to patients with mild renal impairment (CrCl 50-80 ml/min), no dose adjustment is required (see section “Pharmacokinetics”).

Children

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

Rivaroxaban-SZ is not recommended for use in children with moderate or severe renal impairment (GFR <50 ml/min/1.73 m²) due to lack of clinical data (see section “Special Instructions”).

Age/Gender

No dose adjustment based on patient age and gender is required (see section “Pharmacokinetics”).

Body weight

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

The dose in children is determined based on body weight.

Cardioversion for prevention of stroke and systemic embolism

Treatment with Rivaroxaban-SZ can be initiated or continued in patients who may require cardioversion. For cardioversion under transesophageal echocardiography (TEE) control in patients who have not previously received anticoagulant therapy, to ensure adequate anticoagulation, treatment with Rivaroxaban-SZ should be started at least 4 hours before cardioversion. For all patients, confirmation should be obtained before cardioversion that the patient has taken Rivaroxaban-SZ as prescribed. When making decisions about initiation and duration of treatment, current guidelines and recommendations for anticoagulant therapy in patients undergoing cardioversion should be taken into account.

Stroke prevention in patients with atrial fibrillation who have undergone percutaneous coronary intervention (PCI) with stenting

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

Children

The safety and efficacy of Rivaroxaban-SZ 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, Rivaroxaban-SZ 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

Adults

Orally, with food.

Crushing the tablet

If the patient is unable to swallow the tablet whole, the Rivaroxaban-SZ tablet may be crushed and mixed with water or apple puree, immediately before use and oral administration. After taking the crushed tablet, food should be taken immediately. The crushed tablet can be administered via a gastric tube.

The Rivaroxaban-SZ tablet can be crushed, suspended in 50 ml of water, and administered via a nasogastric tube or gastric tube after confirming the tube position in the stomach. After Rivaroxaban-SZ, the tube walls should be rinsed with water to remove drug residue. 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 taking the crushed Rivaroxaban-SZ tablet, enteral nutrition should be administered immediately.

Children

Orally. The patient should swallow the tablet with liquid. Rivaroxaban-SZ should be taken with food at approximately 24-hour intervals.

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

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

Crushing the tablet

If the patient is unable to swallow the tablet whole, Rivaroxaban should be taken in the form of an oral suspension. If an oral suspension is not currently available, a 15 mg or 20 mg tablet is prescribed, which is crushed and mixed with water or apple puree, immediately before use and oral administration. The crushed tablet can be administered via a nasogastric tube or gastric tube – the method of administration for children does not differ from the method of administration for adults.

Adverse Reactions

Summary of the safety profile

The safety of rivaroxaban was evaluated in thirteen main phase III studies (see Table 8).

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

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

** in the COMPASS study, the incidence of anemia is low because a selective approach was used to collect adverse reaction data

*** a selective approach was used to collect adverse reaction data

^# from the VOYAGER PAD study

Tabulated summary of adverse reactions

The frequency of adverse reactions reported in children and adults with the use of rivaroxaban is shown in Table 10 below. Adverse reactions are categorized by system organ class (MedDRA) with the frequency of occurrence: 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 10. All adverse reactions registered in adult patients in Phase III clinical trials or during post-marketing use*, as well as in pediatric patients in two Phase II and two Phase III trials

^Aobserved during VTE prophylaxis in adult patients undergoing elective hip or knee replacement surgery

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

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

* a pre-specified selective approach to collecting adverse reaction data was used in individual Phase III trials. Based on the analysis of data from these trials, 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-SZ 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 “Overdosage”, subsection “Treatment of bleeding”). 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 VKA treatment. Thus, in addition to proper clinical monitoring, laboratory testing of hemoglobin/hematocrit may be significant for detecting occult bleeding and quantifying the clinical significance of overt bleeding in applicable cases. The risk of bleeding may be increased in certain patient groups, for example, in patients with severe uncontrolled arterial hypertension and/or when used concomitantly with drugs affecting hemostasis (see section “Special Instructions”, subsection “Risk of bleeding”). Menstrual bleeding may be heavier and/or prolonged.

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

Known complications secondary to severe bleeding, such as compartment syndrome and renal failure due to hypoperfusion, have been reported with rivaroxaban use. Therefore, the possibility of bleeding should be considered when assessing the condition of any patient receiving anticoagulants.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after registration of a medicinal product to ensure continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse drug reactions through the national adverse reaction reporting system of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to rivaroxaban or to any of the excipients included in the drug;
• Clinically significant active bleeding;
• Lesion or condition associated with an increased risk of major bleeding. For example, 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 malformation, vascular aneurysms or serious pathologies of the 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, dabigatran etexilate, apixaban, 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”);
• Treatment of ACS with antiplatelet agents in patients who have had a stroke or transient ischemic attack (TIA) (see section “Special Instructions”);
• Use in combination with ASA in patients with CAD or PAD, who have previously had a hemorrhagic or lacunar stroke, as well as within the first month after any stroke (see section “Special Instructions”);
• Liver disease accompanied by coagulopathy and risk of clinically significant bleeding, including cirrhosis class B and C according to Child-Pugh classification) (see section “Pharmacokinetics”);
• Pregnancy;
• Breastfeeding period.

Use in Pregnancy and Lactation

Pregnancy

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

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

Breastfeeding period

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

Fertility

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

Use in Hepatic Impairment

Rivaroxaban-SZ is contraindicated in patients with liver disease accompanied by coagulopathy and risk of clinically significant bleeding, including patients with cirrhosis class B and C according to 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, for this category of patients, Rivaroxaban-SZ should be used with caution. Use of the drug is not recommended in patients with CrCl <15 ml/min. In patients with mild (CrCl 50-80 ml/min) or moderate (CrCl 30-49 ml/min) renal impairment, no dose adjustment is required.

Pediatric Use

Rivaroxaban-SZ 2.5 mg tablets are not recommended for use in children under 18 years of age (safety and efficacy in this category of patients have not been established).

Geriatric Use

No dose adjustment is required. The risk of bleeding increases with age.

Special Precautions

In patients after ACS, the efficacy and safety of rivaroxaban 2.5 mg twice daily were studied in combination with antiplatelet agents – ASA or with ASA and clopidogrel/ticlopidine.

In patients at high risk of ischemic events with CAD or PAD, the efficacy and safety of rivaroxaban 2.5 mg twice daily were studied in combination with ASA.

In patients after a recent lower extremity revascularization procedure due to symptomatic PAD, the efficacy and safety of rivaroxaban 2.5 mg twice daily were studied in combination with an antiplatelet agent – ASA or with ASA and short-term clopidogrel therapy. If necessary, dual antiplatelet therapy with clopidogrel should be short-term; long-term dual antiplatelet therapy should be avoided.

Use in combination therapy with other antiplatelet agents (e.g., prasugrel or ticagrelor) has not been studied and is not recommended.

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

Risk of bleeding

As with other anticoagulants, patients taking Rivaroxaban-SZ 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 Rivaroxaban-SZ should be discontinued (see section “Overdosage”).

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 in addition to monotherapy or dual antiplatelet therapy. Thus, in addition to proper clinical monitoring, laboratory testing of hemoglobin/hematocrit may be significant for detecting occult bleeding and quantifying the clinical significance of overt bleeding in applicable cases.

Several patient subgroups, listed below, have an increased risk of bleeding. Therefore, when using Rivaroxaban-SZ in combination with dual antiplatelet therapy in patients with a known increased risk of bleeding, this risk must be weighed against the benefit of preventing atherothrombotic events. Such patients should also 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 “Pharmacological Properties” and “Pharmacokinetics”).

Renal impairment

In patients with severe renal impairment (CrCl <30 ml/min), rivaroxaban plasma concentration may be significantly increased (on average 1.6-fold), which may lead to an increased risk of bleeding. Rivaroxaban-SZ should be used with caution in patients with CrCl 15-29 ml/min. Use of the drug is not recommended in patients with CrCl <15 ml/min. (see sections “Pharmacokinetics” and “Dosage regimen”).

Rivaroxaban-SZ should be used with caution in patients with moderate renal impairment (CrCl 30-49 ml/min) receiving concomitant drugs that increase rivaroxaban plasma concentration (see section “Drug interactions”).

Drug interactions

Use of Rivaroxaban-SZ is not recommended in patients receiving concomitant systemic treatment with azole antifungal agents (e.g., ketoconazole, itraconazole, voriconazole and posaconazole) or HIV protease inhibitors (e.g., ritonavir). These drugs are potent inhibitors of the CYP3A4 isoenzyme and P-glycoprotein. Thus, these drugs may increase rivaroxaban plasma concentration to clinically significant levels (on average 2.6-fold), which may lead to an increased risk of bleeding (see section “Drug interactions”). Caution should be exercised if the patient is simultaneously receiving drugs affecting hemostasis, such as NSAIDs, ASA and platelet aggregation inhibitors or selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs). Patients at risk of GI ulcer formation may be prescribed appropriate prophylactic treatment (see section “Drug interactions”). If patients are receiving Rivaroxaban-SZ and antiplatelet drugs, concomitant NSAID therapy should be used only if the benefit outweighs the bleeding risk.

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.

Use with caution in patients with ACS and CAD/PAD

• Age ≥75 years, if taken together with ASA or ticlopidine. The benefit-risk ratio of treatment should be regularly assessed individually;
• Low body weight (<60 kg), if taken together with ASA or with ASA and clopidogrel/ticlopidine;
• Patients with CAD and severe symptomatic heart failure. Studies indicate that such patients may derive less benefit from rivaroxaban treatment.

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 bleeding risk 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 should not be used for thrombosis prophylaxis in patients who have undergone recent transcatheter aortic valve replacement. The safety and efficacy of Rivaroxaban-SZ have not been studied in patients with prosthetic heart valves, therefore, there are no data confirming that the use of Rivaroxaban-SZ provides sufficient anticoagulant effect in this category of patients. Treatment of such patients with Rivaroxaban-SZ 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-beta₂-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 a History of Stroke and/or TIA

Patients with ACS. The use of Rivaroxaban-SZ 2.5 mg is contraindicated for the treatment of patients with ACS who have a history of stroke or TIA (see section “Contraindications”). Only a few patients with ACS and a history of stroke or TIA were studied, but the limited data obtained demonstrate a lack of clinical benefit from treatment in such patients.

Patients with CAD and PAD. Patients with CAD or PAD with a history of hemorrhagic or lacunar stroke, or who experienced an ischemic non-lacunar stroke within the previous month, were not studied (see section “Contraindications”).

Patients who recently underwent a lower limb revascularization procedure due to symptomatic PAD with a prior stroke or TIA were not studied. In these patients receiving dual antiplatelet therapy, treatment with Rivaroxaban-SZ 2.5 mg should be avoided.

Spinal/Epidural Anesthesia or Puncture

When performing neuraxial (spinal/epidural) anesthesia or spinal/epidural puncture in patients receiving antithrombotic agents 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 the postoperative use of an indwelling epidural catheter or concomitant therapy with medicinal products affecting 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 neuraxial intervention in patients receiving anticoagulants or who are planned to be prescribed anticoagulants for thrombosis prevention.

There is no clinical experience with rivaroxaban 2.5 mg with antiplatelet agents in the described situations. Platelet aggregation inhibitors should be discontinued according to the manufacturer’s instructions.

To reduce the potential risk of bleeding associated with the simultaneous use of rivaroxaban and the performance of neuraxial (epidural/spinal) anesthesia or spinal puncture, the pharmacokinetic profile of rivaroxaban should be taken into account. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of rivaroxaban is assessed as weak (see section “Pharmacokinetics”). However, the exact time to achieve a sufficiently low anticoagulant effect in each patient is unknown.

Recommendations for Taking the Drug Before and After Invasive Procedures and Surgical Interventions

If an invasive procedure or surgical intervention is necessary, the use of Rivaroxaban-SZ 2.5 mg should be discontinued at least 12 hours before the intervention, if possible, and based on the physician’s clinical assessment. If a patient is undergoing a planned surgical intervention and the antiplatelet effect is undesirable, the use of platelet aggregation inhibitors should be discontinued as indicated in the instructions for use provided by the manufacturer.

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

The use of Rivaroxaban-SZ should be resumed as soon as possible after the invasive procedure or surgical intervention, provided the clinical situation allows and adequate hemostasis has been achieved, as determined by the attending physician (see section “Pharmacokinetics”).

Elderly Age

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

Skin Reactions

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

Excipients

Rivaroxaban-SZ contains lactose. Patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this drug.

Effect on Ability to Drive and Operate Machinery

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

Overdose

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

There is a specific antidote (andexanet alfa) that blocks the pharmacodynamic effect of rivaroxaban.

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

Treatment of Bleeding

If a patient receiving Rivaroxaban develops a bleeding complication, the next dose of rivaroxaban should be postponed or, if necessary, treatment with this drug should be discontinued altogether. The T_1/2 of rivaroxaban is approximately 5-13 hours (see section “Pharmacokinetics”). Treatment should be individualized depending on the severity and location of the bleeding. If necessary, appropriate symptomatic treatment can be used, such as mechanical compression (e.g., for severe nosebleeds), surgical hemostasis with bleeding control procedures, fluid replacement therapy and hemodynamic support, the 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 the cessation of bleeding, a specific antidote for factor Xa inhibitor (andexanet alfa), which blocks the pharmacodynamic effect of rivaroxaban, or a specific procoagulant drug, such as prothrombin complex concentrate, activated prothrombin complex concentrate, or recombinant factor VIIa (r-FVIIa), may be administered. However, experience with these drugs in patients receiving Rivaroxaban is currently very limited. These recommendations are also based on limited preclinical 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 Action”).

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 scientific rationale or experience for the use of the systemic hemostatic drug desmopressin in patients receiving Rivaroxaban. Given the high plasma protein binding, Rivaroxaban is not expected to be dialyzable.

Drug Interactions

Inhibitors of CYP3A4 Isoenzyme 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 the pharmacodynamic effects of this drug, which may lead to an increased risk of bleeding. Therefore, Rivaroxaban-SZ is not recommended for use 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 Instructions”).

Active substances that strongly inhibit only one of the elimination pathways of rivaroxaban, either CYP3A4 or P-glycoprotein, are likely to increase rivaroxaban plasma concentrations to a lesser extent.

For example, clarithromycin (500 mg twice daily), which is considered a potent CYP3A4 inhibitor and a moderate P-glycoprotein inhibitor, caused a 1.5-fold increase in the mean AUC of rivaroxaban and a 1.4-fold increase in C_max. The interaction with clarithromycin is considered clinically insignificant for most patients but may be potentially significant for high-risk patients (for patients with renal impairment see section “Special Instructions”).

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

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

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 section “Special Instructions”).

Based on the 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, without any additional effect on coagulation parameters (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 sections “Contraindications” and “Special Instructions”).

NSAIDs/Platelet Aggregation Inhibitors

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

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

Clopidogrel (loading dose of 300 mg, followed by a maintenance dose of 75 mg) did not demonstrate pharmacokinetic interaction with rivaroxaban (15 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 of P-selectin or GPIIb/IIIa receptor.

Caution should be exercised when co-administering NSAIDs (including ASA) and platelet aggregation inhibitors, as the use of these drugs usually increases the risk of bleeding (see section “Special Instructions”).

SSRIs/SNRIs

As with the use of other anticoagulants, an increased risk of bleeding is possible in patients concomitantly using Rivaroxaban with SSRIs or SNRIs, due to the effect of these drugs on platelets. The results of clinical studies of rivaroxaban demonstrated a numerical increase in major and minor clinically significant bleeding in all treatment groups with the concomitant use of these drugs.

Warfarin

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

If it is necessary to investigate the pharmacodynamic effects of rivaroxaban during the transition period, determination of anti-Xa activity, prothrombinase-induced clotting time (PiCT), and HepTest can be used as the necessary 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 investigate the pharmacodynamic effects of warfarin during the transition period, the INR value at the C_trough of rivaroxaban (24 hours after the previous rivaroxaban dose) can be used, as Rivaroxaban has practically no effect on this parameter at that time.

No pharmacokinetic interactions were recorded between warfarin and rivaroxaban.

Inducers of CYP3A4 Isoenzyme

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 preparations of St. John’s wort (Hypericum perforatum)) may also lead to decreased rivaroxaban plasma concentrations. Therefore, simultaneous use of potent CYP3A4 inducers should be avoided, except when the patient is carefully monitored for signs and symptoms of thrombosis.

Other Concomitant Therapy

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

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

Effect on Laboratory Parameters

Rivaroxaban affects blood coagulation parameters (e.g., PT, aPTT, HepTest) due to its mechanism of action (see section “Pharmacological Action”).

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.

The crushed Rivaroxaban-SZ tablet is stable in water and in applesauce for 4 hours.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

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