INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT XARELTO® (XARELTO®)

Composition:

Active substance: rivaroxaban;

1 film-coated tablet contains 10 mg of rivaroxaban;

Excipients: microcrystalline cellulose, sodium croscarmellose, hypromellose 5 cps, lactose monohydrate, magnesium stearate, sodium lauryl sulfate, polyethylene glycol 3350, iron oxide red (E 172), titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: light red, round, biconvex, film-coated tablets with a triangle and the number 10 on one side and a cross-shaped marking "BAYER" on the other.

Pharmacotherapeutic group. Antithrombotic agents. Direct factor Xa inhibitors. Rivaroxaban. ATC code B01AF01.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Rivaroxaban is a highly selective direct inhibitor of factor Xa with sufficiently high oral bioavailability. Inhibition of factor Xa activity interrupts both the intrinsic and extrinsic pathways of the coagulation cascade, thereby suppressing thrombin formation and thrombus development. Rivaroxaban does not directly inhibit thrombin (activated factor II) activity and does not affect platelets.

Pharmacodynamic effects

In humans, dose-dependent inhibition of factor Xa activity has been observed. When using the Neoplastin test, rivaroxaban produces a dose-dependent effect on prothrombin time, which correlates significantly with plasma concentrations (r=0.98). Results may vary when other tests/kits are used. Instrument readings should be recorded in seconds, as the INR (International Normalized Ratio) is calibrated and validated only for coumarins and cannot be used for other anticoagulants. In patients undergoing major orthopedic surgery, the 5/95 percentiles for prothrombin time (Neoplastin test) 2–4 hours after tablet intake (i.e., at peak effect) range from 13 to 25 seconds (baseline values before surgery: 12–15 seconds).

In a clinical pharmacology study evaluating the reversal of rivaroxaban's pharmacodynamic effects in healthy adult volunteers (n=22), the impact of single doses (50 IU/kg) of two types of prothrombin complex concentrate (PCC) was assessed: PCC containing 3 factors (factors II, IX, and X) and PCC containing 4 factors (factors II, VII, IX, and X). Administration of 3-factor PCC resulted in a reduction of mean PT (prothrombin time) (Neoplastin) values by approximately 1.0 second at 30 minutes, while 4-factor PCC reduced these values by about 3.5 seconds. In contrast, 3-factor PCC demonstrated a more potent and faster overall effect on reversing changes in endogenous thrombin generation compared to 4-factor PCC (see section "Overdose").

Rivaroxaban also dose-dependently increases activated partial thromboplastin time (aPTT) and HepTest results; however, these parameters are not recommended for assessing the pharmacodynamic effects of rivaroxaban. Routine monitoring of coagulation parameters is not required during rivaroxaban treatment. However, if clinically necessary, rivaroxaban levels can be measured using calibrated quantitative anti-factor Xa assays (see section "Pharmacokinetics").

Clinical efficacy and safety

Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery

The clinical development program for rivaroxaban was designed to demonstrate its efficacy in preventing VTE—specifically proximal and distal deep vein thrombosis (DVT) and pulmonary embolism (PE)—in patients undergoing major orthopedic surgery of the lower limbs. The RECORD program included controlled, randomized, double-blind phase III clinical trials involving over 9,500 patients (7,050 patients undergoing total hip replacement and 2,531 undergoing total knee replacement). Rivaroxaban 10 mg once daily was administered no sooner than 6 hours post-surgery. Its efficacy was compared with enoxaparin 40 mg once daily, with the first dose given 12 hours before surgery.

In all phase III trials (see Table 1), rivaroxaban significantly reduced the incidence of all VTE events (venographically detected or symptomatic DVT, non-fatal PE, or death) and major VTE events (proximal DVT, non-fatal PE, or VTE-related death)—the pre-specified primary efficacy endpoints. Furthermore, in all three studies, the rate of symptomatic VTE (symptomatic DVT, non-fatal PE, or VTE-related death) was lower in the rivaroxaban group compared to the enoxaparin group. The primary safety endpoint—major bleeding—was similar in patients receiving rivaroxaban 10 mg and those receiving enoxaparin 40 mg.

Table 1. Results of phase III clinical trials on efficacy and safety

An analysis of the pooled results of phase III studies confirmed the data obtained from individual studies comparing the efficacy of rivaroxaban 10 mg once daily and enoxaparin 40 mg once daily regarding reduction in the frequency of all VTE events, serious VTE, and symptomatic VTE.

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

The clinical trial program for rivaroxaban was designed to demonstrate the efficacy of rivaroxaban for initial and long-term treatment of acute DVT and PE, as well as prevention of their recurrence.

Four randomized, controlled phase III clinical trials (Einstein DVT, Einstein PE, Einstein Extension, and Einstein Choice) enrolled over 12,800 patients, and a pre-specified pooled analysis of the Einstein DVT and Einstein PE studies was additionally conducted. The total duration of treatment across all studies was up to 21 months.

In the Einstein DVT study, 3,449 patients with acute DVT were evaluated for the treatment of DVT and prevention of recurrent DVT and PE (patients with clinical signs of PE were not included in this study). Treatment duration was 3, 6, or 12 months, depending on the clinician’s clinical assessment.

For the first 3 weeks of therapy, rivaroxaban 15 mg twice daily was used to treat DVT. After this period, patients received rivaroxaban 20 mg once daily.

In the Einstein PE study, 4,832 patients with acute PE were evaluated for the treatment of PE and prevention of recurrent DVT and PE. Treatment duration was 3, 6, or 12 months, depending on the clinician’s clinical assessment.

For initial treatment of acute PE, rivaroxaban 15 mg twice daily was administered for three weeks, followed by continued treatment with rivaroxaban 20 mg once daily.

In both the Einstein DVT and Einstein PE studies, the comparator treatment regimens consisted of enoxaparin therapy for at least 5 days in combination with a vitamin K antagonist until a therapeutic INR range (≥2.0) was achieved. Thereafter, treatment was continued with a vitamin K antagonist at a dose required to maintain the INR within the therapeutic range of 2.0–3.0.

In the Einstein Extension study, 1,197 patients with DVT or PE were evaluated for prevention of recurrent DVT and PE. Treatment duration was an additional 6 or 12 months in patients who had completed a 6- or 12-month course of anticoagulant therapy for venous thromboembolism, depending on the clinician’s clinical assessment. Rivaroxaban 20 mg once daily was compared with placebo.

In the Einstein DVT, Einstein PE, and Einstein Extension studies, identical pre-specified primary and secondary efficacy endpoints were used. The primary efficacy endpoint was symptomatic recurrent VTE, defined as a composite of recurrent DVT or fatal or non-fatal PE. The secondary efficacy endpoint was defined as a composite of recurrent DVT, non-fatal PE, and death from any cause.

In the Einstein Choice study, 3,396 patients with confirmed symptomatic DVT and/or PE were evaluated for prevention of fatal PE or non-fatal symptomatic recurrent DVT or PE, after completing 6–12 months of anticoagulant therapy. Patients with an indication for long-term anticoagulant therapy at therapeutic doses were excluded from the study. Treatment duration was up to 12 months, depending on individual randomization date (median: 351 days). The efficacy of rivaroxaban 20 mg once daily and 10 mg once daily was compared with that of 100 mg acetylsalicylic acid once daily.

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

In the Einstein DVT study (see Table 2), rivaroxaban demonstrated non-inferiority compared to enoxaparin/vitamin K antagonist for the primary efficacy endpoint (p<0.0001) (non-inferiority criterion); relative risk: 0.680 (0.443–1.042), p=0.076 (superiority criterion). The risk ratio for the pre-specified net clinical benefit (primary efficacy endpoint plus major bleeding) was 0.67 [(95% CI (confidence interval): 0.47–0.95), nominal p=0.024] in favor of rivaroxaban. INR values were within the therapeutic range on average 60.3% of the time over a mean treatment duration of 189 days, and 55.4%, 60.1%, and 62.8% of the time in groups with planned treatment durations of 3, 6, and 12 months, respectively. In the enoxaparin/vitamin K antagonist group, there was no clear relationship between the center-level average time in therapeutic range (TTR) (time maintaining target INR range 2.0–3.0) across equal-sized tertiles and the rate of recurrent VTE (p=0.932 for interaction). Within the highest tertile by center, the risk ratio for rivaroxaban versus warfarin was 0.69 (95% CI: 0.35–1.35).

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

Table 2. Efficacy and safety outcomes from the phase III Einstein DVT study

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

b) Enoxaparin for at least 5 days, with initiation of a vitamin K antagonist during enoxaparin treatment.

* p < 0.0001 (non-inferiority according to pre-specified risk margin of 2.0); risk ratio: 0.680 (0.443–1.042), p=0.076 ("superiority").

In the Einstein PE study (see Table 3), rivaroxaban demonstrated non-inferior efficacy compared to enoxaparin/vitamin K antagonist for the primary efficacy outcome [p=0.0026 (non-inferiority criterion met); risk ratio: 1.123 (0.749–1.684)]. The risk ratio for the pre-specified net clinical benefit (primary efficacy outcome plus major bleeding) was 0.849 [(95% CI: 0.633–1.139), nominal p=0.0275]. INR values were within the therapeutic range on average 63% of the time over a median treatment duration of 215 days, and 57%, 62%, and 65% of the time in groups with planned treatment durations of 3, 6, and 12 months, respectively. In the enoxaparin/vitamin K antagonist group, there was no clear relationship between the center's mean TTR (time in the therapeutic INR range of 2.0–3.0) across equal-sized tertiles and the rate of recurrent VTE (p=0.082 for interaction). Within the highest tertile by center, the risk ratio for rivaroxaban versus warfarin was 0.642 (95% CI: 0.277–1.484).

The incidence of the principal safety outcome (major or clinically relevant non-major bleeding) was slightly lower in the rivaroxaban group [10.3% (249/2412)] than in the enoxaparin/vitamin K antagonist group [11.4% (274/2405)]. The incidence of the secondary safety outcome (major bleeding) was lower in the rivaroxaban group [1.1% (26/2412)] compared to the enoxaparin/vitamin K antagonist group [2.2% (52/2405)], with a risk ratio of 0.493 (95% CI: 0.308–0.789).

Table 3. Efficacy and safety outcomes from the phase III Einstein PE study

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

b) Enoxaparin for at least 5 days, followed by a vitamin K antagonist, the administration of which is initiated during enoxaparin treatment.

* p < 0.0026 (non-inferior efficacy based on the pre-specified risk ratio margin of 2.0); risk ratio: 1.123 (0.749–1.684).

A pooled analysis of the results from the Einstein DVT and Einstein PE studies was performed according to pre-specified criteria (see Table 4).

Table 4. Efficacy and safety outcomes from the pooled analysis of Phase III Einstein DVT and Einstein PE studies

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

b) Enoxaparin for at least 5 days, followed by a vitamin K antagonist, the administration of which is initiated during enoxaparin treatment.

* p < 0.0001 (non-inferior efficacy as predefined risk ratio of 1.75); risk ratio: 0.886 (0.661–1.186).

The risk ratio for predefined net clinical benefit (primary efficacy outcome plus major bleeding) based on pooled analysis was 0.771 [(95% CI: 0.614–0.967), nominal p=0.0244].

In the EINSTEIN Extension study (see Table 5), rivaroxaban demonstrated superiority over placebo with respect to primary and secondary efficacy outcomes. The rate of the main safety outcome (major bleeding) in patients treated with rivaroxaban 20 mg once daily was numerically slightly higher than in those receiving placebo. The rate of the secondary safety outcome (major or clinically non-major bleeding) was higher in patients receiving rivaroxaban 20 mg once daily compared to those treated with placebo.

Table 5. Efficacy and safety outcomes from the Phase III EINSTEIN Extension study

a) Rivaroxaban 20 mg once daily.

* p < 0.0001 ("superior"); risk ratio: 0.185 (0.087–0.393).

In the EINSTEIN Choice study (see Table 6), rivaroxaban at doses of 20 mg and 10 mg demonstrated superiority over acetylsalicylic acid 100 mg with respect to primary and secondary efficacy outcomes. The main safety outcome (major bleeding) was similar in patients receiving rivaroxaban 20 mg or 10 mg compared to acetylsalicylic acid 100 mg.

Table 6. Efficacy and safety outcomes from the phase III EINSTEIN Choice study

* p < 0.0001 ("superior to") rivaroxaban 20 mg once daily compared to acetylsalicylic acid (ASA) 100 mg once daily; risk ratio = 0.34 (0.20–0.59);

**p < 0.0001 ("superior to") rivaroxaban 10 mg once daily compared to ASA 100 mg once daily; risk ratio = 0.26 (0.14–0.47);

• Rivaroxaban 20 mg once daily compared to ASA 100 mg once daily; risk ratio = 0.44 (0.27–0.71), p=0.0009 (nominal);

++ Rivaroxaban 10 mg once daily compared to ASA 100 mg once daily; risk ratio = 0.32 (0.18–0.55), p<0.0001 (nominal).

In addition to the phase III EINSTEIN program trials, a prospective, non-interventional, open-label cohort study (XALIA) with centralized assessment of endpoints, including recurrent VTE, major bleeding, and death, was conducted. To evaluate the long-term safety of rivaroxaban in clinical practice compared to conventional anticoagulant therapy, 5,142 patients with acute DVT were enrolled in the study. In the rivaroxaban group, the incidence of major bleeding was 0.7%, recurrent VTE was 1.4%, and all-cause mortality was 0.5%. Baseline patient characteristics differed, including age, cancer, and renal impairment. A pre-specified propensity score stratified analysis was applied to adjust for baseline differences; however, residual bias may still affect the results. When rivaroxaban was compared with conventional therapy, the adjusted risk ratios for major bleeding, recurrent VTE, and all-cause mortality were 0.77 (95% CI 0.40–1.50), 0.91 (95% CI 0.54–1.54), and 0.51 (95% CI 0.24–1.07), respectively. These real-world results are consistent with the established safety profile for this indication.

In a post-marketing, non-interventional study involving over 162,000 patients with non-valvular atrial fibrillation from four countries, rivaroxaban was prescribed for stroke and systemic embolism prevention. The rate of ischemic stroke was 0.70 (95% CI 0.44–1.13) per 100 patient-years. The rate of bleeding events leading to hospitalization was: 0.43 (95% CI 0.31–0.59) events per 100 patient-years for intracranial bleeding, 1.04 (95% CI 0.65–1.66) for gastrointestinal bleeding, 0.41 (95% CI 0.31–0.53) for genitourinary bleeding, and 0.40 (95% CI 0.25–0.65) for other bleeding.

Patients with positive test results for three antiphospholipid antibodies

Rivaroxaban was compared to warfarin in patients with a history of thrombosis and diagnosed antiphospholipid syndrome (APS) at high risk of thromboembolic events (positive results for all three antiphospholipid antibodies: lupus anticoagulant, anti-cardiolipin antibodies, and anti-beta-2-glycoprotein I antibodies) in a randomized, open-label, multicenter, investigator-sponsored clinical trial with blinded endpoint assessment. The study was prematurely terminated after enrolling 120 patients due to an increased incidence of thromboembolic events in patients receiving rivaroxaban. The mean observation period was 569 days; 59 patients were randomized to receive rivaroxaban 20 mg (15 mg for patients with creatinine clearance < 50 mL/min) and 61 to warfarin (INR 2.0–3.0). Thrombotic events occurred in 12% of patients randomized to rivaroxaban (4 ischemic strokes and 3 myocardial infarctions). No thromboembolic events were recorded in patients randomized to warfarin. Major bleeding occurred in 4 patients (7%) in the rivaroxaban group and 2 patients (3%) in the warfarin group.

Pediatric use

The European Medicines Agency has waived the obligation to submit results of studies on the use of Xarelto® in all pediatric subpopulations for the treatment of thromboembolic conditions. For information on the use of the medicinal product in children, see the "Pediatric population" section.

Pharmacokinetics.

Absorption

Rivaroxaban is rapidly absorbed; maximum concentrations (Cmax) are reached within 2–4 hours after tablet intake.

Following oral administration, rivaroxaban is almost completely absorbed, and its bioavailability after oral administration of 2.5 mg and 10 mg doses is high (80–100%), independent of food intake. Administration of rivaroxaban 2.5 mg and 10 mg tablets with food does not affect the AUC (area under the concentration-time curve) or Cmax of rivaroxaban. Xarelto® 2.5 mg and 10 mg tablets can be taken regardless of food intake (see section "Dosage and administration").

Rivaroxaban exhibits nearly linear pharmacokinetics up to doses of approximately 15 mg (once daily). At higher doses, absorption of rivaroxaban is limited by solubility parameters, resulting in reduced bioavailability and absorption rate. This phenomenon is more pronounced when the drug is taken on an empty stomach than when taken after food. The pharmacokinetics of rivaroxaban are characterized by moderate variability; individual variability (coefficient of variation) ranges from 30% to 40%, except on the day of surgery and the following day, when exposure variability is high (70%).

Absorption of rivaroxaban depends on the site of drug release in the gastrointestinal tract. A 29% and 56% reduction in AUC and Cmax, respectively, was observed when rivaroxaban granules with drug release in the proximal small intestine were used, compared to the tablet formulation. Exposure is further reduced when the active substance is released in the distal small intestine or ascending colon. Administration of rivaroxaban distal to the stomach should be avoided, as this may lead to reduced absorption and a corresponding impact on exposure.

Bioavailability (AUC and Cmax) was comparable for rivaroxaban 20 mg administered orally as a crushed tablet mixed with applesauce or water, delivered via a gastric tube immediately after a liquid meal, and for administration of the whole tablet. Considering the expected dose-proportional pharmacokinetic profile of rivaroxaban, the results of this bioavailability study may likely apply to lower doses of rivaroxiban as well.

Distribution

Plasma protein binding in humans is high, approximately 92%–95%, with serum albumin being the main binding component. The volume of distribution is moderate, with a Vss (steady-state volume of distribution) of approximately 50 L.

Metabolism and elimination

Approximately two-thirds of the administered dose of rivaroxaban is metabolized, with half of the metabolites excreted via the kidneys and the other half via feces. The remainder (one-third) of the administered dose is excreted directly by the kidneys as unchanged active substance in urine, primarily through active renal secretion.

Metabolism of rivaroxaban is mediated by CYP3A4, CYP2J2 isoenzymes, and cytochrome CYP-independent mechanisms. The main sites of biotransformation are the morpholine group, which undergoes oxidative degradation, and the amide groups, which undergo hydrolysis. Based on in vitro data, rivaroxaban is a substrate of the transporter proteins P-gp (P-glycoprotein) and Bcrp (breast cancer resistance protein).

The most important compound in human plasma is unchanged rivaroxaban; no significant or active circulating metabolites have been identified. Rivaroxaban, with a systemic clearance of approximately 10 L/h, can be classified as a drug with low clearance. After intravenous administration of a 1 mg dose, the elimination half-life is approximately 4.5 hours. Following oral administration, elimination is limited by the rate of absorption. The terminal elimination half-life of rivaroxaban from plasma ranges from 5 to 9 hours in young patients and from 11 to 13 hours in elderly patients.

Special patient groups

Sex. Clinically significant differences in pharmacokinetics between men and women were not observed (see section "Dosage and administration").

Elderly patients. In elderly patients, plasma concentrations of rivaroxaban are higher than in younger patients; the mean AUC is approximately 1.5 times higher than in younger patients, primarily due to reduced total and renal clearance. Dose adjustment is not required.

Body weight categories. Extremely low or high body weight (less than 50 kg or more than 120 kg) has only a minor effect on rivaroxaban plasma concentrations (less than 25%). Dose adjustment is not required.

Ethnic differences. No clinically significant differences in pharmacokinetics (PK) and pharmacodynamics (PD) were observed in patients of Caucasian, African American, Latino, Japanese, or Chinese ethnic origin.

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 rivaroxaban AUC). 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 AUC of unbound drug increased 2.6-fold. These patients also showed reduced urinary excretion of rivaroxaban, similar to that observed in patients with moderate renal impairment.

No data are available for patients with severe hepatic impairment.

Factor Xa inhibition was more pronounced (2.6-fold difference) in patients with moderate hepatic impairment compared to healthy volunteers; aPTT was also prolonged (2.1-fold). Patients with moderate hepatic impairment were more sensitive to rivaroxaban, resulting in a steeper pharmacokinetic/pharmacodynamic (PK/PD) concentration-aPTT relationship curve.

Rivaroxaban is contraindicated in patients with liver disease associated with coagulopathy and clinically relevant bleeding risk, including patients with Child–Pugh class B and C liver cirrhosis (see section "Contraindications").

Renal impairment. Increased rivaroxaban exposure, inversely correlated with reduced renal function as measured by creatinine clearance, has been observed. In individuals with mild (creatinine clearance 50–80 mL/min), moderate (creatinine clearance 30–49 mL/min), or severe (creatinine clearance 15–29 mL/min) renal impairment, plasma concentrations of rivaroxaban (AUC) were 1.4, 1.5, and 1.6 times higher, respectively, compared to healthy volunteers. Corresponding increases in pharmacodynamic effects were observed. In individuals with mild, moderate, or severe renal impairment, overall inhibition of factor Xa activity was 1.5, 1.9, and 2 times greater, respectively, compared to healthy volunteers; aPTT was similarly prolonged by 1.3, 2.2, and 2.4 times, respectively. Data in patients with creatinine clearance < 15 mL/min are lacking.

Due to high plasma protein binding, rivaroxaban is not expected to be eliminated by dialysis.

The use of the medicinal product is not recommended in patients with creatinine clearance < 15 mL/min. Rivaroxaban should be used with caution in patients with creatinine clearance of 15–29 mL/min (see section "Special warnings and precautions for use").

Pharmacokinetic data observed in patients. In patients receiving rivaroxaban 10 mg once daily for VTE prophylaxis, the mean geometric plasma concentration (90% prediction interval) at 2–4 hours and nearly 24 hours after dosing (times approximately reflecting peak and trough concentrations between doses) was 101 (7–273) and 14 (4–51) µg/L, respectively.

Pharmacokinetic/pharmacodynamic relationships. Assessment of the pharmacokinetic/pharmacodynamic (PK/PD) relationship between plasma rivaroxaban concentration and certain pharmacodynamic endpoints (factor Xa inhibition, PT, aPTT, HepTest) was performed across a wide dose range (5–30 mg twice daily). The relationship between rivaroxaban concentration and factor Xa activity is best described by an Emax model. For PT, the most reliable data are obtained using a linear segmented model. Depending on different reagents used for PT measurement, the slope coefficient may vary significantly. When Neoplastin reagent is used for PT measurement, the baseline PT is approximately 13 seconds, and the slope coefficient ranges from 3 to 4 seconds per 100 µg/L. PK/PD analyses from phase II and III trials were consistent with data obtained in healthy volunteers. In patients, baseline factor Xa activity and PT were influenced by surgical procedures, resulting in differences in the slope coefficient of the concentration-PT relationship between postoperative and stable states.

Pediatric population. The efficacy and safety of the medicinal product for the indication of venous thromboembolism prophylaxis in children and adolescents (under 18 years of age) have not been studied.

Preclinical safety data

Existing preclinical data obtained from traditional studies of pharmacological safety, single-dose toxicity, genotoxicity, phototoxicity, carcinogenic potential, and reproductive toxicity indicate no specific risks to humans.

In repeated-dose toxicity studies, effects were primarily related to the exaggerated pharmacodynamic action of rivaroxaban.

No effects on fertility were observed in male and female rats. Reproductive toxicity related to the pharmacological mechanism of action of rivaroxaban (hemorrhagic complications) was observed in animal studies.

Clinical characteristics.

Indications.

Prevention of venous thromboembolism (VTE) in adult patients undergoing hip or knee replacement surgery.

Treatment of deep vein thrombosis (DVT), pulmonary embolism (PE), and prevention of recurrence of DVT and PE in adults (see section "Special precautions for use" regarding patients with PE who have hemodynamically unstable conditions).

Contraindications.

Hypersensitivity to rivaroxaban or to any of the excipients of the medicinal product.

Clinically significant active bleeding.

Lesions or conditions associated with a significant risk of bleeding, including current or recently diagnosed gastrointestinal ulcers, 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, detected or suspected esophageal varices, arteriovenous malformations, aneurysms, or significant intraspinal or intracerebral vascular anomalies.

Concomitant use with any other anticoagulants, such as unfractionated heparin, low-molecular-weight heparins (enoxaparin, dalteparin), heparin derivatives (fondaparinux), oral anticoagulants (warfarin, dabigatran etexilate, apixaban), except under specific circumstances of switching to an alternative anticoagulant therapy (see section "Dosage and administration") or cases when unfractionated heparin is administered at doses required to maintain patency of a central venous or arterial catheter (see section "Interaction with other medicinal products and other forms of interaction").

Liver disease associated with coagulopathy and clinically significant risk of bleeding, including Child–Pugh class B and C cirrhosis (see section "Pharmacokinetics").

Patient age under 18 years.

Pregnancy and breastfeeding (see section "Use during pregnancy or breastfeeding").

Special precautions.

Tablet crushing

Rivaroxaban tablets may be crushed and suspended in 50 mL of water and administered via a nasogastric or feeding gastric tube after confirming correct placement of the tube in the stomach. The tube should then be flushed with water. Since absorption of rivaroxaban depends on the site of release of the active substance, administration of rivaroxaban distal to the stomach should be avoided, as this may lead to reduced absorption and consequently reduced efficacy of the active substance. After administration of 10 mg tablets, there is no need to immediately initiate enteral feeding.

Interaction with other medicinal products and other forms of interaction.

CYP3A4 and P-gp inhibitors

Concomitant administration of rivaroxaban with ketoconazole (400 mg once daily) or ritonavir (600 mg twice daily) resulted in a 2.6-fold/2.5-fold increase in mean steady-state AUC of rivaroxaban and a 1.7-fold/1.6-fold increase in mean Cmax of rivaroxaban, accompanied by significantly enhanced pharmacodynamic effects of the drug, increasing the risk of bleeding. Therefore, the use of Xarelto® is not recommended in patients receiving concomitant systemic treatment with azole antifungal agents such as ketoconazole, itraconazole, voriconazole, and posaconazole, or HIV protease inhibitors. These medicinal products are potent inhibitors of CYP3A4 and simultaneously of P-gp (see section "Special precautions for use").

Substances that actively inhibit only one of the elimination pathways of rivaroxaban, CYP3A4 or P-gp, are expected to increase plasma concentrations of rivaroxaban to a lesser extent.

For example, clarithromycin (500 mg twice daily), a potent CYP3A4 inhibitor and moderate P-gp inhibitor, caused a 1.5-fold increase in mean AUC and a 1.4-fold increase in Cmax of rivaroxaban. The interaction with clarithromycin is likely not clinically significant for most patients, but may potentially be significant for high-risk patients (for use in patients with renal impairment, see section "Special precautions for use").

Erythromycin (500 mg three times daily), a moderate inhibitor of CYP3A4 and P-gp, caused a 1.3-fold increase in mean steady-state AUC and Cmax of rivaroxaban. The interaction with erythromycin is likely not clinically significant for most patients, but may potentially be significant for high-risk patients.

In patients with mild renal impairment, unlike patients with normal renal function, administration of erythromycin (500 mg three times daily) resulted in a 1.8-fold increase in mean AUC and a 1.6-fold increase in Cmax of rivaroxaban. In patients with moderate renal impairment, erythromycin was associated with a doubling of mean AUC of rivaroxaban and a 1.6-fold increase in Cmax compared to patients with normal renal function. The effect of erythromycin is additive to the effects of renal impairment (see section "Special precautions for use").

Fluconazole (400 mg once daily), considered a moderate CYP3A4 inhibitor, caused a 1.4-fold increase in mean AUC and a 1.3-fold increase in Cmax of rivaroxaban. The interaction with fluconazole is likely not clinically significant for most patients, but may potentially be significant for high-risk patients (for use in patients with renal impairment, see section "Special precautions for use").

Due to limited clinical data on dronedarone, concomitant use with rivaroxaban should be avoided.

Anticoagulants

An additive effect on factor Xa inhibition activity was observed after combined administration of enoxaparin (single dose 40 mg) and rivaroxaban (single dose 10 mg), without additional changes in coagulation tests [PT (prothrombin time), aPTT (activated partial thromboplastin time)]. Enoxaparin did not alter the pharmacokinetics of rivaroxaban.

Due to increased risk of bleeding, concomitant use with other anticoagulants should be approached with caution (see sections "Contraindications" and "Special precautions for use").

Nonsteroidal anti-inflammatory drugs (NSAIDs)/platelet aggregation inhibitors

Clinically relevant prolongation of bleeding time was not observed after concomitant administration of rivaroxaban (15 mg) and 500 mg naproxen. However, a more pronounced pharmacodynamic response may occur in individual patients.

No clinically significant pharmacokinetic or pharmacodynamic interactions were observed with concomitant administration of Xarelto® and 500 mg acetylsalicylic acid.

No pharmacokinetic interaction was detected between rivaroxaban (15 mg) and clopidogrel (loading dose 300 mg followed by maintenance doses of 75 mg), but in a subgroup of patients, a relevant increase in bleeding time was observed, which did not correlate with platelet aggregation or levels of P-selectin or GPIIb/IIIa receptors.

Caution should be exercised when prescribing rivaroxaban to patients who are concomitantly using NSAIDs (including acetylsalicylic acid) and platelet aggregation inhibitors, as these medicinal products generally increase the risk of bleeding (see section "Special precautions for use").

Selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs)

As with other anticoagulants, the risk of bleeding is increased in patients who concomitantly use SSRIs or SNRIs due to their effects on platelets. During clinical trials, a higher number of clinically significant bleeding events was observed in all treatment groups when these agents were used concomitantly with rivaroxaban.

Warfarin

When switching patients from vitamin K antagonist warfarin (INR 2.0–3.0) to rivaroxaban (20 mg) or from rivaroxaban (20 mg) to warfarin (INR 2.0–3.0), prothrombin time and INR (Neoplastin test) increased more than additively (individual INR values up to 12 were observed), while effects on aPTT, factor Xa inhibition activity, and endogenous thrombin potential (ETP) were additive.

If pharmacodynamic effects of rivaroxaban need to be assessed during the transition period, anti-Xa activity, PiCT, and HepTest assays may be used, as warfarin does not affect the results of these tests. From day 4 after discontinuation of warfarin onwards, all tests (including PT, aPTT, factor Xa inhibition activity, and ETP) reflect only the effect of rivaroxaban.

If pharmacodynamic effects of warfarin need to be assessed during the transition period, INR determination may be used at the time of rivaroxaban's Cmin (24 hours after the previous dose of rivaroxaban), as rivaroxaban has the least influence on INR test results at this time.

No pharmacokinetic interaction was observed between warfarin and rivaroxaban.

CYP3A4 inducers

Concomitant administration of rivaroxaban and rifampicin, a strong inducer of CYP3A4 and P-gp, resulted in approximately a 50% reduction in mean AUC of rivaroxaban and a parallel decrease in its pharmacodynamic effects. Concomitant use of rivaroxaban with other strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, phenobarbital, or St. John's wort-containing products) may also lead to reduced plasma concentrations of rivaroxaban. Therefore, concomitant administration with potent CYP3A4 inducers should be avoided, except when careful patient monitoring for signs and symptoms of thrombosis is ensured.

Other concomitant medicinal products

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

No clinically significant interactions with food were observed (see section "Dosage and administration").

Effect on laboratory parameters

Effects on coagulation parameters (PT, aPTT, HepTest) are predictable, based on the mechanism of action of rivaroxaban (see section "Pharmacological properties").

Special precautions for use.

During the treatment period, clinical monitoring appropriate to the use of anticoagulants is recommended.

Risk of bleeding

As with other anticoagulants, patients receiving the medicinal product Xarelto® should be closely monitored for signs of bleeding. The medicinal product should be used with caution in conditions associated with an increased risk of bleeding. In case of serious bleeding, treatment with Xarelto® should be discontinued (see section "Overdose").

In clinical trials, mucosal bleeding (e.g., epistaxis, gingival bleeding, gastrointestinal bleeding, bleeding from the genitourinary system, including abnormal vaginal bleeding or increased menstrual bleeding) and anaemia occurred more frequently during long-term therapy with rivaroxaban than with vitamin K antagonists. Therefore, in addition to appropriate clinical monitoring, laboratory testing of haemoglobin/hematocrit levels should be considered in relevant cases to detect occult internal bleeding and to assess the clinical significance of overt bleeding.

Certain patient categories, as listed below, have an increased risk of bleeding. Such patients should be closely monitored for symptoms of haemorrhagic complications and anaemia after initiation of treatment (see section "Adverse reactions"). For patients receiving Xarelto® for prevention of VTE after hip or knee replacement surgery, regular medical examinations, careful monitoring of surgical wound drainage, and periodic monitoring of haemoglobin levels are recommended.

Any unexplained decrease in haemoglobin levels or arterial blood pressure requires identification of the source of bleeding.

Although rivaroxaban treatment does not require routine monitoring of its exposure, measurement of rivaroxaban plasma levels using calibrated quantitative anti-factor Xa assays may be useful in exceptional situations where information on rivaroxaban exposure may influence clinical decision-making, particularly in cases of overdose or emergency surgery (see section "Pharmacological properties").

Renal impairment

In patients with severe renal impairment (creatinine clearance < 30 mL/min), plasma concentrations of rivaroxaban may increase significantly (on average by 1.6-fold), which may lead to an increased risk of bleeding.

Xarelto® should be used with caution in patients with creatinine clearance of 15–29 mL/min.

The medicinal product is not recommended for patients with creatinine clearance < 15 mL/min (see sections "Dosage and administration", "Pharmacological properties").

Xarelto® should be used with caution in patients with moderate renal impairment (creatinine clearance 30–49 mL/min) who are concomitantly receiving medicinal products that increase plasma concentrations of rivaroxaban (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products

Concomitant use of Xarelto® is not recommended in patients receiving systemic antifungal azole agents (e.g., ketoconazole, itraconazole, voriconazole, posaconazole) or HIV protease inhibitors (e.g., ritonavir). These agents are potent inhibitors of both CYP3A4 and P-gp isoenzymes and may increase plasma concentrations of rivaroxaban to clinically significant levels (on average by 2.6-fold), potentially increasing the risk of bleeding (see section "Interaction with other medicinal products and other forms of interaction").

Caution is required when prescribing rivaroxaban to patients receiving medicinal products affecting haemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid, platelet aggregation inhibitors, selective serotonin reuptake inhibitors (SSRIs), or serotonin-norepinephrine reuptake inhibitors (SNRIs). If there is a risk of gastrointestinal ulceration, appropriate prophylactic treatment should be considered (see section "Interaction with other medicinal products and other forms of interaction").

Other risk factors for bleeding

As with other antithrombotic agents, rivaroxaban should be used with caution in patients at increased risk of bleeding, including those with:

• congenital or acquired coagulation disorders;
• uncontrolled severe arterial hypertension;
• other gastrointestinal disorders without active ulcers that may potentially lead to haemorrhagic complications (e.g., inflammatory bowel disease, oesophagitis, gastritis, gastroesophageal reflux disease);
• vascular retinopathy;
• bronchiectasis or history of pulmonary haemorrhage.

Patients with malignancy

Patients with malignant diseases may simultaneously have an increased 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 tumour location, anticancer therapy, and disease stage. Tumours located in the gastrointestinal or genitourinary tract have been associated with an increased risk of bleeding during rivaroxaban treatment.

Rivaroxaban is contraindicated in patients with malignant neoplasms at high risk of bleeding (see section "Contraindications").

Patients with prosthetic heart valves

Rivaroxaban should not be used for thromboprophylaxis in patients who have recently undergone transcatheter aortic valve replacement (TAVR). The safety and efficacy of Xarelto® have not been studied in patients with prosthetic heart valves, and there are no data confirming that Xarelto® provides adequate anticoagulation in this patient group. Xarelto® is not recommended for use in these patients.

Surgical procedures for hip fractures

Rivaroxaban has not been studied in interventional clinical trials involving patients after surgical treatment of hip fracture.

Patients with antiphospholipid syndrome

Direct oral anticoagulants, including rivaroxaban, are not recommended for patients with a history of thrombosis and diagnosed antiphospholipid syndrome. In particular, in patients with confirmed positive test results for all three antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibodies, anti-beta-2-glycoprotein I antibodies), therapy with direct oral anticoagulants may be associated with an increased risk of recurrent thrombotic events compared to vitamin K antagonists.

Patients with PE and haemodynamically unstable conditions or those requiring thrombolysis or pulmonary embolectomy

Xarelto® is not recommended as an alternative to unfractionated heparin in patients with pulmonary embolism who have haemodynamically unstable conditions or who may undergo thrombolysis or pulmonary embolectomy, as the safety and efficacy of Xarelto® have not been established in these clinical situations.

Spinal (epidural/spinal) anaesthesia or puncture

In patients receiving antithrombotic agents for prevention of thromboembolic complications, there is a risk of epidural or spinal haematoma during neuraxial anaesthesia (epidural/spinal anaesthesia) or spinal/epidural puncture, which may lead to long-term or permanent paralysis.

The risk of these complications increases with the use of indwelling epidural catheters or concomitant use of medicinal products affecting haemostasis. Traumatic or repeated epidural or spinal punctures may also increase the risk of such complications. Patients should be monitored for signs or symptoms of neurological disorders (e.g., numbness or weakness in the legs, bowel or bladder dysfunction). In case of neurological deficit, urgent diagnosis and treatment are required. The physician should evaluate the potential benefits and risks before performing such procedures in patients receiving or about to receive anticoagulants for thrombosis prophylaxis.

To reduce the potential risk of bleeding associated with concomitant use of rivaroxaban and spinal (epidural/spinal) anaesthesia or puncture, the pharmacokinetic profile of rivaroxaban should be considered. Placement or removal of an epidural catheter or lumbar puncture should ideally be performed when the anticoagulant effect of rivaroxaban is expected to be minimal (see section "Pharmacokinetic properties").

The epidural catheter should not be removed earlier than 18 hours after the last dose of rivaroxaban. Rivaroxaban should not be administered within the first 6 hours after removal of the epidural catheter.

If traumatic puncture occurs, administration of rivaroxaban should be delayed for 24 hours.

Dosing recommendations before and after invasive procedures and surgery (other than hip or knee replacement)

If invasive procedures or surgeries are required, administration of Xarelto® 10 mg should be discontinued at least 24 hours before the procedure, if possible, based on the physician's clinical judgment. If the procedure cannot be delayed, the risk of bleeding and urgency of the intervention should be assessed.

Administration of Xarelto® should be resumed after the invasive procedure or surgery as soon as adequate haemostasis is achieved and provided the overall clinical situation allows, as determined by the physician (see section "Pharmacokinetics").

Elderly patients

The risk of bleeding increases with age (see section "Pharmacokinetics").

Dermatological reactions

Serious skin reactions, including Stevens-Johnson syndrome / toxic epidermal necrolysis and DRESS syndrome (drug reaction with eosinophilia and systemic symptoms), have been reported during the post-marketing period with rivaroxaban (see section "Adverse reactions"). The risk of these reactions is likely highest at the beginning of therapy, with most cases occurring within the first weeks of treatment. Rivaroxaban should be discontinued at the first signs of severe skin rash (e.g., generalization, intensification, and/or blister formation) or any other signs of hypersensitivity combined with mucosal involvement.

Information on excipients

Xarelto® contains lactose. Patients with rare hereditary conditions associated with galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy. The efficacy and safety of Xarelto® in pregnant women have not been studied.

Animal studies indicate reproductive toxicity (see section "Pharmacological properties"). Due to potential reproductive toxicity, high risk of bleeding, and placental transfer of rivaroxaban, Xarelto® is contraindicated during pregnancy (see section "Contraindications").

Women of reproductive potential should avoid pregnancy during treatment with rivaroxaban.

Breastfeeding. The efficacy and safety of Xarelto® in women during breastfeeding have not been studied. Animal studies have shown that rivaroxaban is excreted in breast milk. Therefore, Xarelto® is contraindicated during breastfeeding (see section "Contraindications"). A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from therapy.

Fertility. No specific studies evaluating the effect of rivaroxaban on human fertility have been conducted. Fertility studies in male and female rats showed no effect (see section "Pharmacological properties").

Ability to affect reaction speed when driving or operating machinery.

Xarelto® has a negligible influence on the ability to drive or operate machinery. Adverse reactions such as syncope (frequency: uncommon) or dizziness (frequency: common) have been reported (see section "Adverse reactions").

Patients experiencing such adverse reactions should not drive or operate machinery.

Method of Administration and Dosage

Dosage

Prophylaxis of venous thromboembolism (VTE) in adult patients undergoing hip or knee replacement surgery

The recommended dose is 10 mg of rivaroxaban orally once daily. The first dose should be administered 6–10 hours after surgery, provided that adequate hemostasis has been achieved.

The duration of treatment depends on the individual patient's risk and the type of orthopedic surgical procedure:

• After hip replacement surgery, the recommended duration of treatment is 5 weeks.
• After knee replacement surgery, the recommended duration of treatment is 2 weeks.

If a dose is missed, the patient should take Xarelto® immediately, and the next day resume the once-daily dosing regimen as before.

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

For the first 3 weeks in the treatment of acute DVT and PE, the recommended dose is one 15 mg Xarelto® tablet twice daily. This is followed by 20 mg Xarelto® once daily for long-term treatment and prevention of recurrent DVT and PE.

Short-term therapy (for at least 3 months) should be prescribed for patients with DVT or PE associated with transient risk factors (e.g., recent surgery or trauma). Long-term therapy should be prescribed for patients with DVT or PE not associated with transient risk factors, idiopathic DVT or PE, or those with a history of recurrent DVT or PE.

When extended prevention of recurrent DVT or PE is indicated (after completing at least 6 months of treatment for DVT and PE), the recommended dose is 10 mg once daily. In patients at high risk of recurrent DVT or PE, those with concomitant diseases, or those who experienced a recurrence of DVT or PE while receiving Xarelto® 10 mg once daily for prevention, it may be appropriate to use Xarelto® 20 mg once daily.

The duration of treatment should be determined individually following careful assessment of the benefits of therapy versus the potential risk of bleeding (see section "Special Warnings and Precautions for Use").

If a dose of Xarelto® 15 mg tablet is missed during treatment with 15 mg of the medicinal product twice daily (days 1–21), the patient should take the Xarelto® tablet immediately to ensure a total daily dose of 30 mg of Xarelto®. In this case, two 15 mg tablets may be taken simultaneously. The following day, the patient should continue with the usual regimen of 15 mg twice daily as recommended.

If a dose is missed during once-daily treatment, the patient should take a Xarelto® tablet immediately and continue the next day with once-daily dosing according to the recommended dosage. A double dose should not be taken on the same day to compensate for the missed tablet.

Switching from vitamin K antagonists to Xarelto®

In patients being treated for VTE, PE, and for prevention of their recurrence, therapy with vitamin K antagonists should be discontinued and Xarelto® should be initiated when the INR value is ≤ 2.5.

When switching patients from vitamin K antagonists to Xarelto®, INR values may be falsely elevated after administration of Xarelto®. INR is not a validated method for assessing the anticoagulant activity of Xarelto® and therefore should not be used (see section "Interaction with other medicinal products and other forms of interaction").

Switching from Xarelto® to vitamin K antagonists

There is a possibility of inadequate anticoagulation during the transition period from Xarelto® to a vitamin K antagonist. As with any switch to an alternative anticoagulant, continuous adequate anticoagulation must be ensured. It should be noted that falsely elevated INR values may be observed during Xarelto® treatment.

When switching from Xarelto® to a vitamin K antagonist, the latter should be started concurrently with Xarelto® until the INR reaches ≥ 2.

Standard dosing of the vitamin K antagonist may be used during the first two days of the transition period. Thereafter, the dose of the vitamin K antagonist should be adjusted based on INR values.

While the patient is taking both Xarelto® and a vitamin K antagonist, INR should be measured no earlier than 24 hours after the last dose of Xarelto® (before administration of the next Xarelto® dose). After discontinuation of Xarelto®, INR can be reliably measured at least 24 hours after the last dose of Xarelto® (see sections "Interaction with other medicinal products and other forms of interaction", "Pharmacological properties").

Switching from parenteral anticoagulants to Xarelto®

In patients receiving parenteral anticoagulants, Xarelto® should be initiated 0–2 hours before the next scheduled administration of the parenteral agent (e.g., low molecular weight heparin) or at the time of discontinuation of a continuously administered parenteral agent (e.g., unfractionated heparin for intravenous infusion).

Switching from Xarelto® to parenteral anticoagulants

The first dose of the parenteral anticoagulant should be administered at the time when the next dose of Xarelto® would have been taken.

Special patient populations

Patients with renal impairment

Limited clinical data in patients with severe renal impairment (creatinine clearance 15–29 mL/min) indicate a significant increase in plasma concentrations of rivaroxaban. Therefore, Xarelto® should be used with caution in these patients. Use of the medicinal product is not recommended in patients with creatinine clearance <15 mL/min (see sections "Special precautions for use" and "Pharmacokinetics").

• For prevention of VTE in adult patients undergoing hip or knee replacement surgery: dose adjustment is not required in patients with mild (creatinine clearance 50–80 mL/min) or moderate (creatinine clearance 30–49 mL/min) renal impairment (see section "Pharmacokinetics").
• For treatment of DVT, PE, and prevention of recurrent DVT and PE: dose adjustment is not required in patients with mild renal impairment (creatinine clearance 50–80 mL/min) (see section "Pharmacokinetics").

Patients with moderate (creatinine clearance 30–49 mL/min) or severe (creatinine clearance 15–29 mL/min) renal impairment: should receive Xarelto® 15 mg twice daily for the first 3 weeks. Thereafter, when the recommended dose is 20 mg once daily, consideration should be given to reducing the dose from 20 mg to 15 mg once daily if the estimated risk of bleeding outweighs the risk of recurrent DVT and PE. The recommendation to use 15 mg is based on pharmacokinetic modeling and has not been studied under clinical conditions (see sections "Special precautions for use", "Pharmacodynamics", and "Pharmacokinetics").

If the recommended dose is 10 mg once daily, no dose adjustment is required.

Patients with hepatic impairment

Xarelto® is contraindicated in patients with liver disease associated with coagulopathy leading to clinically significant bleeding risk, including patients with Child-Pugh class B and C cirrhosis (see sections "Contraindications" and "Pharmacokinetics").

Elderly patients

No dose adjustment is required (see section "Pharmacokinetics").

Body weight

No dose adjustment is required (see section "Pharmacokinetics").

Gender

No dose adjustment is required (see section "Pharmacokinetics").

Method of administration

For oral use.

The 10 mg Xarelto® tablet can be taken independently of food intake (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacokinetics").

Crushing tablets

For patients unable to swallow whole tablets, the tablet may be crushed and mixed with water or soft food such as applesauce immediately before oral administration.

Crushed tablets may be administered through a gastric tube (see sections "Pharmacokinetics" and "Special precautions for safety").

Children

The safety and efficacy of Xarelto® 10 mg film-coated tablets in children (under 18 years of age) have not been established. Data in this population are lacking. Therefore, the use of Xarelto® 10 mg film-coated tablets is not recommended in children (under 18 years of age).

Overdose

Rare cases of overdose up to 1960 mg have been reported. In case of overdose, the patient should be carefully monitored for complications such as bleeding or other adverse reactions (see below "Management of bleeding"). Due to limited absorption when doses significantly exceeding therapeutic levels (50 mg or higher) are administered, a saturation effect is expected without further increase in mean plasma levels.

A specific reversal agent (andexanet alfa) that counteracts the pharmacological effects of rivaroxaban is available (see summary of product characteristics for andexanet alfa). In cases of overdose, activated charcoal may be used to reduce absorption of rivaroxaban.

Management of bleeding

In the event of bleeding complications, the next dose of rivaroxaban should be delayed or treatment discontinued, depending on the clinical situation. The elimination half-life of rivaroxaban is approximately 5–13 hours (see section "Pharmacological properties"). Treatment should be individualized based on the severity and location of bleeding. If necessary, appropriate symptomatic treatment should be initiated, such as mechanical compression for severe epistaxis, surgical hemostasis with bleeding control procedures, restoration of fluid and electrolyte balance and hemodynamic support, blood transfusion (red blood cell concentrate or fresh frozen plasma, depending on the condition—anaemia or coagulopathy—or platelets).

If bleeding persists after the above measures, consideration should be given to using a specific reversal agent (andexanet alfa), an inhibitor of factor Xa that counteracts the pharmacological effects of rivaroxaban, or procoagulant agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (aPCC), or recombinant factor VIIa (r-FVIIa). However, experience with the use of these medicinal products in rivaroxaban overdose is limited. Recommendations are also based on limited non-clinical data. Dose adjustment and titration of recombinant factor VIIa should be performed according to the degree of bleeding control achieved. In cases of major bleeding, consultation with a hematologist should be considered, depending on the clinical situation (see section "Pharmacological properties").

Protamine sulfate and vitamin K are not expected to influence the anticoagulant activity of rivaroxaban. Limited experience exists with tranexamic acid, and there is no experience with aminocaproic acid or aprotinin in patients receiving rivaroxaban. There is no scientific rationale or experience supporting the use of the systemic hemostatic agent desmopressin to manage symptoms of rivaroxaban overdose. Due to high plasma protein binding, dialysis is not expected to effectively eliminate rivaroxaban from the body.

Adverse reactions

The safety of rivaroxaban was evaluated in 13 pivotal phase III studies (see Table 7).

Overall, 69,608 adult patients in nineteen phase III studies and 488 pediatric patients in two phase II and two phase III studies were exposed to rivaroxaban.

Table 7. Number of patients enrolled in the study, total daily dose, and maximum duration of treatment in adult and pediatric patients in phase III studies.

* Patients who received at least 1 dose of rivaroxaban.

** From the VOYAGER PAD study.

The most commonly reported adverse reactions in patients receiving rivaroxaban were bleeding events (see section "Special precautions for use" and the subsection below "Information on selected adverse reactions"). The most frequent bleeding events reported were epistaxis (4.5%) and gastrointestinal tract bleeding (3.8%).

Table 8. Frequency of bleeding* and anemia in patients who received rivaroxaban during completed Phase III studies in adult and pediatric patients

* For all rivaroxaban studies, all bleeding events were collected, reported, and evaluated.

** In the COMPASS study, the frequency of anemia was low using a systematic approach to adverse event collection.

*** A systematic approach was used for collecting information on adverse events.

From the VOYAGER PAD study.

The following Table 9 presents the frequency of adverse reactions occurring during treatment with Xarelto® in adult and pediatric patients. Adverse reactions are grouped and described using the MedDRA organ system classification. Within each group, adverse reactions are listed in order of decreasing severity.

The frequency of adverse reactions is defined as follows: 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 available data).

Table 9. All adverse reactions observed in adult patients after initiation of treatment during Phase III studies or in the post-marketing period* and in pediatric patients in two Phase II and two Phase III studies

A Observed during VTE prophylaxis in adult patients undergoing elective hip or knee replacement surgery.

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

C Were identified as uncommon when used for prevention of atherothrombotic events in patients who have had ACS (following percutaneous intervention).

* A predefined, targeted approach to collecting information on adverse reactions was applied in individual phase III studies. The frequency of adverse reactions did not increase, and no new adverse reactions were identified following analysis of these studies.

Information on selected adverse reactions

Due to the pharmacological mechanism of action of rivaroxaban, the use of Xarelto® may be associated with an increased risk of internal or external bleeding in any tissues and organs, which may lead to post-hemorrhagic anemia. Signs, symptoms, and severity (including potentially fatal outcomes) vary depending on the location and extent of bleeding and/or anemia (see section "Overdose. Management of bleeding"). During clinical trials, mucosal bleeding (e.g., epistaxis, gingival bleeding, gastrointestinal bleeding, bleeding from genitourinary organs, including abnormal vaginal bleeding or increased menstrual bleeding) and anemia occurred more frequently with long-term rivaroxaban treatment compared to vitamin K antagonists. Therefore, in addition to appropriate clinical monitoring, laboratory testing of hemoglobin/hematocrit levels is recommended in appropriate cases to detect occult internal bleeding and to assess the clinical significance of overt bleeding. The risk of bleeding may be higher in certain patient groups, for example, in patients with uncontrolled severe arterial hypertension and/or in patients receiving concomitant medications affecting hemostasis (see section "Special warnings and precautions for use. Risk of bleeding"). The intensity and/or duration of menstrual bleeding may be increased. Manifestations of hemorrhagic complications may include weakness, pallor, dizziness, headache, unexplained swelling, dyspnea, or shock of unknown etiology. In some cases, symptoms of myocardial ischemia such as chest pain or angina have been observed as a consequence of anemia.

There have been reports of secondary complications known to result from severe bleeding, such as compartment syndrome and renal failure due to hypoperfusion, or kidney injury associated with anticoagulant use. Therefore, when evaluating a patient for anticoagulant therapy, the risk of bleeding should be carefully considered.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization of the medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions.

Shelf life.

3 years.

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

Storage conditions.

Store at temperatures not exceeding 30 °C, in a place inaccessible to children.

Packaging.

No. 5 (5×1): 5 tablets in a blister; 1 blister per cardboard pack;

No. 10 (10×1), No. 100 (10×10): 10 tablets in a blister; 1 or 10 blisters per cardboard pack;

No. 14 (14×1): 14 tablets in a blister; 1 blister per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

Bayer AG.

Bayer Bitterfeld GmbH.

Manufacturer's address and location of its operations.

Kaiser-Wilhelm-Allee, 51368 Leverkusen, Germany.

Ortscheit Gräppin, Seilgaster Strasse 1, 06803 Bitterfeld-Wolfen, Germany.