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

Composition:

Active substance: rivaroxaban;

granules contain 19.7 mg rivaroxaban per 1 gram;

1 vial contains 51.7 or 103.4 mg rivaroxaban;

after reconstitution, the oral suspension contains 1 mg rivaroxaban per 1 ml;

Excipients: citric acid anhydrous, hypromellose 5cP, mannitol (E 421), microcrystalline cellulose, sodium croscarmellose, sodium benzoate (E 211), sucralose, xanthan gum, creamy sweet flavor: flavoring substances, maltodextrin (corn), propylene glycol (E 1520), acacia gum (E 414).

Pharmaceutical form. Granules for oral suspension.

Main physicochemical properties: granules from white to almost white in color.

Pharmacotherapeutic group. Antithrombotic agents. Direct factor Xa inhibitors.

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 demonstrates 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 receiving rivaroxaban for the treatment of DVT (deep vein thrombosis), PE (pulmonary embolism), and prevention of recurrent DVT and PE, the 5/95 percentiles for prothrombin time (Neoplastine) 2–4 hours after tablet intake (i.e., at peak effect) range from 17 to 32 seconds for 15 mg tablets taken twice daily or from 15 to 30 seconds for 20 mg tablets taken once daily, respectively. At the minimum concentration of rivaroxaban (8–16 hours after tablet intake), the 5/95 percentiles with a 15 mg dose twice daily range from 14 to 24 seconds, and for a 20 mg dose once daily (18–30 hours after tablet intake) from 13 to 20 seconds.

In patients with non-valvular atrial fibrillation receiving rivaroxaban for stroke and systemic embolism prevention, the 5/95 percentiles for prothrombin time (Neoplastin) 1–4 hours after tablet intake (i.e., at peak effect) range from 14 to 40 seconds in patients receiving 20 mg once daily, or from 10 to 50 seconds in patients with moderate renal impairment receiving 15 mg once daily. At the minimum concentration (16–36 hours after tablet intake), the 5/95 percentiles in patients receiving 20 mg once daily range from 12 to 26 seconds, and in patients with moderate renal impairment receiving 15 mg once daily, from 12 to 26 seconds.

In a clinical pharmacology study evaluating the reversal of rivaroxaban pharmacodynamics in healthy adult volunteers (n = 22), the effects of single doses (50 IU/kg) of two types of prothrombin complex concentrates (PCC) were assessed: 3-factor PCC (factors II, IX, and X) and 4-factor PCC (factors II, VII, IX, and X). With 3-factor PCC, mean PT (prothrombin time) values (Neoplastin) decreased by approximately 1.0 second at 30 minutes, whereas with 4-factor PCC, the decrease was about 3.5 seconds. In contrast, 3-factor PCC demonstrated a more potent and faster overall effect in reversing endogenous thrombin generation changes 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 rivaroxaban's pharmacodynamic effects. Routine monitoring of coagulation parameters is not required during rivaroxaban therapy. However, if clinically necessary, rivaroxaban levels can be measured using calibrated quantitative anti-factor Xa assays (see section "Pharmacokinetics").

Pediatric patients

PT (using Neoplastin test), PCC, and anti-factor Xa assay (calibrated quantitative) show a strong correlation with rivaroxaban plasma concentrations in children. The correlation between anti-Xa activity and plasma concentrations is linear with a slope close to 1. Isolated discrepancies with higher or lower anti-Xa values compared to corresponding plasma concentrations may occur. Routine monitoring of coagulation parameters is not necessary during clinical treatment with rivaroxaban. However, if clinically indicated, rivaroxaban concentrations can be measured using calibrated quantitative anti-factor Xa assays in µg/L (see Table 3 in the "Pharmacokinetics" section for observed plasma concentration ranges in children). The lower limit of quantification should be considered when using the anti-Xa assay for quantitative assessment of rivaroxaban plasma concentrations in children. Threshold values for efficacy or safety have not been established.

Clinical efficacy and safety

Treatment of DVT and prevention of recurrent DVT in pediatric patients

A total of 727 children with confirmed acute VTE, of whom 528 received rivaroxaban, were studied in six open-label, multicenter pediatric trials. When dosed according to body weight in patients from birth to 18 years of age, rivaroxaban exposure was similar to that observed in adult patients with DVT receiving rivaroxaban 20 mg once daily, as confirmed in a Phase III study (see section "Pharmacokinetics").

The EINSTEIN Junior Phase III study was a randomized, open-label, multicenter clinical trial with active control involving 500 pediatric patients (from birth to <18 years of age) with confirmed acute VTE. The study included 276 children aged 12 to <18 years, 101 children aged 6 to <12 years, 69 children aged 2 to <6 years, and 54 children aged <2 years.

VTE events were classified as: catheter-related VTE (CVC-VTE; 90/335 patients in the rivaroxaban group, 37/165 in the comparator group); cerebral venous and sinus thrombosis (CVST; 74/335 in the rivaroxaban group, 43/165 in the comparator group); and all others, including DVT and PE (non-CVC-VTE; 171/335 in the rivaroxaban group, 85/165 in the comparator group). The most common thrombosis presentation was non-CVC-VTE in children aged 12 to <18 years: 211 (76.4%); CVST in children aged 6 to <12 years and 2 to <6 years: 48 (47.5%) and 35 (50.7%), respectively; and CVC-VTE in children aged <2 years: 37 (68.5%). No children under 6 months of age with CVST were included in the rivaroxaban group. CNS infection was present in 22 patients with CVST (13 in the rivaroxaban group and 9 in the comparator group).

In 438 (87.6%) children, VTE was triggered by persistent, transient, or both persistent and transient risk factors.

Patients received initial treatment with therapeutic doses of unfractionated heparin (UFH), low molecular weight heparin (LMWH), or fondaparinux for at least 5 days and were then randomized in a 2:1 ratio to receive either rivaroxaban at body weight-adjusted doses or the comparator (heparins, VKAs) for 3 months during the main treatment period of the study (1 month for children <2 years with CVC-VTE). At the end of the main treatment period, diagnostic imaging performed at study entry was repeated if clinically feasible. Study treatment could be discontinued at this point or, at the investigator’s discretion, continued for up to 12 months (up to 3 months for children <2 years with CVC-VTE).

The primary efficacy endpoint was symptomatic recurrent VTE. The primary safety endpoint was the composite of major bleeding and clinically relevant non-major bleeding (CRNMB). All efficacy and safety outcomes were centrally adjudicated by an independent committee blinded to treatment assignment. Efficacy and safety results are presented in Tables 1 and 2 below.

Recurrent VTE occurred in 4 of 335 patients in the rivaroxaban group and in 5 of 165 patients in the comparator group. The composite of major bleeding and CRNMB was recorded in 10 of 329 patients (3%) receiving rivaroxaban and in 3 of 162 patients (1.9%) receiving the comparator drug. Events comprising the net clinical benefit endpoint (composite of symptomatic recurrent VTE and major bleeding) were recorded in 4 of 335 patients in the rivaroxaban group and in 7 of 165 patients in the comparator group. Thrombus recanalization classified as "normalization" on repeat imaging was observed in 128 of 335 patients receiving rivaroxaban and in 43 of 165 patients in the comparator group. These results were generally consistent across age groups. Any bleeding occurring during treatment was reported in 119 (36.2%) children in the rivaroxaban group and in 45 (27.8%) children in the comparator group.

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

* Full analysis set, all children who were randomized.

Table 2. Safety results at the end of the main treatment period

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

The efficacy and safety profile of rivaroxaban was largely similar in the paediatric population with VTE and the adult population with DVT/PE; however, the proportion of subjects with any bleeding was higher in the paediatric population with VTE compared to the adult population with DVT/PE.

Thromboprophylaxis in children with congenital heart defect after Fontan procedure

In a prospective, open-label, two-part (Part B, active-controlled) study UNIVERSE, the efficacy and safety of rivaroxaban for thromboprophylaxis compared to acetylsalicylic acid over 12 months were evaluated in 110 children aged 2 to 8 years with congenital heart defects and single-ventricle hemodynamics who had undergone the Fontan procedure within 4 months prior to enrollment. Patients received either body weight-adjusted doses of rivaroxaban ([n = 76], exposure corresponding to the adult 10 mg daily dose) or acetylsalicylic acid ([n = 34], approximately 5 mg/kg). The dosing investigated in UNIVERSE for thromboprophylaxis was thus lower and cannot be extrapolated from the approved paediatric dose for VTE treatment.

In the UNIVERSE study, several thromboembolic events were observed: 1 (1.6%) in the rivaroxaban group versus 3 (8.8%) in the acetylsalicylic acid group. The number of bleeding events was similar between treatment groups: 5 (7.8%) clinically relevant bleeding events (including 1 major) in the rivaroxaban group versus 3 (8.8%; no major events) in the acetylsalicylic acid group.

Patients with positive test results for three antiphospholipid antibodies

Rivaroxaban was compared with 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, anticardiolipin antibodies, 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 median observation period was 569 days; 59 patients were randomized to the rivaroxaban group (20 mg once daily; 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 events occurred in 4 patients (7%) in the rivaroxaban group and 2 patients (3%) in the warfarin group.

Pharmacokinetics.

Absorption

The information below is based on data obtained in adult patients.

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

The absolute bioavailability of rivaroxaban is high, ranging from 80–100% after administration of 2.5 mg and 10 mg tablet formulations, regardless of food intake.

When administered fasting, a bioavailability of 66% was determined for the 20 mg rivaroxaban tablet formulation due to reduced absorption. When the 20 mg rivaroxaban tablet was administered with food, the mean AUC increased by 39% compared to fasting administration, indicating nearly complete absorption and high oral bioavailability.

The pharmacokinetics of rivaroxaban are approximately linear when administered at doses up to 15 mg once daily under fasting conditions. When taken with food, the pharmacokinetics of the 10 mg, 15 mg, and 20 mg rivaroxaban tablet formulations are dose-proportional. At higher doses, absorption of rivaroxaban is limited by solubility characteristics, resulting in reduced bioavailability and absorption extent.

Bioequivalence has been demonstrated for the granules for oral suspension compared to the 10 mg tablet administered fasting, as well as the 20 mg tablet administered with food.

Rivaroxaban pharmacokinetics are characterized by moderate variability; individual variability (coefficient of variation) ranges from 30% to 40%.

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 compared to the tablet formulation. Exposure is further reduced with drug release 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 consequently reduced exposure.

Bioavailability (AUC and Cmax) of 20 mg rivaroxaban administered orally as a crushed tablet mixed with apple puree or water, delivered via a gastric tube immediately after a liquid meal, was comparable to that of the intact tablet. Given the expected dose-proportional pharmacokinetic profile of rivaroxaban, the results of this bioavailability study are likely applicable to lower doses of rivaroxaban as well.

Paediatric patients

Children received rivaroxaban tablets or oral suspension during or immediately after feeding or food intake, along with a typical fluid volume to ensure reliable dosing. As in adults, rivaroxaban is readily absorbed in children after oral administration as tablets or granules for oral suspension. No differences in rate or extent of absorption were observed between the rivaroxaban tablet formulation and the granules for oral suspension. There are no data on pharmacokinetics (PK) after intravenous administration in children; therefore, the absolute bioavailability of rivaroxaban in children is unknown. A decrease in relative bioavailability with increasing dose (in mg/kg body weight) has been observed, indicating absorption limitations at higher doses, even when administered with food.

Rivaroxaban oral suspension should be taken during feeding or with food (see section "Dosage and administration").

Distribution

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

Paediatric patients

There are no data on plasma protein binding of rivaroxaban specific to children. No PK data are available after intravenous administration of rivaroxaban in children. The Vss, estimated by population pharmacokinetic modeling in children (age range 0 to <18 years) after oral administration of rivaroxaban, is body weight-dependent and can be described by an allometric function, with a mean value of 113 L for a subject weighing 82.8 kg.

Metabolism and elimination

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

Metabolism of rivaroxaban is mediated by CYP3A4 and CYP2J2 isoenzymes, as well as by cytochrome CYP-independent mechanisms. The primary sites of biotransformation are the morpholinone group, which undergoes oxidative cleavage, 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 main component in human plasma is unchanged rivaroxaban; significant or active circulating metabolites have not been identified. Rivaroxaban, with a systemic clearance of approximately 10 L/h, is classified as a drug with low clearance. After intravenous administration of a 1 mg dose, the elimination half-life is approximately 4.5 hours. After oral administration, elimination is absorption-rate limited. 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 individuals.

Paediatric patients

In vitro data do not indicate significant differences in plasma protein binding of rivaroxaban in children across different age groups compared to adults.

There are no data on pharmacokinetics after intravenous administration of rivaroxaban in children. Clearance, estimated by population pharmacokinetic modeling in children (age range 0 to <18 years) after oral administration of rivaroxaban, is body weight-dependent and can be described by an allometric function, with a mean value of 8 L/h for a subject weighing 82.8 kg. The mean geometric values of elimination half-life (t1/2), estimated by population pharmacokinetic modeling, decrease with decreasing patient age, ranging from 4.2 hours in adolescents to approximately 3 hours in children aged 2 to 12 years, and to 1.9 and 1.6 hours in children aged 0.5 to <2 years and <0.5 years, respectively.

Special patient populations

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 healthy control 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 renal excretion of rivaroxaban, similar to that observed in patients with moderate renal impairment. There are no data in patients with severe hepatic dysfunction.

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.

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 cirrhosis (see section "Contraindications").

Renal impairment. There are no clinical data on the use of rivaroxaban in children aged 1 year and older with moderate or severe renal impairment (glomerular filtration rate < 50 mL/min/1.73 m²) or in children under 1 year of age with serum creatinine levels above the 97.5th percentile (see section "Special precautions").

In adults, exposure to rivaroxaban increased inversely proportional to the degree of renal function decline, as measured by creatinine clearance. 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-fold higher, respectively, compared to healthy volunteers. Correspondingly, pharmacodynamic effects were increased. In individuals with mild, moderate, or severe renal impairment, overall inhibition of factor Xa activity was 1.5-, 1.9-, and 2-fold higher, respectively, compared to healthy volunteers; aPTT was similarly prolonged by 1.3-, 2.2-, and 2.4-fold, 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.

Sex. In adult men and women, no clinically relevant differences in pharmacokinetics were observed. A post hoc analysis did not reveal relevant differences in rivaroxaban exposure between male and female paediatric patients.

Body weight categories. In adults, very low or very high body weight (less than 50 kg or more than 120 kg) has only a minor effect on rivaroxaban plasma concentrations (deviation less than 25%).

In children, rivaroxaban doses are adjusted based on body weight. A post hoc analysis in paediatric patients did not reveal a relevant impact of low body weight or obesity on rivaroxaban exposure.

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

A post hoc analysis did not reveal relevant ethnic differences in rivaroxaban exposure in paediatric patients of Japanese, Chinese, or other Asian ethnicities outside Japan and China compared to the general paediatric population.

Pharmacokinetic data observed in patients.

In paediatric patients with acute VTE receiving rivaroxaban (at body weight-adjusted doses resulting in exposure similar to that in adult patients with DVT receiving 20 mg once daily), the mean geometric concentrations (90% interval) at sampling times approximately reflecting peak and trough concentrations between dose administrations are summarized in Table 3.

Table 3. Summary statistics (geometric mean (90% interval)) of steady-state plasma concentrations of rivaroxaban (µg/L) by dosing regimen and age

Pharmacokinetic/pharmacodynamic relationships.

The pharmacokinetic/pharmacodynamic (PK/PD) relationship between rivaroxaban plasma concentration and several pharmacodynamic endpoints (factor Xa inhibition, PT, aPTT, HepTest) was evaluated across a wide range of doses (5–30 mg twice daily). The relationship between rivaroxaban concentration and factor Xa activity was best described by an Emax model. For PT, the most reliable data were obtained using a linear segmented regression model. Depending on the different reagents used for PT determination, the slope coefficient may vary substantially. When Neoplastin reagent was used for PT measurement, the baseline PT was approximately 13 seconds, and the slope coefficient ranged from 3 to 4 seconds/(100 μg/L). The results of PK/PD analyses in Phase II and III studies were consistent with those obtained in healthy volunteers.

Preclinical safety data

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

Findings observed during repeated-dose toxicity studies were primarily related to the excessive pharmacological activity of rivaroxaban.

No effects on fertility in male or female animals were observed. Reproductive toxicity related to the pharmacological mechanism of action of rivaroxaban (particularly hemorrhagic lesions) was observed in animal studies. Embryo-fetal toxicity (post-implantation losses, delayed/advanced ossification, scattered light-colored spots) and increased incidence of general malformations and placental changes were observed at clinically relevant plasma concentrations. In prenatal and postnatal studies in rats, reduced offspring viability was observed at doses that were toxic to the dams.

A study of rivaroxaban in young rats, administered for 3 months starting on postnatal day 4, showed a dose-independent increase in the frequency of peri-insular hemorrhages. There was no evidence of toxicity to target organs.

Clinical characteristics.

Indications.

For the treatment of venous thromboembolism (VTE) and prevention of recurrent VTE in term neonates, infants, young children, children, and adolescents (up to 18 years of age) following at least 5 days of initial parenteral anticoagulant therapy.

Contraindications.

• Hypersensitivity to rivaroxaban or to any of the excipients of the medicinal product.
• Clinically significant active bleeding.
• Conditions or injuries associated with a significant risk of bleeding, including current or recently diagnosed gastrointestinal ulcers, malignant tumors with high bleeding risk, recent trauma to the brain or spinal cord, recent surgery on the brain, spinal cord, or eyes, recent intracranial hemorrhage, esophageal varices (confirmed or suspected), arteriovenous malformations, vascular aneurysms, or significant intraspinal or intracerebral vascular abnormalities.
• Concomitant use with any other anticoagulants, including unfractionated heparin, low-molecular-weight heparins (e.g., enoxaparin, dalteparin), heparin derivatives (e.g., fondaparinux), or oral anticoagulants (e.g., warfarin, dabigatran etexilate, apixaban), except under specific circumstances of transition to alternative anticoagulant therapy (see section "Dosage and administration") or when unfractionated heparin is administered at doses required for maintaining patency of central venous or arterial catheters (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").
• Pregnancy or breastfeeding (see section "Use during pregnancy or breastfeeding").

Safety precautions.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Suspension

Prior to administration, granules must be suspended in a homogeneous suspension using non-carbonated water to achieve a final concentration of 1 mg per 1 mL.

The volume of water required is:

• 50 mL for the vial containing 2.625 g granules (51.7 mg rivaroxaban), resulting in a total volume of 51.7 mL after reconstitution;
• 100 mL for the vial containing 5.25 g granules (103.4 mg rivaroxaban), resulting in a total volume of 103.4 mL after reconstitution.

After reconstitution, the vial should be shaken for 60 seconds and before each administration for 10 seconds.

After reconstitution, the medicinal product forms a suspension ranging from white to almost white in color.

Syringes (1 mL, 5 mL, or 10 mL) are provided for dosing the suspension (see section "Dosage and administration", Table 4).

Complete information on the preparation and administration of the oral suspension can be found in the section "Dosage and administration".

The suspension may be administered via nasogastric or gastric feeding tube. Placement of the feeding tube should be confirmed before administration of Xarelto®. Since rivaroxaban absorption depends on the site of active substance release, administration distal to the stomach should be avoided, as this may lead to reduced absorption and consequently lower drug exposure. After administration, the feeding tube should be flushed with water. Nasogastric or gastric feeding should be initiated immediately thereafter.

Interaction with other medicinal products and other forms of interaction.

The extent of interaction in the pediatric population is unknown. The interaction data provided below were obtained in adults; for the pediatric population, the warnings in the section "Special precautions for use" should be considered.

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 a marked enhancement of the pharmacodynamic effects of the drug, increasing the risk of bleeding. Therefore, the use of Xarelto® is not recommended in patients receiving concomitant systemic antifungal azole agents such as ketoconazole, itraconazole, voriconazole, or posaconazole, or HIV protease inhibitors. These agents are potent inhibitors of both CYP3A4 and P-gp (see section "Special precautions for use").

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

For example, clarithromycin (500 mg twice daily), a strong inhibitor of CYP3A4 and moderate inhibitor of P-gp, caused a 1.5-fold increase in mean AUC and a 1.4-fold increase in Cmax of rivaroxaban. The interaction with clarithromycin is unlikely to be clinically significant for most patients but could 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 both CYP3A4 and P-gp, caused a 1.3-fold increase in mean steady-state AUC and Cmax of rivaroxaban. The interaction with erythromycin is unlikely to be clinically significant for most patients but could potentially be significant for high-risk patients.

In patients with mild renal impairment, as compared to those 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 led to a doubling of mean AUC and a 1.6-fold increase in Cmax of rivaroxaban 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 inhibitor of CYP3A4, caused a 1.4-fold increase in mean AUC and a 1.3-fold increase in Cmax of rivaroxaban. The interaction with fluconazole is unlikely to be clinically significant for most patients but could 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

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

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

Non-steroidal anti-inflammatory drugs (NSAIDs)/platelet aggregation inhibitors

Clinically relevant prolongation of bleeding time was not observed after co-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 when Xarelto® and 500 mg acetylsalicylic acid were administered concomitantly.

No pharmacokinetic interaction was detected between rivaroxaban (15 mg) and clopidogrel (loading dose 300 mg followed by maintenance doses of 75 mg); however, 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 receptor.

Caution is required 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 receiving SSRIs or SNRIs concomitantly due to their effects on platelets. During clinical trials, a higher incidence of clinically significant bleeding was observed in all treatment groups when these agents were used concomitantly with rivaroxaban.

Warfarin

When switching patients from vitamin K antagonist warfarin (INR 2–3) to rivaroxaban (20 mg), or from rivaroxaban (20 mg) to warfarin (INR 2.0–3.0), prothrombin time and INR (Neoplastin) increased more than additively (individual INR values up to 12 were observed), while the effects on aPTT, factor Xa activity inhibition, and endogenous thrombin potential (ETP) were additive.

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

If monitoring of the pharmacodynamic effects of warfarin is desired during the transition period, INR measurement may be performed at the time of rivaroxaban's Cmin (24 hours after the previous dose of rivaroxaban), as rivaroxaban has minimal influence on INR 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 corresponding decrease in its pharmacodynamic effects. Concomitant use of rivaroxaban with other strong inducers of CYP3A4 (e.g., phenytoin, carbamazepine, phenobarbital, or St. John’s wort) may also lead to decreased plasma concentrations of rivaroxaban. Therefore, concomitant administration with potent CYP3A4 inducers should be avoided, except when close 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-glycoprotein substrate), atorvastatin (CYP3A4 and P-gp substrate), or omeprazole (proton pump inhibitor). Rivaroxaban does not inhibit or induce any major cytochrome P450 isoenzymes, such as CYP3A4.

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 practice of anticoagulant use is recommended.

Dosing of rivaroxaban has not been reliably established and has not been studied in the following patient groups; therefore, it is not recommended in children under 6 months of age who:

• were born at a gestational age of less than 37 weeks, or
• have a body weight below 2.6 kg, or
• have been on oral feeding for less than 10 days.

Risk of bleeding

As with other anticoagulants, patients receiving 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 the event of serious bleeding, Xarelto® should be discontinued (see section "Overdose").

In clinical studies, mucosal bleeding (e.g., epistaxis, gingival bleeding, gastrointestinal bleeding, bleeding from the genitourinary tract, including abnormal vaginal bleeding or increased menstrual bleeding) and anaemia occurred more frequently during long-term therapy with rivaroxaban compared to vitamin K antagonists. Therefore, in addition to appropriate clinical monitoring, laboratory testing of haemoglobin/haematocrit levels may be appropriate in relevant cases to detect occult 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 after initiation of treatment for symptoms of haemorrhagic complications and anaemia (see section "Adverse reactions").

Any decrease in haemoglobin level or arterial blood pressure of unknown origin requires identification of the source of bleeding.

Although rivaroxaban therapy does not require routine monitoring of its exposure, measurement of rivaroxaban 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").

Limited data are available in children with cerebral venous and sinus thrombosis who have central nervous system (CNS) infection (see "Pharmacodynamics"). The risk of bleeding should be carefully assessed before and during rivaroxaban therapy.

Renal impairment

The use of Xarelto® is not recommended in children aged 1 year and older with moderate to severe renal impairment (glomerular filtration rate < 50 mL/min/1.73 m²) due to lack of clinical data.

The use of Xarelto® is not recommended in children under 1 year of age with serum creatinine levels above the 97.5th percentile due to lack of clinical data.

Interaction with other medicinal products

There are no clinical data in children receiving concomitant systemic treatment with strong inhibitors of CYP3A4 and P-gp.

The use of Xarelto® is not recommended in patients receiving concomitant systemic treatment with azole antifungal agents (e.g., ketoconazole, itraconazole, voriconazole, posaconazole) or HIV protease inhibitors (e.g., ritonavir). These agents are potent inhibitors of both CYP3A4 isoenzymes and P-gp, and may increase plasma concentrations of rivaroxaban to a clinically significant level (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 taking medicinal products affecting haemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid, and platelet aggregation inhibitors, or selective serotonin reuptake inhibitors (SSRIs) and 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 is not recommended in patients with an 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);
• retinal vasculopathy;
• bronchiectasis or history of pulmonary haemorrhage.

Patients with oncological disease

Patients with malignancies 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 therapy.

The use of 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. The use of Xarelto® is not recommended for the treatment of such patients.

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-β2-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 or requiring thrombolysis or pulmonary embolectomy

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

Spinal (epidural/spinal) anaesthesia or puncture

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

The risk of such complications is increased with the use of indwelling epidural catheters or concomitant use of medicinal products affecting haemostasis. Traumatic or repeated epidural or spinal punctures also increase the risk of these complications. Patients should be monitored for signs of neurological impairment (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 scheduled to receive anticoagulants for thrombosis prophylaxis. There is no clinical experience with the use of rivaroxaban in such situations.

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 low. However, the exact time to achieve sufficient reduction in anticoagulant effect varies between individual patients and should be weighed against the urgency of the diagnostic procedure.

There are no data on the timing of placement or removal of neuraxial catheters in children during treatment with Xarelto®. In such cases, rivaroxaban should be discontinued and the use of a short-acting parenteral anticoagulant should be considered.

Dosing recommendations before and after invasive procedures and surgery

If invasive procedures or surgery are required, Xarelto® 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 presence of an increased risk of bleeding and the urgency of the intervention should be assessed.

Xarelto® should be resumed as soon as adequate haemostasis is achieved and the clinical situation allows, as determined by the physician (see "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 in association with rivaroxaban use (see section "Adverse reactions"). The risk of these reactions is likely highest at the beginning of therapy: most reactions occurred within the first weeks of treatment. Rivaroxaban should be discontinued at the first signs of severe skin rash (e.g., generalisation, intensification, and/or blistering) or the appearance of any other signs of hypersensitivity in combination with mucosal involvement.

Information on excipients

Xarelto®, granules for oral suspension, contains 1.8 mg of sodium benzoate (E 211) per millilitre of oral suspension. Sodium benzoate may exacerbate jaundice (yellowing of the skin and eyes) in neonates (up to 4 weeks). Increased bilirubinaemia due to displacement from albumin may worsen neonatal jaundice, potentially progressing to kernicterus (deposition of unconjugated bilirubin in brain tissue).

This medicinal product contains less than 1 mmol sodium (23 mg) per millilitre, 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 "Preclinical safety data"). Due to the potential reproductive toxicity, significant 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 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. Specific studies on the effect of rivaroxaban on human fertility have not been conducted. In fertility studies in male and female rats, no effect was observed (see section "Preclinical safety data").

Ability to affect the speed of reactions while 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

The dosage and frequency of administration are determined according to the patient's body weight (see Table 4).

Table 4. Recommended dose of XARELTO® for pediatric patients from birth (term neonates after at least 10 days of oral feeding and with body weight of at least 2.6 kg) up to < 18 years of age

Body weight of the child must be monitored, and the dose should be regularly reviewed, especially in children with body weight up to 12 kg. This is necessary to maintain a therapeutic dose. Dose adjustments should be made only based on changes in body weight.

Dosing frequency:

• For once-daily regimen: doses should be taken approximately 24 hours apart.
• For twice-daily regimen: doses should be taken approximately 12 hours apart.
• For thrice-daily regimen: doses should be taken approximately 8 hours apart.

Oral suspension should be used in patients with body weight from 2.6 kg to 30 kg. Do not split Xarelto® tablets or use lower-dose Xarelto® tablets in an attempt to achieve doses for children with body weight less than 30 kg.

Patients with body weight of at least 30 kg may receive either oral suspension or Xarelto® 15 mg or 20 mg tablets once daily.

Xarelto®, oral suspension, is supplied with blue 1 mL or 5 mL and 10 mL syringes (oral dosing syringe) and an adapter. To ensure accurate dosing, the use of blue syringes is recommended as follows (see Table 4):

• The 1 mL blue syringe (graduated in 0.1 mL increments) should be used when administering the medicinal product to patients with body weight less than 4 kg.
• The 5 mL blue syringe (graduated in 0.2 mL increments) may be used when administering the medicinal product to patients with body weight from 4 to 30 kg.
• The 10 mL blue syringe (graduated in 0.5 mL increments) is recommended only for patients with body weight of 12 kg and above.

For patients with body weight from 12 kg to 30 kg, either the 5 mL or 10 mL blue syringe may be used.

It is recommended that a healthcare professional advise the patient or caregiver which blue syringe to use to ensure correct volume administration.

Initiation of treatment

• Paediatric patients from term neonates to infants up to 6 months of age

Treatment of paediatric patients from term neonates to infants up to 6 months of age, who were born at or after 37 weeks of gestation, weighed at least 2.6 kg at birth, and have been on oral feeding for at least 10 days, should be initiated after at least 5 days of initial parenteral anticoagulant therapy (see sections "Special precautions for use" and "Pharmacodynamics"). Xarelto® should be dosed according to body weight using oral suspension (see Table 4).

• Paediatric patients from 6 months to 18 years of age

Treatment in children from 6 months to 18 years of age should be initiated after at least 5 days of initial parenteral anticoagulant therapy (see "Pharmacodynamics"). Xarelto® should be dosed according to body weight (see Table 4).

Treatment duration

• All children except children up to 2 years of age with catheter-related thrombosis

Treatment should be continued for at least 3 months. If clinically indicated, treatment may be extended up to 12 months. There are no data on dose reduction in children after 6 months of treatment. The benefit-risk balance of continuing therapy beyond 3 months should be evaluated on an individual basis, considering the risk of recurrent thrombosis versus the potential risk of bleeding.

• Children up to 2 years of age with catheter-related thrombosis

Treatment should be continued for at least 1 month. If clinically indicated, treatment may be extended up to 3 months. The benefit-risk balance of continuing therapy beyond 1 month should be evaluated on an individual basis, considering the risk of recurrent thrombosis versus the potential risk of bleeding.

Missed doses

• Once-daily regimen

If a once-daily dose is missed, it should be taken as soon as possible on the same day it is remembered. If this is not possible, the patient should skip the missed dose and continue with the next scheduled dose. The patient should not take a double dose to make up for the missed dose.

• Twice-daily regimen

If a morning dose is missed, it should be taken immediately when remembered and may be taken together with the evening dose. A missed evening dose may only be taken on the same evening; the patient should not take a double dose the following morning.

• Thrice-daily regimen

If a dose is missed with a thrice-daily regimen, resume the usual thrice-daily schedule with approximately 8-hour intervals after the next scheduled dose, without making up for the missed dose.

The next day, the child should continue the usual dosing regimen of once, twice, or thrice daily.

Switching from parenteral anticoagulants to Xarelto®

In patients receiving parenteral anticoagulants, initiation of Xarelto® should occur 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 the next dose of Xarelto® would have been due.

Switching from vitamin K antagonists to Xarelto®

Vitamin K antagonist therapy 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 Xarelto® administration. INR is not a validated method for assessing the anticoagulant activity of Xarelto® and 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 potential for inadequate anticoagulation during the transition 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 INR values may be falsely elevated during Xarelto® therapy.

Children switching from Xarelto® to a vitamin K antagonist should continue taking Xarelto® for 48 hours after the first dose of the vitamin K antagonist. After two days of concomitant administration, the INR should be measured before the next scheduled dose of Xarelto®. Concomitant administration of Xarelto® and the vitamin K antagonist is recommended until an INR value ≥ 2.0 is achieved. After discontinuation of Xarelto®, INR can be reliably measured at least 24 hours after the last dose of Xarelto® (see above and section "Interaction with other medicinal products and other forms of interaction").

Special patient populations

Patients with renal impairment

• Children aged 1 year and older with moderate renal impairment (glomerular filtration rate 50–80 mL/min/1.73 m²): dose adjustment is not required based on data in adults and limited data in paediatric patients (see section "Pharmacokinetics").
• Children aged 1 year and older with severe renal impairment (glomerular filtration rate < 50 mL/min/1.73 m²): use of Xarelto® is not recommended due to lack of clinical data (see section "Special precautions for use").
• Children under 1 year of age: renal function should be assessed using serum creatinine only. Use of Xarelto® is not recommended in children under 1 year of age with serum creatinine levels above the 97.5th percentile (see Table 5) due to lack of data (see section "Special precautions for use").

Table 5. Reference values for serum creatinine in children under 1 year of age (Boer et al, 2010)

Patients with hepatic impairment

There are no clinical data available in children with hepatic impairment.

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

Body weight

The dose for children is determined based on body weight (see above).

Gender

Dose adjustment is not required (see section "Pharmacokinetics").

Route of administration

For oral use.

The oral suspension should be taken during feeding or with food (see "Pharmacokinetics").

For detailed instructions on the preparation and administration of the oral suspension, refer to the section "Special precautions for handling and disposal".

The oral suspension can be administered via a nasogastric or gastric tube (see sections "Pharmacokinetics" and "Special precautions for handling and disposal").

Immediately after each dose, one standard serving of liquid should be consumed. This standard serving may include the volume of liquid used for feeding.

If the patient spits out the dose or vomits within 30 minutes after administration, another dose should be given. However, if the patient vomits more than 30 minutes after taking the dose, the dose should not be repeated, and the next scheduled dose should be taken as planned.

If the oral suspension is not immediately available when a 15 mg or 20 mg rivaroxaban dose is due, it may be prepared by crushing a 15 mg or 20 mg tablet and mixing it with water or apple puree immediately before administration. The resulting mixture should be administered orally (see "Pharmacokinetics" and section "Special precautions for handling and disposal").

Preparation of the oral suspension

Step 1.1. Preparation

Suspension preparation should be performed once with each new package.

Before preparing the suspension:

Step 1.2. Filling with the required volume of water

Each time you start a new package, use only the new materials contained in the new package.

For the 100 ml bottle pack:

For the package with a 250 ml vial:

Step 1.3. Adding water to the granules

Step 1.4. Attaching the adapter and mixing the oral suspension

The adapter is used to fill the blue syringe with the suspension.

a. Unpack the bottle adapter.

Warning. To ensure accurate dosing, the suspension must not contain any lumps or sediment.

d. If you notice lumps or sediment, repeat steps h.–d.

If there are no lumps or sediment, the suspension is ready for use.

Do not add more water to the bottle.

The shelf life of the suspension is 14 days when stored at room temperature.

1. Setting the prescribed dose for each new blue syringe

An accurate dose of the suspension is necessary to avoid overdose or underdose.

Before drawing up the first dose from the vial, the blue syringe provided in the package must be set to the dose prescribed by the child's doctor. This information can be found in the designated field on the packaging. If no information is indicated in this field, consult your child's doctor or pharmacist.

After the dose has been set, the same blue syringe can be used for each administration of the suspension drawn from the vial prepared in step 1.

Once the dose is set on the blue syringe, it cannot be changed.

1. Administration of the oral suspension

Perform the steps described below for each required administration.

Step 3.1. Mixing the oral suspension

Warning. Wait until the suspension reaches room temperature if it has been stored in the refrigerator.

Step 3.2. Preparing the required dose

Step 3.3. Administration of the prescribed dose

1. Cleaning and Storage of the Syringe

The blue syringe should be cleaned after each use.

Perform the steps below to clean the device. A total of three cleaning cycles are required to ensure proper cleaning.

Before you begin, prepare the following items for step 4.1:

Two containers (e.g., a cup or bowl)

• one container filled with drinking water,
• one container empty.

Step 4.1. Cleaning the Syringe

Step 4.2. Storage of the syringe

Store the blue syringe until next use in a clean and dry place, for example in the packaging of the medicinal product Xarelto®.

Protect from sunlight.

Warning. The blue syringe can be used for up to a maximum of 14 days.

Store the suspension at a temperature below 30 °C.

Do not freeze the suspension.

The prepared suspension retains its properties at room temperature for up to 14 days (date of preparation plus 14 days).

Keep Xarelto® out of the reach and sight of children.

Store in an upright position.

1. Disposal

Any unused medicinal product or waste, syringes, and adapters should be disposed of in accordance with local requirements.

1. Damage / malfunction

Any serious incidents related to the product should be reported to the manufacturer and the relevant authority in your country.

Children.

The safety and efficacy of Xarelto® in children (aged 0 to 18 years) have not been established, except for the indications of treatment of venous thromboembolism and prevention of recurrent venous thromboembolism. Data for other indications are lacking or insufficient (see also section "Pharmacodynamics"). Therefore, the use of Xarelto® in children (under 18 years of age) is not recommended, except for the indications of treatment of venous thromboembolism (VTE) and prevention of recurrent VTE.

Overdose.

Isolated 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 "Treatment of bleeding"). Due to limited absorption when administering doses significantly exceeding therapeutic levels (50 mg or higher), a saturation effect is expected, without further increase in plasma concentrations.

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

Treatment of bleeding

If a patient receiving rivaroxaban experiences complications in the form of bleeding, 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 "Pharmacokinetics"). Treatment should be individualized based on the severity and location of bleeding. If necessary, appropriate symptomatic treatment may be administered, such as mechanical compression for severe epistaxis, surgical hemostasis with bleeding control procedures, restoration of fluid and electrolyte balance and hemodynamic support, transfusion of blood products (packed red blood cells or fresh frozen plasma depending on associated anemia or coagulopathy), or platelets.

If bleeding persists after the above measures, consideration should be given to administering a specific reversal agent (andexanet alfa), an inhibitor of factor Xa that counteracts the pharmacological effects of rivaroxaban, or specific procoagulant agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (aPCC), or recombinant factor VIIa (rFVIIa).

However, clinical experience with the use of these medicinal products in rivaroxaban overdose is limited. Recommendations are also based on limited preclinical data. The decision on dosing and titration of recombinant factor VIIa should be made considering the degree of bleeding control. In cases of massive bleeding, consultation with a hematologist should be considered as appropriate (see section "Pharmacological properties").

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

Adverse reactions

The safety of rivaroxaban was evaluated in 13 pivotal Phase III studies (see Table 6).

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 6. Number of patients, total daily dose, and maximum treatment duration in adult and pediatric patients during Phase III studies

* Patients who received at least one 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" and the subsection below "Information on selected adverse reactions") (see Table 7). The most frequent were reports of epistaxis (4.5%) and gastrointestinal bleeding (3.8%).

Table 7. Frequency of bleeding* and anemia in patients who received rivaroxaban during completed Phase III studies involving adult and pediatric patients

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

** In the COMPASS study, the frequency of anemia was low due to the use of a selected approach to collecting adverse event information.

*** A selected approach to collecting information on adverse events was applied.

From the VOYAGER PAD study.

The adverse reactions occurring during treatment with Xarelto® in adult and pediatric patients are listed in Table 8 below. Adverse reactions are categorized by system organ classes (MedDRA) and frequency. 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 the available data).

Table 8. All adverse reactions observed in adult patients participating in 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 Observed during treatment of DVT, PE, and prevention of recurrent events very commonly in women under 55 years of age.

C Were identified as uncommon during prevention of atherothrombotic events in patients who had experienced ACS (after PCI).

* A pre-specified, targeted approach to collecting adverse reaction data was applied in certain 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 specific 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. Symptoms and severity (including fatal outcomes) depend 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, genitourinary bleeding, including abnormal vaginal bleeding or increased menstrual bleeding) and anemia occurred more frequently with long-term rivaroxaban treatment than with vitamin K antagonists. Because of this, in addition to appropriate clinical monitoring, laboratory monitoring of hemoglobin/hematocrit levels should be considered in appropriate cases to detect occult bleeding and assess the clinical significance of overt bleeding. The risk of bleeding may be higher in certain patient groups, such as patients with uncontrolled severe arterial hypertension and/or patients receiving concomitant medications affecting hemostasis (see section "Special precautions / Risk of bleeding"). Increased intensity and/or duration of menstrual bleeding is possible. Manifestations of hemorrhagic complications may include weakness, pallor, dizziness, headache, or unexplained swelling, dyspnea, or shock of unknown etiology. In some cases, symptoms of myocardial ischemia such as chest pain or angina were observed as a consequence of anemia.

Secondary complications known to result from severe bleeding, such as compartment syndrome, renal failure due to hypoperfusion, or kidney injury associated with anticoagulant use, have been reported with Xarelto®. Therefore, when assessing a patient receiving anticoagulants, the risk of bleeding should be carefully considered.

Pediatric patients

Treatment of VTE and prevention of recurrent VTE

The safety assessment in children and adolescents is based on safety data from two open-label phase II studies with active control and one phase III study involving children up to 18 years of age. Safety results were generally similar between rivaroxaban and the comparator drug across different pediatric age groups. Overall, the safety profile in 412 children and adolescents receiving rivaroxaban was similar to that in adults and consistent across age subgroups, although assessment is limited by the small number of patients.

In pediatric patients, headache (very common, 16.7%), fever (very common, 11.7%), epistaxis (very common, 11.2%), vomiting (very common, 10.7%), tachycardia (common, 1.5%), increased bilirubin levels (common, 1.5%), and elevated conjugated bilirubin (uncommon, 0.7%) were reported more frequently compared to adults. As in the adult population, menorrhagia was observed in 6.6% (common) of post-menarche female adolescents. Thrombocytopenia, which was observed in the post-marketing period in adults, was common (4.6%) in pediatric clinical trials. Adverse reactions in pediatric patients were mostly mild or moderate in severity.

Reporting suspected adverse reactions

Reporting of adverse reactions after drug authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

3 years.

After preparation, the suspension is stable for 14 days.

Storage conditions.

Store at temperatures not exceeding 30°C. Do not freeze.

The syringe containing the prepared suspension should be stored in an upright position.

Packaging.

1 vial of 100 mL containing 2.625 g of granules; 1 vial per cardboard box with 1 plastic syringe of 50 mL graduated in 1.0 mL increments, 2 plastic dosing devices of 1 mL graduated in 0.1 mL increments, and 1 adapter, together with instructions for medical use; or 1 vial of 250 mL containing 5.25 g of granules; 1 vial per cardboard box with 1 plastic syringe of 100 mL graduated in 2.0 mL increments, 2 plastic dosing devices of 5 mL graduated in 0.2 mL increments, 2 plastic dosing devices of 10 mL graduated in 0.5 mL increments, and 1 adapter, together with instructions for medical use.

Prescription status.

Prescription only.

Manufacturer.

Bayer AG.

Address.

Kaiser-Wilhelm-Allee, 51368 Leverkusen, Germany.