Rombidux

CHARACTERISTICS OF THE MEDICINAL PRODUCT

1. NAME OF THE MEDICINAL PRODUCT

Rombidux, 10 mg, film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 10 mg of rivaroxaban.
Excipient with known effect
Each film-coated tablet contains 53.57 mg of lactose monohydrate, see section 4.4.
Full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet)
Pink, round, biconvex film-coated tablets with "R" engraved on one side and "10" on the other side.

4. CLINICAL PARTICULARS

4.1 Therapeutic Indications

Prevention of venous thromboembolic disease (VTE) in adult patients after elective hip or knee replacement surgery.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of recurrent DVT and PE in adults (see section 4.4 Patients with hemodynamic instability due to pulmonary embolism).

4.2 Posology and Method of Administration

Posology
Prevention of venous thromboembolic disease (VTE) in adult patients after elective hip or knee replacement surgery
Elective hip or knee replacement surgery
The recommended dose is 10 mg rivaroxaban taken orally once daily. The initial dose should be taken 6 to 10 hours after surgery, provided that hemostasis has been established.
The duration of treatment depends on the individual risk of venous thromboembolism, which is influenced by the type of orthopedic surgery.

• In patients undergoing major hip surgery, treatment should be continued for 5 weeks.
• In patients undergoing major knee surgery, treatment should be continued for 2 weeks.

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If a dose is missed, the patient should take Rombidux as soon as possible and continue with the next dose as scheduled.
Treatment of DVT, PE, and prevention of recurrent DVT and PE
The recommended dose for the initial treatment of acute DVT or PE is 15 mg twice daily for the first 3 weeks, followed by 20 mg once daily for continued treatment and prevention of recurrent DVT and PE.
Short-term treatment (at least 3 months) should be considered for patients with DVT or PE caused by transient risk factors (e.g., recent major surgery or trauma). Longer treatment durations should be considered for patients with unprovoked DVT or PE, or with recurrent DVT or PE.
If extended prevention of recurrent DVT and PE is required (at least 6 months after the acute DVT or PE event), the recommended dose is 10 mg once daily. For patients at high risk of recurrence, such as those with complicated comorbidities or recurrent DVT or PE during extended prevention with Rombidux 10 mg once daily, consideration should be given to continuing Rombidux 20 mg once daily.
Treatment duration and dose should be individualized after careful assessment of the benefit of treatment against the risk of bleeding (see section 4.4).

If a dose is missed during the twice-daily treatment phase (Day 1-21), the patient should take Rombidux as soon as possible to ensure that the daily dose of 30 mg is maintained. It is possible to take two 15 mg tablets at the same time. The next day, the patient should continue with the regular twice-daily dosing regimen.
If a dose is missed during the once-daily treatment phase, the patient should take Rombidux as soon as possible and continue with the next dose as scheduled. The dose should not be doubled to make up for a missed dose on the same day.
Switching from vitamin K antagonists (VKAs) to Rombidux
For patients being treated for DVT, PE, and prevention of recurrence, discontinue VKA treatment and start Rombidux when the INR is ≤2.5.
When switching patients from VKA to Rombidux, International Normalized Ratio (INR) values will be falsely elevated after the intake of Rombidux. INR is not a suitable test to measure the anticoagulant activity of Rombidux and should not be used (see section 4.5).
Switching from Rombidux to vitamin K antagonists (VKAs)
There is a potential for inadequate anticoagulation during the transition from Rombidux to VKA. During any switch, close monitoring is required to ensure adequate anticoagulation. It should be noted that Rombidux may increase INR.
Patients switching from Rombidux to VKA should be given VKA concurrently, until INR ≥2.0. For the first two days of the transition period, standard initial VKA dosing should be used, followed by VKA dosing as per INR testing. If patients are being treated with both Rombidux and VKA, INR should not be tested earlier than 24 hours after the last dose, but prior to the next dose of Rombidux. After discontinuation of Rombidux, reliable INR results can be obtained at least 24 hours after the last dose (see sections 4.5 and 5.2).
Switching from parenteral anticoagulants to Rombidux
For patients currently receiving a parenteral anticoagulant, discontinue the parenteral anticoagulant and start Rombidux 0 to 2 hours before the next scheduled administration of the parenteral anticoagulant (e.g., low molecular weight heparin) or at the time of discontinuation of a continuously administered parenteral anticoagulant (e.g., intravenous unfractionated heparin).
Switching from Rombidux to parenteral anticoagulants
The first dose of the parenteral anticoagulant should be given at the time the next dose of Rombidux would have been taken.
Special populations
Renal impairment
Limited clinical data are available in patients with severe renal impairment (creatinine clearance 15-29 ml/min). Rivaroxaban systemic exposure is significantly increased in these patients. Therefore, caution should be exercised when using Rombidux in this patient population. Rombidux is not recommended in patients with creatinine clearance <15 ml min (see sections 4.4 and 5.2).< p>

• In the prevention of venous thromboembolic disease (VTE) in adult patients after elective hip or knee replacement surgery, no dose adjustment is required for patients with mild (creatinine clearance 50-80 ml/min) or moderate (creatinine clearance 30-49 ml/min) renal impairment (see section 5.2).
• In the treatment of DVT, PE, and prevention of recurrent DVT and PE, no dose adjustment is required for patients with mild (creatinine clearance 50-80 ml/min) renal impairment (see section 5.2).

Patient with moderate (creatinine clearance 30-49 ml/min) or severe (creatinine clearance 15-29 ml/min) renal impairment: should be treated with 15 mg twice daily for the first 3 weeks. Thereafter, when the recommended dose is 20 mg once daily, a dose reduction to 15 mg once daily should be considered only if the patient's risk of bleeding outweighs the risk of recurrent DVT and PE. The recommendation for the 15 mg dose is based on PK modeling and has not been studied in this clinical setting (see sections 4.4, 5.1, and 5.2).
If the recommended dose is 10 mg once daily, no dose adjustment is required.
Hepatic impairment
Rombidux is contraindicated in patients with liver disease associated with coagulopathy and clinically relevant bleeding risk, including cirrhosis Child-Pugh B and C (see sections 4.3 and 5.2).
Elderly
No dose adjustment is required (see section 5.2).
Body weight
No dose adjustment is required (see section 5.2).
Gender
No dose adjustment is required (see section 5.2).
Paediatric population
The safety and efficacy of Rombidux in children aged 0 to 18 years have not been established. No data are available. Rombidux is not recommended for use in children below 18 years of age.
Method of administration
Oral use
Rombidux 10 mg film-coated tablets can be taken with or without food (see sections 4.5 and 5.2).
For patients who cannot swallow whole tablets, Rombidux tablets may be crushed and mixed with water or apple sauce immediately before use, and administered orally. Crushed Rombidux tablets may also be given through a gastric tube after confirmation of the correct tube position.

• (See section 5.2).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Active clinically significant bleeding.
Conditions or diseases that increase the risk of significant bleeding, including active or recent gastrointestinal ulcer, malignant neoplasms with high risk of bleeding, recent intracranial or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial hemorrhage, known or suspected oesophageal varices, arteriovenous malformations, or major vascular anomalies.
Concomitant treatment with other anticoagulants, e.g., unfractionated heparin, low molecular weight heparin (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, apixaban, etc.) except when switching between anticoagulants (see section 4.2) or when unfractionated heparin is given at doses necessary to maintain a patent central venous or arterial catheter (see section 4.5).
Liver disease associated with coagulopathy and clinically relevant bleeding risk, including cirrhosis Child-Pugh B and C (see section 5.2).
Pregnancy and breast-feeding (see section 4.6).

4.4 Special Warnings and Precautions for Use

During treatment, clinical monitoring is recommended, as per standard anticoagulant practice.
Bleeding risk
As with other anticoagulants, patients taking Rombidux are to be closely monitored for signs of bleeding. Caution should be exercised in patients with an increased risk of bleeding.
In clinical trials, during long-term treatment with rivaroxaban compared to VKA treatment, more bleeding events from mucocutaneous sites (e.g., nosebleeds, gingival, gastrointestinal, genitourinary, including abnormal vaginal or menstrual bleeding) and anaemia were observed. Therefore, in addition to adequate clinical surveillance, laboratory testing of haemoglobin/hematocrit may be useful in detecting occult bleeding and evaluating the severity of any overt bleeding event, if deemed appropriate.
Patient groups at increased risk of bleeding include:
Patients with renal impairment (see section 4.2 and 5.2).
Patients with hepatic impairment (see section 4.3 and 5.2).
Patients with platelet count <90,000/mm3 (<90 x 10^9 l) (see section 5.2).
Patients with diabetics (see section 5.2).
Patients with uncontrolled hypertension (see section 5.2).
Patients with vascular retinopathy (see section 5.2).
Patients with bronchiectasis or history of pulmonary bleeding (see section 5.2).

• congenital or acquired coagulation disorders,
• uncontrolled severe hypertension,
• other gastrointestinal diseases without current peptic ulceration that may increase the risk of bleeding (e.g., inflammatory bowel disease, oesophagitis, gastritis, and gastroesophageal reflux disease),
• vascular retinopathy,
• bronchiectasis or history of pulmonary bleeding.

Patients with prosthetic heart valves
Rivaroxaban should not be used for the prevention of thromboembolic events in patients with prosthetic heart valves, including patients who have undergone valve replacement or repair, due to a lack of data.
Surgical procedure for hip fracture
No interventional clinical trials have been conducted to evaluate the efficacy and safety of rivaroxaban in patients with hip fracture surgery.
Haemodynamically unstable patients with pulmonary embolism or patients who require thrombolytic therapy or pulmonary embolectomy
Rombidux is not recommended as an alternative to unfractionated heparin in patients with pulmonary embolism who are haemodynamically unstable or may receive thrombolytic therapy or pulmonary embolectomy, as the safety and efficacy of Rombidux have not been established in these clinical settings.
Spinal or epidural anesthesia/analgesia
When neuraxial anesthesia (spinal or epidural) or spinal puncture is performed, patients treated with anticoagulants for thromboprophylaxis are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis. The risk of these complications may be increased by the use of post-operative indwelling epidural catheters or the concomitant use of drugs affecting hemostasis. The risk may also be increased by traumatic or repeated epidural or spinal puncture.
Patients should be frequently monitored for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, bowel or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment are necessary.
Before performing any spinal or epidural procedure, the physician should consider the potential benefit versus the risk in anticoagulated patients, and the timing of the procedure in relation to the last dose of Rombidux.
To minimize the risk of bleeding, the timing of the procedure should be based on the pharmacokinetic profile of rivaroxaban.
Removal of an epidural catheter should occur at least 18 hours after the last administration of rivaroxaban.
The next dose of Rombidux should be administered at least 6 hours after the removal of the catheter.
In case of traumatic puncture, administration of Rombidux should be delayed for 24 hours.

4.5 Interaction with Other Medicinal Products and Other Forms of Interaction

CYP3A4 and P-glycoprotein inhibitors
Concomitant administration of rivaroxaban with ketoconazole (400 mg once daily) or ritonavir (600 mg twice daily) resulted in a 2.6-fold and 2.5-fold increase in mean rivaroxaban AUC, respectively, and a 1.7-fold and 1.6-fold increase in mean rivaroxaban Cmax, respectively, with significant enhancement of pharmacodynamic effects, which may increase the risk of bleeding. Therefore, concomitant use of Rombidux with systemic azole antifungals (such as ketoconazole, itraconazole, voriconazole, and posaconazole) and HIV protease inhibitors (such as ritonavir) is contraindicated (see section 4.4).
Substances that are strong inhibitors of only one of the rivaroxaban elimination pathways, either CYP3A4 or P-glycoprotein, are expected to increase rivaroxaban plasma concentrations to a lesser extent than those that potently inhibit both pathways. For example, clarithromycin (500 mg twice daily), considered a strong inhibitor of CYP3A4 and a moderate inhibitor of P-glycoprotein, resulted in a 1.5-fold increase in mean rivaroxaban AUC and a 1.4-fold increase in mean rivaroxaban Cmax. The interaction with clarithromycin is likely to be clinically relevant for a minority of patients and is not expected to be clinically significant for the majority of patients, but may be potentially clinically relevant for patients at high risk of bleeding (see section 4.4 for patients with renal impairment).
Administration of erythromycin (500 mg three times a day), which is a moderate inhibitor of both CYP3A4 and P-glycoprotein, resulted in a 1.3-fold increase in mean rivaroxaban AUC and Cmax. The interaction with erythromycin is likely to be clinically relevant for a minority of patients and is not expected to be clinically significant for the majority of patients, but may be potentially clinically relevant for patients at high risk of bleeding.
Anticoagulants
After concomitant administration of enoxaparin (40 mg single dose) and rivaroxaban (10 mg single dose), additive effects on anti-factor Xa activity were observed, without any significant effect on clotting times (PT, APTT). Enoxaparin did not affect the pharmacokinetics of rivaroxaban.
Caution should be exercised when patients are treated concomitantly with other anticoagulants (see sections 4.3 and 4.4).
Non-steroidal anti-inflammatory drugs (NSAIDs)/antiplatelet agents
After concomitant administration of rivaroxaban (15 mg) and naproxen (500 mg), no clinically significant interactions were observed regarding bleeding risk or pharmacodynamic effects.
After concomitant administration of rivaroxaban and acetylsalicylic acid (500 mg), no clinically significant interactions were observed regarding bleeding risk or pharmacodynamic effects.
Administration of clopidogrel (300 mg loading dose, followed by 75 mg maintenance dose) did not result in a pharmacokinetic interaction with rivaroxaban (15 mg), but in a subgroup of patients, a significant increase in bleeding time was observed, which was not correlated with platelet aggregation, P-selectin, or GPIIb/IIIa receptor levels.
Caution should be exercised when patients are treated concomitantly with NSAIDs (including acetylsalicylic acid) or antiplatelet agents, as these may increase the risk of bleeding (see section 4.4).
SSRI/SNRI
As with other anticoagulants, the risk of bleeding may be increased when rivaroxaban is co-administered with SSRIs or SNRIs due to their reported effect on platelets (see section 4.4).
Warfarin
Switching from warfarin (INR 2.0-3.0) to rivaroxaban (20 mg) or from rivaroxaban (20 mg) to warfarin (INR 2.0-3.0) resulted in a non-additive increase in prothrombin time/INR (Neoplastin) (values up to 12 have been reported), whereas the effect on APTT, anti-factor Xa activity, and endogenous thrombin potential was additive.
If it is necessary to assess the anticoagulant activity of rivaroxaban during the transition period, it is recommended to use anti-factor Xa activity, PiCT, and HepTest, as these tests are not affected by warfarin. Four days after the last warfarin dose, all tests (including PT, APTT, anti-factor Xa activity, and ETP) reflected only the effect of rivaroxaban.
If it is necessary to assess the anticoagulant activity of warfarin during the transition period, it is recommended to use INR at Cmax of rivaroxaban (24 hours after the previous intake of rivaroxaban), as rivaroxaban has a minimal effect on this test at this time point.
No pharmacokinetic interaction was observed between warfarin and rivaroxaban.
CYP3A4 inducers
Concomitant use of rivaroxaban with strong CYP3A4 inducers, such as rifampicin, phenytoin, carbamazepine, phenobarbital, or St. John's Wort (Hypericum perforatum), may lead to reduced rivaroxaban plasma concentrations, which may decrease its anticoagulant effects. Therefore, concomitant use of strong CYP3A4 inducers should be avoided unless the patient is closely monitored for signs and symptoms of thrombosis (see section 4.4).
Other concomitant therapies
No pharmacokinetic or pharmacodynamic interactions were observed when rivaroxaban was administered concomitantly with midazolam (a CYP3A4 substrate), digoxin (a P-glycoprotein substrate), atorvastatin (a CYP3A4 and P-glycoprotein substrate), or omeprazole (a proton pump inhibitor) (see section 4.4).
Rivaroxaban neither inhibits nor induces any of the major CYP isoforms, including CYP3A4.
No clinically significant interactions were observed when rivaroxaban was administered concomitantly with food (see section 4.2).
Laboratory tests
Results of laboratory tests for coagulation (e.g., PT, APTT, HepTest) are expected to change as a function of rivaroxaban's mechanism of action (see section 5.1).

4.6 Fertility, Pregnancy and Lactation

Pregnancy
The use of Rombidux is contraindicated in pregnancy (see section 4.3).
Women of childbearing potential should avoid becoming pregnant during treatment with rivaroxaban.
Breast-feeding
The use of Rombidux is contraindicated during breast-feeding (see section 4.3).
A decision should be made whether to discontinue breast-feeding or to discontinue/abstain from Rombidux therapy.
Fertility
No specific fertility studies with rivaroxaban have been conducted in humans. Studies in rats did not show any effect on fertility (see section 5.3).

4.7 Effects on Ability to Drive and Use Machines

Rivaroxaban has a minor influence on the ability to drive and use machines. Adverse reactions such as dizziness (frequency: common) and syncope (frequency: uncommon) have been reported (see section 4.8). Patients experiencing these adverse reactions should not drive or use machines.

4.8 Undesirable Effects

Summary of the safety profile
The safety of rivaroxaban has been evaluated in 13 phase III studies, including 53,103 patients who received rivaroxaban (see Table 1).

Table 1: Number of patients treated, total daily dose, and maximum treatment duration in phase III studies

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*Patients who received at least one dose of rivaroxaban
The most frequently reported adverse reactions in patients receiving rivaroxaban were bleeding events (see Table 2) (see also section 4.4 and "Description of selected adverse reactions" below).
The most common bleeding events were epistaxis (4.5%) and gastrointestinal tract bleeding (3.8%).

Table 2: Percentage of bleeding events and anaemia in patients treated with rivaroxaban in completed phase III studies

*In all rivaroxaban studies, all bleeding events were collected, reported, and adjudicated.
**In the COMPASS study, a low rate of anaemia was reported, as a selective approach to collecting adverse events was used.
Tabular list of adverse reactions
The frequency of adverse reactions reported with rivaroxaban is presented in the following table according to system organ class (MedDRA) and frequency category.
Frequencies are defined as:
very common (≥1/10)
common (≥1/100 to <1>uncommon (≥1/1,000 to <1>rare (≥1/10,000 to <1>very rare (<1>frequency not known (cannot be estimated from the available data).

4.9 Overdose

Rare cases of overdose up to 600 mg have been reported without bleeding complications or other adverse reactions. Due to limited absorption, a plateau effect is expected without further increase in mean plasma exposure after supratherapeutic doses of 50 mg of rivaroxaban or higher.
A specific reversal agent (andexanet alfa) is available, which reverses the pharmacodynamic effects of rivaroxaban (see the Summary of Product Characteristics for andexanet alfa).
In the event of rivaroxaban overdose, activated charcoal may be considered to reduce absorption.
Procedure in case of bleeding
In the event of a bleeding complication in a patient taking rivaroxaban, the next dose of rivaroxaban should be delayed or treatment should be discontinued, depending on the clinical situation. The half-life of rivaroxaban is approximately 5 to 13 hours (see section 5.2).
The procedure should be tailored to the severity and location of the bleeding. If necessary, appropriate symptomatic treatment may be used, such as mechanical compression (e.g., in severe nosebleeds), surgical hemostasis with bleeding control procedures, fluid administration, and hemodynamic support, transfusion of blood products (red blood cells or fresh frozen plasma, depending on associated anemia or coagulopathy) or platelets.
If bleeding cannot be controlled with the above measures, the administration of a specific Xa inhibitor reversal agent (andexanet alfa), which reverses the pharmacodynamic effects of rivaroxaban, or a specific procoagulant reversal agent, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (aPCC), or recombinant factor VIIa (rFVIIa), should be considered. Currently, there is very limited clinical experience with the use of these medicinal products in patients taking rivaroxaban. This recommendation is based on limited non-clinical data. Depending on the degree of bleeding reduction, the re-administration of recombinant factor VIIa and gradual increase in its dose should be considered. In the event of severe bleeding, consultation with a hematologist should be considered, depending on local availability (see section 5.1).
Protamine sulfate and vitamin K should not affect the anticoagulant effect of rivaroxaban. There is limited experience with tranexamic acid and no experience with aminocaproic acid and aprotinin in patients taking rivaroxaban.
There is no scientific basis and experience to support the benefits of using the general hemostatic agent desmopressin in patients taking rivaroxaban.
Due to the high degree of binding to plasma proteins, it is not expected that rivaroxaban will be subject to dialysis.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: anticoagulants, direct factor Xa inhibitors, ATC code: B01AF01
Mechanism of action
Rivaroxaban is a highly selective, direct inhibitor of factor Xa, which is orally bioavailable. Inhibition of factor Xa activity disrupts both the intrinsic and extrinsic coagulation pathways, inhibiting both thrombin formation and clot formation. Rivaroxaban does not inhibit thrombin (activated factor II) and does not affect platelet aggregation.
Pharmacodynamic effects
In humans, the inhibition of factor Xa activity was dose-dependent. Rivaroxaban affects the prothrombin time (PT) in a dose-dependent manner. For the determination using the Neoplastin reagent, there is a close correlation with the concentration of the active substance in plasma (r value of 0.98). When using other reagents, the results may vary. The PT value should be reported in seconds, as the International Normalized Ratio (INR) is calibrated and validated only for coumarins, and therefore cannot be used for other anticoagulants.
In patients undergoing major orthopedic surgery, for the 5th/95th percentile of the PT result (Neoplastin), during the period from 2 to 4 hours after taking the rivaroxaban tablet (i.e., at the time of its maximum effect), values ranging from 13 to 25 seconds (baseline values before surgery 12 to 15 seconds) were obtained.
In a pharmacological clinical trial evaluating the reversal of rivaroxaban's pharmacodynamics in healthy adult subjects (n=22), the effects of single doses (50 mg/kg) of two different types of PCC were evaluated - a three-factor PCC (factors II, IX, and X) and a four-factor (factors II, VII, IX, and X). The three-factor PCC shortened the mean PT (Neoplastin) values by approximately 1.0 second over 30 minutes, compared to the four-factor PCC, which caused a shortening of PT by approximately 3.5 seconds. In comparison to the four-factor PCC, the three-factor PCC showed a stronger and faster effect in reversing changes in endogenous thrombin generation (see section 4.9).
The activated partial thromboplastin time (APTT) and HepTest are also prolonged in a dose-dependent manner; however, it is not recommended to use these tests to evaluate the pharmacodynamic effect of rivaroxaban. There is no need to monitor coagulation parameters during rivaroxaban treatment in everyday clinical practice. However, in case of a clinical indication, the concentration of rivaroxaban can be measured by a calibrated quantitative anti-Xa test (see section 5.2)
Patient with a high risk of antiphospholipid syndrome with three positive results for marker antibodies
In an open, randomized, multicenter study with blinded outcome assessment, rivaroxaban was compared to warfarin in patients with thrombosis and confirmed antiphospholipid syndrome at high risk of thrombotic events (positive results in 3 tests for antiphospholipid antibodies: lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2 glycoprotein I antibodies). The study was terminated prematurely after the inclusion of 120 patients due to an increased number of events in patients receiving rivaroxaban. The observation period lasted an average of 569 days. 59 patients were randomly assigned to the group receiving 20 mg of rivaroxaban (15 mg to patients with creatinine clearance (CrCl) <50 ml min) and 61 patients to the warfarin group (inr 2.0-3.0). thrombotic events occurred in 12% of randomly assigned rivaroxaban (4 non-fatal strokes 3 myocardial infarctions). group, no were reported. serious bleeding 4 (7%) 2 (3%) group.
Clinical efficacy and safety
Prophylaxis of venous thromboembolic disease (VTE) in adult patients after elective hip or knee replacement surgery
The clinical trial program for rivaroxaban was designed to demonstrate its efficacy in preventing venous thromboembolic disease (VTE), i.e., proximal and distal deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients undergoing major orthopedic surgery of the lower limbs. In controlled, randomized, double-blind Phase III clinical trials of the RECORD program, over 9,500 patients were enrolled (7,050 underwent total hip replacement surgery, and 2,531 underwent total knee replacement surgery).
Rivaroxaban, which was started at least 6 hours after surgery at a dose of 10 mg once daily, was compared to enoxaparin, which was started 12 hours before surgery at a dose of 40 mg once daily.
In all three Phase III clinical trials (see Table 4), rivaroxaban significantly reduced the incidence of all VTE events (any identified thrombographic or symptomatic DVT, non-fatal PE, and VTE-related death) and severe VTE (proximal DVT, non-fatal PE, and VTE-related death), i.e., predefined primary and main secondary endpoints for efficacy assessment. Additionally, in all three clinical trials, the incidence of symptomatic VTE (symptomatic DVT, non-fatal PE, and VTE-related death) was lower in patients treated with rivaroxaban compared to those treated with enoxaparin.
For the primary safety endpoint, i.e., major bleeding, a similar incidence was observed in the group of patients receiving 10 mg of rivaroxaban compared to patients receiving 40 mg of enoxaparin.

Table 4: Efficacy and safety results from Phase III clinical trials

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A pooled analysis of the Phase III clinical trials confirmed the data obtained from individual trials regarding the reduction in the incidence of all VTE events, severe VTE, and symptomatic VTE after administration of 10 mg of rivaroxaban once daily compared to 40 mg of enoxaparin once daily.
In addition to the Phase III program, a post-marketing, non-interventional, open, cohort study (XAMOS) was conducted in a group of 17,413 patients undergoing major orthopedic surgery of the hip or knee. The study aimed to compare rivaroxaban with other pharmacological anticoagulant prophylaxis (standard treatment) in everyday practice. Symptomatic VTE occurred in 57 (0.6%) patients receiving rivaroxaban (n=8,778) and in 88 (1.0%) patients receiving standard treatment (n=8,635; HR 0.63; 95% CI 0.43–0.91); safety population. Major bleeding occurred in 35 (0.4%) and 29 (0.3%) patients receiving rivaroxaban and standard treatment, respectively (HR 1.10; 95% CI 0.67–1.80). The results of the non-interventional study were consistent with the results of the key randomized trials.
Treatment of DVT and PE and prevention of recurrent DVT and PE
The clinical trial program for rivaroxaban was designed to demonstrate its efficacy in the initial and continued treatment of acute DVT and PE and for the prevention of recurrence.
Over 12,800 patients were enrolled in four randomized, controlled Phase III clinical trials (Einstein DVT, Einstein PE, Einstein Extension, and Einstein Choice) and a preliminary pooled analysis was performed for Einstein DVT and Einstein PE. The total duration of treatment in all studies was up to 21 months.
In the Einstein DVT study, 3,449 patients with acute DVT were enrolled to evaluate the treatment of DVT and prevention of recurrent DVT and PE (patients with symptomatic PE were excluded from this study). The duration of treatment was 3, 6, or 12 months, depending on the clinical assessment of the investigator.
In the initial 3-week treatment of acute DVT, 15 mg of rivaroxaban was administered twice daily. Subsequently, 20 mg of rivaroxaban was administered once daily.
In the Einstein PE study, 4,832 patients with acute PE were enrolled to evaluate the treatment of PE and prevention of recurrent DVT and PE. The duration of treatment was 3, 6, or 12 months, depending on the clinical assessment of the investigator.
In the initial treatment of acute PE, 15 mg of rivaroxaban was administered twice daily for three weeks. Subsequently, 20 mg of rivaroxaban was administered once daily.
In both the Einstein DVT and Einstein PE studies, the comparative treatment regimen consisted of enoxaparin administered for at least 5 days in combination with a vitamin K antagonist, with an INR of 2.0-3.0.
The Einstein Extension study enrolled 1,197 patients with DVT or PE to evaluate the prevention of recurrent DVT and PE. The duration of treatment was an additional 6 or 12 months in patients who had completed 6 or 12 months of DVT treatment, depending on the clinical assessment of the investigator. Rivaroxaban 20 mg once daily was compared to placebo.
The Einstein DVT, PE, and Extension studies used the same pre-defined primary and secondary efficacy endpoints. The primary efficacy endpoint was symptomatic recurrent VTE, defined as a composite of recurrent DVT or PE, fatal or non-fatal. The secondary efficacy endpoint was defined as a composite of recurrent VTE, non-fatal PE, and all-cause mortality.
In the Einstein DVT study (see Table 5), rivaroxaban was shown to be equivalent to enoxaparin/VKA for the primary efficacy endpoint (p <0.0001 (equivalence test); hazard ratio: 0.680 (0.443-1.042), p = 0.076 (superiority test)). The pre-defined net clinical benefit (primary efficacy endpoint plus major bleeding) was reported with a hazard ratio of 0.67 ((95% CI = 0.47-0.95), nominal p-value = 0.027) in favor of rivaroxaban. INR values were within the therapeutic range for a mean of 60.3% of the time for a mean treatment duration of 189 days and for 55.4%, 60.1%, and 62.8% of the time for groups with planned treatment durations of 3, 6, and 12 months, respectively. In the enoxaparin/antagonist vitamin K group, when centers were divided into tertiles, there was no clear correlation between the mean level of TTR control (percentage of time INR was within the therapeutic range 2.0-3.0) and the incidence of recurrent VTE (p=0.932 for interaction). Within the tertile of centers with the highest control, the hazard ratio for rivaroxaban compared to warfarin was 0.69 (95% CI: 0.35-1.35).
The rates of the primary safety endpoint (major or clinically relevant non-major bleeding) as well as the secondary safety endpoint (major bleeding) were similar for both treatment groups.

Table 5: Efficacy and safety results from the Phase III Einstein DVT study

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In the Einstein PE study (see Table 6), rivaroxaban was shown to be equivalent to enoxaparin/VKA for the primary efficacy endpoint (p=0.0026 (equivalence test); hazard ratio: 1.123 (0.749-1.684)). The pre-defined net clinical benefit (primary efficacy endpoint plus major bleeding) was reported with a hazard ratio of 0.849 ((95% CI: 0.633-1.139), nominal p-value=0.275). INR values were within the therapeutic range for a mean of 63% of the time for a mean treatment duration of 215 days and for 57%, 62%, and 65% of the time for groups with planned treatment durations of 3, 6, and 12 months, respectively. In the enoxaparin/antagonist vitamin K group, when centers were divided into tertiles, there was no clear correlation between the mean level of TTR control (percentage of time INR was within the therapeutic range 2-3) and the incidence of recurrent VTE (p=0.082 for interaction). Within the tertile of centers with the highest control, the hazard ratio for rivaroxaban compared to warfarin was 0.642 (95% CI: 0.277-1.484). The rates of the primary safety endpoint (major or clinically relevant non-major bleeding) were slightly lower in the rivaroxaban group (10.3% (249/2412)) than in the enoxaparin/VKA group (11.4% (274/2405)). The rates of the secondary safety endpoint (major bleeding) were lower in the rivaroxaban group (1.1% (26/2412)) than in the enoxaparin/VKA group (2.2% (52/2405)) with a hazard ratio of 0.493 (95% CI: 0.308-0.789).

Table 6: Efficacy and safety results from the Phase III Einstein PE study

21

A preliminary pooled analysis of the Einstein DVT and Einstein PE studies was performed (see Table 7).

Table 7: Pooled analysis of efficacy and safety results from the Phase III Einstein DVT and Einstein PE studies

Table 7: Pooled analysis of efficacy and safety results from the Phase III Einstein DVT and PE studies

The pre-defined net clinical benefit of the pooled analysis (primary efficacy endpoint plus major bleeding) was reported with a hazard ratio of 0.771 ((95% CI: 0.614-0.967), nominal p-value=0.0244).
In the Einstein Extension study (see Table 8), rivaroxaban was superior to placebo for both primary and secondary efficacy endpoints. For the primary safety endpoint (major bleeding), a numerically non-significant higher incidence was observed in patients treated with rivaroxaban 20 mg once daily compared to placebo. The secondary safety endpoint (major or clinically relevant non-major bleeding) showed higher incidence rates for patients treated with rivaroxaban 20 mg once daily compared to placebo.

Table 8: Efficacy and safety results from the Phase III Einstein Extension study

22

In the Einstein Choice study (see Table 9), both rivaroxaban 20 mg and 10 mg were superior to aspirin 100 mg once daily for the primary endpoint. The result for the primary safety endpoint (major bleeding) was similar for patients treated with rivaroxaban 20 mg and 10 mg once daily compared to patients treated with aspirin 100 mg.

5.2 Pharmacokinetic Properties

Absorption Rivaroxaban is rapidly absorbed with maximum plasma concentrations (Cmax) reached within 2 to 4 hours after tablet intake.

24

Absorption is almost complete, and oral bioavailability is high (80-100%) for the 2.5 mg and 10 mg tablet, regardless of food intake. Taking rivaroxaban with food does not affect AUC or Cmax. Rivaroxaban 2.5 mg and 10 mg can be taken with or without food. The pharmacokinetics of rivaroxaban are linear up to doses of about 15 mg once daily. At higher doses, absorption is limited by decreased solubility and reduced absorption rate, which is more pronounced under fasting conditions. The variability of rivaroxaban pharmacokinetics is moderate, with an inter-individual variability (CV%) ranging from 30% to 40%, except on the day of surgery and the following day, when variability in exposure values is high (70%).

Rivaroxaban absorption is dependent on the site of its release in the gastrointestinal tract. A 29% and 56% decrease in AUC and Cmax, respectively, was reported when rivaroxaban granules were released in the proximal small intestine. Exposure is further reduced when rivaroxaban is released in the distal small intestine or ascending colon. Therefore, rivaroxaban should not be administered distally to the stomach, as this may lead to reduced absorption and exposure to rivaroxaban.

Systemic exposure (AUC and Cmax) was comparable for 20 mg rivaroxaban administered orally as a crushed tablet mixed in applesauce or as an aqueous suspension administered through a nasogastric tube with a subsequent liquid meal compared to the whole tablet. Given the predictable, dose-proportional pharmacokinetic profile of rivaroxaban, the bioavailability results from this study are likely applicable to lower doses of rivaroxaban.

Distribution In humans, rivaroxaban is highly bound to plasma proteins, approximately 92% to 95%, mainly to albumin. The volume of distribution at steady state is moderate, with a volume of distribution at steady state (Vss) of about 50 liters.

Metabolism and Elimination About two-thirds of the administered dose of rivaroxaban is metabolized, with half excreted via the kidneys and the other half via the feces. The remaining one-third of the administered dose of rivaroxaban, in the form of unchanged compound, is excreted via the kidneys with urine, mainly through active renal secretion.

Rivaroxaban is metabolized by CYP3A4, CYP2J2, and non-CYP-dependent pathways. The main mechanisms of biotransformation are oxidative degradation of the morpholinone ring and hydrolysis of amide bonds. According to in vitro studies, rivaroxaban is a substrate for the transport proteins P-gp (P-glycoprotein) and Bcrp (breast cancer resistance protein).

Rivaroxaban in its unchanged form is the most important compound present in human plasma; neither a major nor an active circulating metabolite exists. The systemic clearance is about 10 L/h, so rivaroxaban can be considered a low-clearance substance. After intravenous administration of a dose of 1 mg, the terminal half-life in the elimination phase is about 4.5 hours. After oral administration, elimination is limited by the rate of absorption. The elimination of rivaroxaban from plasma occurs with a terminal half-life of 5 to 9 hours in young individuals and a terminal half-life of 11 to 13 hours in elderly individuals.

Special Populations

Sex

25

No clinically significant differences in pharmacokinetic and pharmacodynamic properties were observed between male and female patients.

Elderly Patients

In elderly patients, higher plasma concentrations of the product were observed compared to younger individuals, with mean AUC values about 1.5-fold higher, mainly due to decreased (apparent) total and renal clearance. No dose adjustment is necessary.

Body Weight Differences

For extreme body weights (<50 kg or>120 kg), only a small effect on rivaroxaban plasma concentrations was observed (less than 25%). No dose adjustment is necessary.

Ethnic Differences

No clinically significant differences in pharmacokinetic and pharmacodynamic properties of rivaroxaban were observed between patients of Caucasian, African American, Latino, Japanese, or Chinese origin.

Renal Impairment

In patients with liver cirrhosis with mild impairment of liver function (Child-Pugh Class A), only minor changes in rivaroxaban pharmacokinetics were observed (mean 1.2-fold increase in rivaroxaban AUC), which were almost comparable to those in the corresponding healthy control group.

In patients with liver cirrhosis and moderate impairment of liver function (Child-Pugh Class B), a significant 2.3-fold increase in mean rivaroxaban AUC was observed compared to healthy volunteers. The AUC for unbound rivaroxaban was 2.6-fold higher. In patients with this condition, as well as those with moderate renal impairment, decreased renal excretion of rivaroxaban was observed. There are no data available for patients with severe liver impairment.

Compared to healthy volunteers, inhibition of factor Xa activity was 2.6-fold stronger in patients with moderate liver impairment; similarly, PT was 2.1-fold longer. Patients with moderate liver impairment were more sensitive to the effects of rivaroxaban, as evidenced by a steeper slope of the PK/PD (pharmacokinetic/pharmacodynamic) curve between concentration and PT.

The use of rivaroxaban is contraindicated in patients with liver disease associated with coagulopathy and a risk of bleeding of clinical significance, including patients with liver cirrhosis Child-Pugh Class B and C (see section 4.3).

Renal Impairment

An increase in exposure to rivaroxaban was correlated with the degree of renal impairment, as determined by creatinine clearance measurements. In patients with mild (creatinine clearance 50-80 mL/min), moderate (creatinine clearance 30-49 mL/min), and severe (creatinine clearance 15-29 mL/min) renal impairment, rivaroxaban plasma concentrations (AUC) were increased by 1.4-, 1.5-, and 1.6-fold, respectively. Corresponding to these increases, pharmacodynamic effects were more pronounced. In patients with mild, moderate, and severe renal impairment, overall inhibition of factor Xa activity was 1.5-, 1.9-, and 2-fold stronger, respectively, compared to healthy volunteers; similarly, PT was 1.3-, 2.2-, and 2.4-fold longer, respectively. There are no data available for patients with creatinine clearance <15 ml min.< p>

Given the high degree of plasma protein binding of rivaroxaban, it is not expected to be dialyzable. Rivaroxaban is not recommended in patients with creatinine clearance <15 ml min. caution should be exercised when administering rivaroxaban to patients with creatinine clearance 15-29 min (see section 4.4).< p>

Pharmacokinetic Data in Patients

In patients receiving rivaroxaban 10 mg once daily for the prevention of venous thromboembolism, the geometric mean concentrations (90% prediction interval) 2 to 4 hours and approximately 24 hours after intake (roughly representing peak and trough concentrations within the dosing interval) were 101 (7-273) μg/L and 14 (4-51) μg/L, respectively.

Pharmacokinetic/Pharmacodynamic Relationships

The pharmacokinetic/pharmacodynamic relationship (PK/PD) between rivaroxaban plasma concentration and several pharmacodynamic endpoints (inhibition of factor Xa, PT, APTT, HepTest) was evaluated over a wide range of doses (5-30 mg administered twice daily). The relationship between rivaroxaban concentration and factor Xa activity was best described by an Emax model. For PT, a linear cutoff model was usually better. Depending on the reagent used to determine PT, significant differences in the slope of the curve were observed.

After administration of the Neoplastin reagent, the baseline PT was 13 seconds, and the slope of the curve was approximately 3 to 4 seconds/(100 μg/L). The results of the PK/PD analysis from phase II and III studies were consistent with those obtained in healthy volunteer studies.

The baseline values of factor Xa activity and PT varied in patients in relation to surgical procedures, resulting in differences in the slope of the concentration-PT relationship between the day after surgery and steady state.

Children and Adolescents

The safety and efficacy of rivaroxaban have not been established in children under 18 years of age.

5.3 Preclinical Safety Data

Non-clinical data reveal no special hazard for humans based on conventional studies of pharmacological safety, single-dose toxicity, phototoxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development.

Effects observed in repeated-dose toxicity studies were mainly due to the exaggerated pharmacodynamic activity of rivaroxaban. In rats, at exposure levels of clinical relevance, increased IgG and IgA concentrations in plasma were observed. No effects on fertility were observed in male and female rats. In animal studies, reproductive toxicity was observed, which was related to the pharmacological mechanism of action of rivaroxaban (e.g., bleeding complications). At exposure levels of clinical relevance, developmental toxicity was observed (embryo-foetal toxicity, including post-implantation loss, increased resorptions, and dead foetuses, delayed or accelerated ossification, multiple light-coloured spots in the liver, and increased incidence of common skeletal anomalies), as well as changes in the placenta. In pre- and post-natal studies in rats, using doses toxic to the dams, decreased offspring viability was observed.

6. Pharmaceutical Particulars

6.1 List of Excipients

Sodium lauryl sulfate Lactose monohydrate Hypromellose 2910 Microcrystalline cellulose Sodium croscarmellose 27

Magnesium stearate Coating: Hypromellose Titanium dioxide (E 171) Macrogol 4000 Iron oxide red (E 172)

6.2 Incompatibilities

None.

6.3 Shelf Life

2 years

6.4 Special Precautions for Storage

Store in a temperature not exceeding 25°C.

6.5 Nature and Contents of Container

PVC/PVDC/Aluminium foil blisters in a cardboard box. Packaging: 30 (3x10) film-coated tablets.

6.6 Special Precautions for Disposal

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

7. Marketing Authorisation Holder

Responsible for Batch Release

Merck Sp. z o.o. Al. Jerozolimskie 142B 02-305 Warsaw

8. Marketing Authorisation Number

Marketing Authorisation Number

9. Date of First Authorisation

Renewal of the Authorisation

Date of first authorisation:

10. Date of Revision of the Text

Revision of the Summary of Product Characteristics

28

Information to be Included in the Outer Packaging

Carton

1. Name of the Medicinal Product

Rombidux, 10 mg, film-coated tablets Rivaroxabanum

2. Qualitative and Quantitative Composition

Each film-coated tablet contains 10 mg of rivaroxaban.

3. List of Excipients

The medicine contains lactose monohydrate and sodium. For further information, see the package leaflet.

4. Pharmaceutical Form and Contents of the Container

30 film-coated tablets Code

5. Method and Route of Administration

Oral use Read the package leaflet before use.

6. Warning About Storage of the Medicinal Product

Out of Sight and Reach of Children

Keep the medicine out of sight and reach of children.

7. Other Special Warnings

8. Expiry Date

Expiry date

9. Special Storage Conditions

Store below 25°C.

10. Special Precautions for Disposal of Unused Medicinal Product or Waste Materials

If Appropriate

11. Name and Address of the Marketing Authorisation Holder

Marketing Authorisation Holder:

Merck Sp. z o.o. Al. Jerozolimskie 142B 02-305 Warsaw

12. Marketing Authorisation Number

Marketing Authorisation Number

13. Batch Number

Batch Number (Lot)

14. General Category of the Medicinal Product

Rp - Prescription-only medicine.

15. Instructions for Use

16. Braille Code

Rombidux 10 mg

17. Unique Identifier - 2D Code

Includes a 2D code that is a carrier of a unique identifier.

18. Unique Identifier - Human Readable Data

PC SN NN 30

Minimum Information to be Included on the Blister Packs or Foil Strips

Blister

1. Name of the Medicinal Product

Rombidux, 10 mg, film-coated tablets Rivaroxabanum

2. Name of the Marketing Authorisation Holder

Merck Sp. z o.o.

3. Expiry Date

EXP

4. Batch Number

Lot

5. Other

31

Patient Card

Patient Card

Merck (Logo) Rombidux Rivaroxabanum

Rombidux 10 mg (box to mark the prescribed dose)

Rombidux 15 mg (box to mark the prescribed dose)

Rombidux 20 mg (box to mark the prescribed dose)

• Always carry this card with you
• Show this card to your doctor or dentist before any treatmentThe patient may report any side effects. Information on reporting side effects can be found in the package leaflet for the patient.

What You Need to Know About Rombidux

• Rombidux reduces the tendency to form blood clots, thereby preventing the formation of dangerous blood clots.
• Rombidux should be taken exactly as directed by your doctor. To prevent blood clots, never miss a dose of Rombidux.
• Do not stop taking Rombidux without consulting your doctor, as the risk of blood clots may increase.
• Before starting Rombidux, tell your doctor about all the medicines you are currently taking or have recently taken, as well as any medicines you plan to take.
• Before any surgery or invasive procedure, inform your doctor that you are taking Rombidux.

When to Consult Your Doctor

During treatment with an anticoagulant like Rombidux, it is essential to be aware of the possible side effects. Bleeding is the most common side effect. Do not start taking Rombidux without consulting your doctor if you know you are at increased risk of bleeding. Inform your doctor immediately if you experience any signs of bleeding, such as:

• pain,
• swelling or discomfort,
• headache, dizziness, or weakness,
• excessive bruising, nosebleeds, or bleeding gums, or prolonged bleeding from cuts, which do not stop for a long time,
• heavy or prolonged menstrual bleeding or vaginal bleeding,
• blood in urine, which may give a pink or brown color to the urine, or red or black color to the stool,
• coughing up blood or vomiting blood or coffee ground-like material.

How to Take Rombidux

• To prevent blood clots in the veins after hip or knee replacement surgery: the recommended dose is one Rombidux 10 mg tablet once daily.
• For the treatment of blood clots in the veins of the legs, blood clots in the lungs, and to prevent new blood clots: after at least 6 months of treatment for blood clots, the recommended dose is one Rombidux 10 mg tablet once daily or one Rombidux 20 mg tablet once daily. Your doctor has prescribed Rombidux 10 mg once daily for you.

The tablet should be swallowed, preferably with water. Rombidux can be taken with or without food. If you have difficulty swallowing the whole tablet, you should talk to your doctor about other ways to take Rombidux. The tablet can be crushed and mixed with water or applesauce, just before taking it. If necessary, your doctor may administer the crushed Rombidux tablet through a nasogastric tube.

When to Take Rombidux

Take one tablet each day until your doctor decides to stop the treatment. It is best to take the tablet at the same time every day, as it will be easier to remember. Your doctor will decide how long you should continue the treatment. To prevent blood clots in the veins after hip or knee replacement surgery: take the first tablet 6 to 10 hours after surgery. In patients after major hip replacement surgery, treatment usually lasts for 5 weeks. In patients after major knee replacement surgery, treatment usually lasts for 2 weeks.

Accidental Overdose

If you have taken more Rombidux than you should, contact your doctor immediately. Taking too much Rombidux may increase the risk of bleeding.

Missed Dose

If you forget to take a dose, take it as soon as you remember. Take the next tablet the next day, and then take your tablets as usual, once a day. Do not take a double dose to make up for a forgotten tablet.

Stopping Rombidux

Do not stop taking Rombidux without consulting your doctor, as this may increase the risk of blood clots. If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible Side Effects

Like all medicines, Rombidux can cause side effects, although not everybody gets them. As with other medicines of this type (anticoagulants), Rombidux may cause bleeding, which can be life-threatening. Bleeding may not always be obvious or visible.

Possible Side Effects That May Be a Sign of Bleeding

Tell your doctor immediatelyif you experience any of the following side effects:

• prolonged or excessive bleeding,
• unusual weakness, tiredness, paleness, dizziness, headache, or unexplained swelling, which may be signs of bleeding. Your doctor may decide to monitor you closely or change your treatment.

Possible Side Effects That May Be a Sign of a Skin Reaction

Tell your doctor immediatelyif you experience any of the following skin reactions:

• widespread, severe skin rash, blistering, or peeling of the skin (Stevens-Johnson syndrome, toxic epidermal necrolysis). The frequency of these side effects is very rare (less than 1 in 10,000 patients);
• drug reaction that causes a rash, fever, inflammation of internal organs, blood abnormalities, and systemic symptoms (DRESS syndrome). The frequency of these side effects is very rare (less than 1 in 10,000 patients).

Possible Side Effects That May Be a Sign of a Severe Allergic Reaction

Tell your doctor immediatelyif you experience any of the following side effects:

• swelling of the face, lips, tongue, or throat; difficulty swallowing; hives; and difficulty breathing; sudden drop in blood pressure. The frequency of these side effects is very rare (anaphylactic reactions, including anaphylactic shock, may occur in less than 1 in 10,000 patients) and uncommon (angioedema and allergic oedema may occur in 1 in 100 patients).

General List of Possible Side Effects

Common(may affect up to 1 in 10 people)

• reduction in red blood cell count, which may make you pale and feel tired or weak;
• bleeding from the stomach or intestine, bleeding from the urinary tract (including blood in the urine) and heavy or prolonged menstrual bleeding, nosebleeds, and bleeding from the gums;
• bleeding into the eye (including bleeding into the retina);
• bleeding into tissues or body cavities (haematoma, bruising);
• coughing up blood while coughing;
• bleeding into the skin or bleeding under the skin;
• bleeding after an operation;
• oozing of blood or fluid from the wound after an operation;
• swelling of the limbs;
• limb pain;
• kidney problems (which can be seen in tests done by your doctor);
• fever;
• stomach pain, indigestion, nausea, or vomiting, constipation, diarrhoea;
• low blood pressure (which may cause dizziness or fainting);
• general weakness and lack of energy (weakness, tiredness), headache, dizziness;
• rash, itching;
• increased activity of some liver enzymes, which can be seen in blood tests. 38

Uncommon(may affect up to 1 in 100 people)

• bleeding into the brain or spinal cord;
• bleeding into a joint, which may cause pain and swelling;
• low platelet count (thrombocytopenia);
• allergic reactions, including allergic skin reactions;
• liver problems (which can be seen in tests done by your doctor);
• blood tests may show increased levels of bilirubin, some liver or pancreatic enzymes, or platelet count;
• fainting;
• malaise;
• rapid heartbeat;
• dry mouth;
• hives.

Rare(may affect up to 1 in 1,000 people)

• bleeding into a muscle;
• cholestasis (bile flow obstruction), liver inflammation, including liver cell damage;
• jaundice (yellowing of the skin and eyes);
• localised swelling;
• collection of blood (haematoma) in the groin as a complication of cardiac catheterisation, when a catheter is inserted into an artery in the leg (pseudoaneurysm).

Frequency Not Known(frequency cannot be estimated from the available data)

• kidney failure after severe bleeding;
• increased pressure in the muscles of the arms and legs, which can cause pain, swelling, changes in sensation, numbness, or paralysis (compartment syndrome due to bleeding).

5. Package Leaflet: Information for the User

Rombidux, 10 mg, film-coated tablets

Rivaroxabanum

Read the package leaflet carefully before taking this medicine.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you, do not pass it on to others. It may harm them, even if their symptoms are the same as yours.
• If you experience any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the Package Leaflet

• 1. What Rombidux is and what it is used for
• 2. Important information before taking Rombidux
• 3. How to take Rombidux
• 4. Possible side effects
• 5. How to store Rombidux
• 6. Contents of the pack and other information

1. What Rombidux is and what it is used for

Rombidux contains the active substance rivaroxaban and is used in adults to:

• prevent the formation of blood clots in the veins after hip or knee replacement surgery. Your doctor has prescribed this medicine because the risk of blood clots is increased after surgery;
• treat blood clots in the veins of the legs and blood clots in the lungs, and to prevent new blood clots from forming.

Rombidux belongs to a group of medicines called anticoagulants. Its action is to block the factor Xa involved in blood clotting and thus reduce the tendency to form blood clots.

2. Important information before taking Rombidux

When Not to Take Rombidux:

• -if you are allergic to rivaroxaban or any of the other ingredients of this medicine (listed in section 6),
• if you have bleeding that is not under control,
• if you have a disease or condition that increases the risk of major bleeding (e.g., stomach or intestinal ulcer, recent or upcoming surgery of the brain or eyes, or recent intracranial haemorrhage),
• if you are taking other medicines that prevent blood clotting (e.g., warfarin, dabigatran, apixaban, or heparin), except when switching from one anticoagulant to another or when heparin is given to maintain the patency of a venous or arterial catheter,
• if you have liver disease that increases the risk of bleeding,
• if you are pregnant or breastfeeding.

Do not take Rombiduxif any of the above applies to you. Tell your doctorbefore taking Rombidux if you have:

Warnings and Precautions

Before taking Rombidux, tell your doctor or pharmacist if:

When to Exercise Caution When Taking Rombidux:

• you have an increased risk of bleeding, such as:
• moderate or severe kidney disease, as kidney function may affect the amount of medicine in your body;
• if you are taking other medicines that prevent blood clotting (e.g., warfarin, dabigatran, apixaban, or heparin), during the transition from one anticoagulant to another or when heparin is given to maintain the patency of a venous or arterial catheter (see "Rombidux with other medicines");
• bleeding disorders;
• very high blood pressure that does not respond to treatment;
• stomach or intestinal diseases that may cause bleeding, such as gastritis or oesophagitis;
• eye diseases that may cause bleeding, such as diabetic retinopathy;
• lung disease, such as bronchiectasis or previous bleeding from the lungs;
• you have a prosthetic heart valve;
• you have uncontrolled high blood pressure or are planning to undergo a procedure to remove a blood clot from the lungs.

Tell your doctorbefore taking Rombidux if any of the above applies to you. Your doctor will decide whether to prescribe Rombidux and whether you need to be closely monitored.

If You Need to Have Surgery

• It is very important to take Rombidux at the exact time specified by your doctor before or after surgery, as directed by your doctor.
• If you are to undergo spinal or epidural anaesthesia, or a spinal puncture:
• it is very important to take Rombidux at the exact time specified by your doctor,
• due to the need for caution, you should immediately inform your doctor if, after the anaesthesia, you experience: numbness or weakness of the legs, problems with the bowels or bladder.

Children and Adolescents

Rombidux is not recommended for children under 18 years of age. There is limited data on the use of Rombidux in children and adolescents.

Rombidux with Other Medicines

Tell your doctor or pharmacist about all the medicines you are taking, have recently taken, or might take, including those obtained without a prescription.

If You Are Taking

• certain antifungal medicines (e.g., fluconazole, itraconazole, voriconazole, posaconazole), unless they are used only on the skin,
• ketokonazole tablets (used to treat Cushing's syndrome, a condition where the body produces too much cortisol),
• certain antibiotics (e.g., clarithromycin, erythromycin),
• certain antiviral medicines used to treat HIV or AIDS (e.g., ritonavir),
• other medicines that prevent blood clotting (e.g., enoxaparin, clopidogrel, or vitamin K antagonists, such as warfarin or acenocoumarol),
• anti-inflammatory or pain-relieving medicines (e.g., naproxen or aspirin),
• dronedarone, a medicine used to treat irregular heart rhythms,
• certain medicines used to treat depression (selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs)).

Tell your doctorbefore taking Rombidux if any of the above applies to you, as the effect of Rombidux may be increased. Your doctor will decide whether to prescribe Rombidux and whether you need to be closely monitored.

If You Are Taking

• certain medicines used to treat epilepsy (e.g., phenytoin, carbamazepine, phenobarbital),
• St. John's Wort (Hypericum perforatum), a herbal medicine used to treat depression,
• rifampicin, an antibiotic.

Tell your doctorbefore taking Rombidux if any of the above applies to you, as the effect of Rombidux may be reduced. Your doctor will decide whether to prescribe Rombidux and whether you need to be closely monitored.

Pregnancy and Breastfeeding

Do not take Rombidux if you are pregnant or breastfeeding. If there is a risk that you may become pregnant, you should use effective contraception during treatment with Rombidux. If you become pregnant while taking this medicine, you should inform your doctor immediately, who will decide on your treatment.

Driving and Using Machines

Rombidux may cause dizziness (common side effect) or fainting (uncommon side effect) (see section 4 "Possible side effects"). Patients who experience these side effects should not drive or operate machinery.

Rombidux Contains Lactose Monohydrate and Sodium

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine. The medicine contains less than 1 mmol sodium (23 mg) per tablet, which is essentially "sodium-free".

3. How to Take Rombidux

Take this medicine exactly as your doctor has told you. If you are not sure, ask your doctor or pharmacist.

How Many Tablets to Take

• To prevent blood clots in the veins after hip or knee replacement surgery: the recommended dose is one Rombidux 10 mg tablet once daily.
• For the treatment of blood clots in the veins of the legs, blood clots in the lungs, and to prevent new blood clots: after at least 6 months of treatment for blood clots, the recommended dose is one Rombidux 10 mg tablet once daily or one Rombidux 20 mg tablet once daily. Your doctor has prescribed Rombidux 10 mg once daily for you.

Swallow the tablet with water, preferably with water. Rombidux can be taken with or without food. If you have difficulty swallowing the whole tablet, you should talk to your doctor about other ways to take Rombidux. The tablet can be crushed and mixed with water or applesauce, just before taking it. If necessary, your doctor may administer the crushed Rombidux tablet through a nasogastric tube.

When to Take Rombidux

Take one tablet each day until your doctor decides to stop the treatment. It is best to take the tablet at the same time every day, as it will be easier to remember. Your doctor will decide how long you should continue the treatment. To prevent blood clots in the veins after hip or knee replacement surgery: take the first tablet 6 to 10 hours after surgery. In patients after major hip replacement surgery, treatment usually lasts for 5 weeks. In patients after major knee replacement surgery, treatment usually lasts for 2 weeks.

Accidental Overdose

If you have taken more Rombidux than you should, contact your doctor immediately. Taking too much Rombidux may increase the risk of bleeding.

Missed Dose

If you forget to take a dose, take it as soon as you remember. Take the next tablet the next day, and then take your tablets as usual, once a day. Do not take a double dose to make up for a forgotten tablet.

Stopping Rombidux

Do not stop taking Rombidux without consulting your doctor, as this may increase the risk of blood clots. If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible Side Effects

Like all medicines, Rombidux can cause side effects, although not everybody gets them. As with other medicines of this type (anticoagulants), Rombidux may cause bleeding, which can be life-threatening. Bleeding may not always be obvious or visible.

Possible Side Effects That May Be a Sign of Bleeding

Tell your doctor immediatelyif you experience any of the following side effects:

• prolonged or excessive bleeding,
• unusual weakness, tiredness, paleness, dizziness, headache, or unexplained swelling, which may be signs of bleeding. Your doctor may decide to monitor you closely or change your treatment.

Possible Side Effects That May Be a Sign of a Skin Reaction

Tell your doctor immediatelyif you experience any of the following skin reactions:

• widespread, severe skin rash, blistering, or peeling of the skin (Stevens-Johnson syndrome, toxic epidermal necrolysis). The frequency of these side effects is very rare (less than 1 in 10,000 patients);
• drug reaction that causes a rash, fever, inflammation of internal organs, blood abnormalities, and systemic symptoms (DRESS syndrome). The frequency of these side effects is very rare (less than 1 in 10,000 patients).

Possible Side Effects That May Be a Sign of a Severe Allergic Reaction

Tell your doctor immediatelyif you experience any of the following side effects:

• swelling of the face, lips, tongue, or throat; difficulty swallowing; hives; and difficulty breathing; sudden drop in blood pressure. The frequency of these side effects is very rare (anaphylactic reactions, including anaphylactic shock, may occur in less than 1 in 10,000 patients) and uncommon (angioedema and allergic oedema may occur in 1 in 100 patients).

General List of Possible Side Effects

Common(may affect up to 1 in 10 people)

• reduction in red blood cell count, which may make you pale and feel tired or weak;
• bleeding from the stomach or intestine, bleeding from the urinary tract (including blood in the urine) and heavy or prolonged menstrual bleeding, nosebleeds, and bleeding from the gums;
• bleeding into the eye (including bleeding into the retina);
• bleeding into tissues or body cavities (haematoma, bruising);
• coughing up blood while coughing;
• bleeding into the skin or bleeding under the skin;
• bleeding after an operation;
• oozing of blood or fluid from the wound after an operation;
• swelling of the limbs;
• limb pain;
• kidney problems (which can be seen in tests done by your doctor);
• fever;
• stomach pain, indigestion, nausea, or vomiting, constipation, diarrhoea;
• low blood pressure (which may cause dizziness or fainting);
• general weakness and lack of energy (weakness, tiredness), headache, dizziness;
• rash, itching;
• increased activity of some liver enzymes, which can be seen in blood tests. 38

Uncommon(may affect up to 1 in 100 people)

• bleeding into the brain or spinal cord;
• bleeding into a joint, which may cause pain and swelling;
• low platelet count (thrombocytopenia);
• allergic reactions, including allergic skin reactions;
• liver problems (which can be seen in tests done by your doctor);
• blood tests may show increased levels of bilirubin, some liver or pancreatic enzymes, or platelet count;
• fainting;
• malaise;
• rapid heartbeat;
• dry mouth;
• hives.

Rare(may affect up to 1 in 1,000 people)

• bleeding into a muscle;
• cholestasis (bile flow obstruction), liver inflammation, including liver cell damage;
• jaundice (yellowing of the skin and eyes);
• localised swelling;
• collection of blood (haematoma) in the groin as a complication of cardiac catheterisation, when a catheter is inserted into an artery in the leg (pseudoaneurysm).

Frequency Not Known(frequency cannot be estimated from the available data)

• kidney failure after severe bleeding;
• increased pressure in the muscles of the arms and legs, which can cause pain, swelling, changes in sensation, numbness, or paralysis (compartment syndrome due to bleeding).

5. How to store Rombidux

The medicinal product should be stored out of sight and reach of children. Do not use this medicinal product after the expiry date stated on the blister or carton after: "EXP"/"Expiry Date (EXP)". The expiry date refers to the last day of the month stated. Store in a temperature below 25°C. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Package contents and other information

What Rombidux contains

• The active substance of the medicinal product is rivaroxaban. One film-coated tablet contains 10 mg of rivaroxaban.
• The other ingredients are: tablet core: sodium lauryl sulfate, lactose monohydrate, hypromellose 2910, microcrystalline cellulose, sodium croscarmellose, magnesium stearate; coating: hypromellose, titanium dioxide (E 171), macrogol 4000, iron oxide red (E 172).

What Rombidux looks like and contents of the pack

Light pink, round, biconvex film-coated tablets with "R" embossed on one side and "10" on the other side. PVC/PVCD/Aluminum blisters in a carton box containing 30 (3x10) film-coated tablets. Not all pack sizes may be marketed.

Marketing authorization holder

Merck Sp. z o.o., Al. Jerozolimskie 142B, 02-305 Warsaw, Poland

Importer

Merck Healthcare KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany

This medicinal product is authorized in the Member States of the European Economic Area under the following names:

Rombidux: Greece, Poland, Portugal, Romania, Hungary, Slovakia

Date of last revision of the leaflet:

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