Rombidux

CHARACTERISTICS OF THE MEDICINAL PRODUCT

1. NAME OF THE MEDICINAL PRODUCT

Rombidux, 20 mg, film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 20 mg of rivaroxaban.
Excipient with known effect
Each film-coated tablet contains 107.14 mg of lactose monohydrate, see section 4.4.
Full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet)
White, round, biconvex film-coated tablets with "R" engraved on one side and "20" on the other side.

4. CLINICAL PARTICULARS

4.1 Therapeutic Indications

Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors, such as congestive heart failure, hypertension, age ≥75 years, diabetes, stroke or transient ischaemic attack in history.
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 haemodynamically unstable PE).

4.2 Posology and Method of Administration

Posology
Prevention of stroke and systemic embolism
The recommended dose is 20 mg once daily, which is also the maximum recommended dose.
Rivaroxaban treatment should be continued long-term provided that the benefit of prevention of stroke and systemic embolism outweighs the risk of bleeding (see section 4.4).
In case of a missed dose, the patient should take Rombidux as soon as possible and continue with the once daily dosing regimen the next day. A double dose should not be taken to make up for a missed dose.
Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE
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The recommended dose for the initial treatment of acute DVT or PE is 15 mg twice daily for the first three 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 (i.e. recent major surgery or trauma). Longer treatment duration should be considered for patients with unprovoked DVT or PE, or with recurrent DVT or PE in history.
If extended prevention of recurrent DVT and PE is required (at least 6 months after completion of treatment of DVT or PE), the recommended dose is 10 mg once daily. In patients at high risk of recurrence of DVT or PE, such as patients with complicated comorbidities or with recurrent DVT or PE during extended prevention with Rombidux 10 mg once daily, consideration should be given to continuing Rombidux 20 mg once daily.
The duration and dose of treatment should be individualised based on a careful assessment of the benefit of treatment to the risk of bleeding (see section 4.4).

In case of a missed dose during the treatment phase with a dosing regimen of 15 mg twice daily (day 1-21), the patient should take Rombidux as soon as possible to ensure intake of 30 mg of Rombidux per day. In such cases, it is possible to take two 15 mg tablets simultaneously. The next day, the patient should continue with the regular prescribed dosing regimen of 15 mg twice daily.
In case of a missed dose during the treatment phase with a once daily dosing regimen, the patient should take Rombidux as soon as possible and continue with the once daily dosing regimen the next day. A double dose should not be taken on the same day to make up for a missed dose.
Switching from vitamin K antagonists (VKAs) to Rombidux
Rombidux
For patients being treated for prevention of stroke and systemic embolism, discontinue VKA treatment and start Rombidux when the INR is ≤3.0.
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, 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 therefore 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 to an alternative anticoagulant, continuous adequate anticoagulation should be ensured. It should be noted that Rombidux may increase INR.
Patients converting from Rombidux to VKAs should have VKAs started concurrently with the last dose of Rombidux and INR should be measured at least 24 hours after the last dose of Rombidux but prior to the next dose of VKA. Once INR is ≥2.0, the VKA can be continued according to standard care and Rombidux can be discontinued. After discontinuing Rombidux, INR assays may be reliably used to measure the effects of VKA.
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 patient 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 these patients. Rombidux is not recommended in patients with creatinine clearance <15 ml min (see sections 4.4 and 5.2).
For patients with moderate (creatinine clearance 30-49 ml/min) or severe (creatinine clearance 15-29 ml/min) renal impairment, the following dose recommendations apply:

• for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation, the recommended dose is 15 mg once daily (see section 5.2);
• for the treatment of DVT, PE and prevention of recurrent DVT and PE: patients 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 in patients at high risk of bleeding and in patients with DVT or PE in whom the risk of recurrent DVT or PE is low (see sections 4.4, 5.1 and 5.2).

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For patients with mild renal impairment (creatinine clearance 50-80 ml/min), no dose adjustment is required (see section 5.2).
If the recommended dose is 10 mg once daily, no dose adjustment is required.
Hepatic impairment
Rombidux is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including cirrhotic patients with 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 from 0 to 18 years have not been established. No data are available. Rombidux is not recommended in children under 18 years of age.
Patients undergoing cardioversion
Rombidux may be initiated or continued in patients who may require cardioversion.
In patients not previously treated with anticoagulants, anticoagulation with Rombidux should be started at least 4 hours before cardioversion to allow adequate anticoagulation to be achieved. In all patients, confirmation should be sought before cardioversion that the patient has taken Rombidux as prescribed. When deciding on the duration of anticoagulation, guidelines for anticoagulation in patients undergoing cardioversion should be taken into consideration.
Patients with non-valvular atrial fibrillation undergoing transoesophageal echocardiogram (TEE) guided cardioversion
There is limited experience with reduced dose of 15 mg Rombidux once daily (or 10 mg Rombidux once daily in patients with moderate renal impairment [creatinine clearance 30-49 ml/min]) in combination with a P2Y12 inhibitor for up to 12 months, in patients with non-valvular atrial fibrillation undergoing transoesophageal echocardiogram (TEE) guided cardioversion (see sections 4.4 and 5.1).
Method of administration
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Oral administration
Rombidux 15 mg or 20 mg film-coated tablets should be taken with food (see section 5.2).
For patients who cannot swallow whole tablets, Rombidux tablet may be crushed and mixed with water or apple sauce immediately before use and administered orally. After administration of crushed Rombidux 15 mg or 20 mg film-coated tablets, the patient should be instructed to eat immediately.
The crushed tablet may also be administered via a nasogastric tube after confirmation of the correct placement of the tube. The crushed tablet should be administered in a small amount of water via a nasogastric tube and then flushed with water (see section 5.2).

After administration of crushed Rombidux 15 mg or 20 mg film-coated tablets, the patient should be instructed to eat immediately (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 associated with increased risk of haemorrhage, such as:
- Active or recent gastrointestinal ulceration
- Presence of malignant neoplasms at high risk of bleeding
- Recent brain or spinal injury
- Recent brain, spinal or ophthalmic surgery
- Recent intracranial haemorrhage
- Known or suspected oesophageal varices
- Arteriovenous malformations
- Vascular aneurysms or major vascular ectasia
Concomitant treatment with any other anticoagulants, e.g. unfractionated heparin, low molecular weight heparin (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, apixaban, dabigatran etexilate, 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).
Hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including cirrhotic patients with 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 with Rombidux, patients should be instructed to report immediately to their physician in case of any signs or symptoms of bleeding or anaemia, such as a decrease in haemoglobin, treatment for bleeding, blood transfusions, or the need for surgical intervention due to bleeding.
Bleeding risk
As with other anticoagulants, patients taking Rombidux are to be carefully monitored for signs of bleeding. In case of increased bleeding risk, caution should be exercised.
In clinical studies, rivaroxaban was associated with an increased risk of bleeding compared to VKA treatment. The most common bleeding complications were epistaxis, gastrointestinal and genitourinary bleeding.
Patients with the following conditions are at increased risk of bleeding and should be carefully monitored:
- Congenital or acquired bleeding disorders
- Uncontrolled severe arterial hypertension
- Other gastrointestinal diseases without current bleeding, which may increase the risk of bleeding (e.g. inflammatory bowel disease, oesophagitis, gastritis and gastro-oesophageal reflux disease)
- Diabetic retinopathy
- Bronchiectasis or history of pulmonary bleeding

• congenital or acquired bleeding disorders,
• uncontrolled severe arterial hypertension,
• other gastrointestinal diseases without current bleeding, which may increase the risk of bleeding (e.g. inflammatory bowel disease, oesophagitis, gastritis and gastro-oesophageal reflux disease),
• diabetic retinopathy,
• bronchiectasis or history of pulmonary bleeding.

Patients with prosthetic heart valves
Rivaroxaban has not been studied in patients with prosthetic heart valves, and therefore its use in these patients is not recommended due to a lack of data on the efficacy and safety of rivaroxaban in this population.
Patient with non-valvular atrial fibrillation undergoing percutaneous coronary intervention (PCI) with stent placement
There is limited clinical experience with the reduced dose of 15 mg Rombidux once daily (or 10 mg Rombidux once daily in patients with moderate renal impairment [creatinine clearance 30-49 ml/min]) in combination with a P2Y12 inhibitor for up to 12 months, in patients with non-valvular atrial fibrillation undergoing PCI with stent placement (see sections 4.2 and 5.1).
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 patient populations.
Spinal or epidural anaesthesia or puncture
When neuraxial anaesthesia (spinal or epidural) or spinal puncture is performed, patients treated with anticoagulants for prevention of thromboembolic complications are at risk of developing an epidural or spinal haematoma, which may result in long-term or permanent paralysis. The risk of these complications is increased by the use of indwelling epidural catheters or the concomitant use of drugs affecting haemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other anticoagulants (see section 4.5).
The risk may be further increased by a traumatic or repeated puncture. Patients should be frequently monitored for signs and symptoms of neurological impairment, such as numbness or weakness of the legs, or bowel or bladder dysfunction. If such signs or symptoms are observed, urgent diagnosis and treatment are required.
Before any neuraxial intervention is employed, the physician should consider the potential benefit versus risk in patients taking Rombidux for thromboprophylaxis.
There is no clinical experience with the use of 20 mg dose in these situations.
To reduce the potential risk of bleeding associated with the use of rivaroxaban in patients undergoing neuraxial anaesthesia or spinal puncture, it is recommended to consider the pharmacokinetic profile of rivaroxaban. The placement or removal of a spinal catheter should be performed when the anticoagulant effect of rivaroxaban is estimated to be low (see section 5.2).
The exact timing of when the anticoagulant effect is low enough to allow for safe removal of the catheter is not known, but based on the Rivaroxaban pharmacokinetic profile, it is estimated that the procedure should not be performed until at least 18 hours after the last administration of rivaroxaban in patients with normal renal function (creatinine clearance ≥80 ml/min), and at least 26 hours after the last administration of rivaroxaban in patients with moderate renal impairment (creatinine clearance 50-79 ml/min).
The next dose of rivaroxaban should not be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, administration of rivaroxaban should be delayed for 24 hours.

4.5 Interaction with Other Medicinal Products and Other Forms of Interaction

Inhibitors of CYP3A4 and P-gp
Concomitant administration of rivaroxaban with ketoconazole (400 mg once daily) or ritonavir (600 mg twice daily) led to a 2.6-fold or 2.5-fold increase in mean rivaroxaban AUC and a 1.7-fold or 1.6-fold increase in mean rivaroxaban C, 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) or HIV protease inhibitors (such as ritonavir) is not recommended (see section 4.4).
Substances that inhibit only one of the pathways of rivaroxaban elimination, either CYP3A4 or P-gp, are expected to increase rivaroxaban plasma concentrations to a lesser extent. For example, clarithromycin (500 mg twice daily), considered a strong inhibitor of CYP3A4 and a moderate inhibitor of P-gp, led to a 1.5-fold increase in mean rivaroxaban AUC and a 1.4-fold increase in mean rivaroxaban C. The interaction with clarithromycin is likely to be clinically relevant in a limited number of patients with high bleeding risk.
Concomitant use of erythromycin (500 mg three times a day), which is a moderate inhibitor of CYP3A4 and P-gp, led to a 1.3-fold increase in mean rivaroxaban AUC and C. The interaction with erythromycin is likely to be clinically relevant in a limited number of patients with high bleeding risk.
Anticoagulants
After concomitant administration of enoxaparin (40 mg single dose) and rivaroxaban (10 mg single dose), no clinically relevant pharmacokinetic or pharmacodynamic interactions were observed. Enoxaparin did not affect the pharmacokinetics of rivaroxaban.
Caution should be exercised when co-administering Rombidux 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 increase in bleeding time was observed. However, in some patients, additive effects on bleeding may occur.
After concomitant administration of rivaroxaban and acetylsalicylic acid (500 mg), no clinically significant interactions were observed in terms of pharmacokinetics or pharmacodynamics.
Concomitant 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 subset of patients, a significant increase in bleeding time was observed, which was not correlated with platelet aggregation, P-selectin expression or GPIIb/IIIa receptor inhibition.
Caution should be exercised when co-administering Rombidux with NSAIDs (including acetylsalicylic acid) or platelet inhibitors, as these concomitant medications may increase the risk of bleeding (see section 4.4).
SSRI/SNRI
As with other anticoagulants, the risk of bleeding may be increased when Rombidux is co-administered with SSRIs or SNRIs (see section 4.4).
Warfarin
Switching from VKA warfarin (INR 2.0-3.0) to rivaroxaban (20 mg) or from rivaroxaban (20 mg) to warfarin (INR 2.0-3.0) increased INR/PT (Neoplastin) more than additively (individual INR values up to 12 were observed), whereas effects on APTT, inhibition of Factor Xa and endogenous thrombin potential were additive.
If it is necessary to measure the anticoagulant effect of rivaroxaban during the transition period, it is recommended to use one of the following coagulation tests: anti-Factor Xa activity, PiCT or HepTest, as these tests are not affected by warfarin. On the fourth day after the last dose of warfarin, all these tests reflect only the effect of rivaroxaban.
If it is necessary to measure the anticoagulant effect of warfarin during the transition period, it is recommended to use INR (at C 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.
Inducers of CYP3A4
Concomitant use of rivaroxaban with strong CYP3A4 inducers (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital or St. John's Wort (Hypericum perforatum)) may decrease rivaroxaban plasma concentrations, which may decrease its anticoagulant effect. Therefore, concomitant use of strong CYP3A4 inducers is not recommended (unless the patient is closely monitored for signs and symptoms of thrombosis).
Other concomitant therapies
No clinically relevant pharmacokinetic or pharmacodynamic interactions were observed when rivaroxaban was co-administered with midazolam (a CYP3A4 substrate), digoxin (a P-gp substrate), atorvastatin (a CYP3A4 and P-gp substrate) or omeprazole (a CYP2C19 substrate and a proton pump inhibitor). Rivaroxaban neither inhibits nor induces any of the major CYP enzymes in humans, including CYP3A4.
Laboratory tests
Results of laboratory tests used to assess haemostasis (e.g. PT, APTT, HepTest) are expected to be affected by treatment with rivaroxaban (see section 5.1).

4.6 Fertility, Pregnancy and Lactation

Pregnancy
The use of Rombidux is not recommended during pregnancy. Animal studies have shown reproductive toxicity (see section 5.3).
Women of childbearing potential should avoid becoming pregnant during treatment with rivaroxaban.
Breast-feeding
The use of Rombidux is not recommended during breast-feeding. Animal studies have shown that rivaroxaban is excreted in milk. Therefore, Rombidux should not be used 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 studies with rivaroxaban in humans have been conducted to evaluate effects on fertility. In a fertility study in rats, no effect on male and female fertility was observed (see section 5.3).

4.7 Effects on Ability to Drive and Use Machines

Rivaroxaban has no or negligible 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, total daily dose and maximum treatment duration in phase III studies

* Patients who received at least one dose of rivaroxaban
The most common adverse reactions in patients receiving rivaroxaban were bleeding complications (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%).
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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 adverse event collection was employed.
Tabulated list of adverse reactions
The frequency of adverse reactions for rivaroxaban is based on the analysis of data from 53,103 patients in phase III studies and is presented in the following table according to system organ class (MedDRA) and frequency category.

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, the use of 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 cell concentrate or fresh frozen plasma, depending on the associated anemia or coagulopathy) or platelets.
If the above measures do not stop the bleeding, 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 that would confirm the benefits of using a general anti-hemorrhagic 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

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Therapeutic group: anticoagulants, direct Xa inhibitors, ATC code: B01AF01
Mechanism of action
Rivaroxaban is a highly selective, direct inhibitor of factor Xa, with high oral bioavailability. Inhibition of factor Xa activity interrupts both the intrinsic and extrinsic coagulation pathways, inhibiting both thrombin formation and clot formation. Rivaroxaban does not inhibit thrombin (activated factor II) and has not been shown to affect platelets.
Pharmacodynamic effects
In humans, the inhibition of factor Xa activity was dose-dependent. Rivaroxaban affects prothrombin time (PT) in a dose-dependent manner. For the Neoplastin reagent, there is a close correlation with the plasma concentration of the active substance (r value of 0.98). When using other reagents, the results may vary.
PT values should be reported in seconds, as the International Normalized Ratio (INR) is calibrated and validated only for coumarins, and therefore should not be used for other anticoagulants.
In patients receiving rivaroxaban for the treatment of DVT and PE and for the prevention of recurrent DVT and PE, for the 5/95th percentile of PT (Neoplastin) results, 2-4 hours after tablet intake (i.e., at the time of its maximum effect), 15 mg of rivaroxaban twice daily resulted in values from 17 to 32 seconds, and 20 mg of rivaroxaban once daily from 15 to 30 seconds. At the lowest point (8-16 hours after tablet intake), for the 5/95th percentile, 15 mg twice daily resulted in values from 14 to 24 seconds, and 20 mg once daily (18-30 hours after tablet intake) from 13 to 20 seconds.
In patients with non-valvular atrial fibrillation receiving rivaroxaban for the prevention of stroke and systemic embolism, for the 5/95th percentile of PT (Neoplastin) results, 1-4 hours after tablet intake (i.e., at the time of its maximum effect), 20 mg of rivaroxaban once daily resulted in values from 14 to 40 seconds, and in patients with moderate renal impairment treated with 15 mg once daily from 10 to 50 seconds. At the lowest point (16-36 hours after tablet intake), for the 5/95th percentile, in patients treated with 20 mg once daily, values from 12 to 26 seconds were obtained, and in patients with moderate renal impairment treated with 15 mg once daily from 12 to 26 seconds.
In a pharmacological clinical study on the reversal of rivaroxaban's pharmacodynamics in healthy adult subjects (n=22), the effect of single doses (50 IU/kg) of two different types of PCC - three-factor PCC (factors II, IX, and X) and four-factor (factors II, VII, IX, and X) - was evaluated. 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 resulted in a shortening of PT by approximately 3.5 seconds. In contrast 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).
Activated partial thromboplastin time (APTT) and HepTest are also prolonged in a dose-dependent manner; however, these tests are not recommended for assessing the pharmacodynamic effect of rivaroxaban. There is no need to monitor coagulation parameters during rivaroxaban treatment in everyday clinical practice. However, if clinically indicated, the rivaroxaban plasma concentration can be measured using a calibrated quantitative anti-Xa assay (see section 5.2)
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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 diagnosed antiphospholipid syndrome at high risk of thromboembolic 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 among 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). thromboembolic events occurred in 12% of randomly assigned rivaroxaban (4 ischemic strokes 3 myocardial infarctions). group, no were reported. serious bleeding 4 (7%) 2 (3%) group.
Clinical efficacy and safety
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation
The rivaroxaban clinical trial program was designed to demonstrate the efficacy of rivaroxaban for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation.
The main, double-blind, randomized study ROCKET AF included 14,264 patients who were assigned to receive 20 mg of rivaroxaban once daily (15 mg once daily in patients with creatinine clearance of 30-49 ml/min) or warfarin with a target INR of 2.5 (therapeutic range 2.0-3.0). The median duration of treatment was 19 months, and the overall treatment duration was up to 41 months.
34.9% of patients were treated with aspirin, and 11.4% were treated with class III antiarrhythmic drugs, including amiodarone.
Rivaroxaban was equivalent to warfarin in terms of the primary efficacy endpoint, a composite of stroke and systemic embolism. Analysis in the groups as randomized, rivaroxaban-treated patients had a stroke or systemic embolism rate of 1.71% per year (188 patients), and warfarin-treated patients had a rate of 2.16% per year (241 patients) (hazard ratio [HR] 0.79; 95% confidence interval [CI]: 0.66-0.96; p<0.001 for non-inferiority). Among all randomized patients analyzed as treated (ITT), the primary endpoint occurred in 269 rivaroxaban-treated patients (2.12% per year) and in 306 warfarin-treated patients (2.42% per year) (HR 0.88; 95% CI: 0.74-1.03; p<0.001 for non-inferiority; p=0.117 for superiority).
Results for secondary endpoints, tested hierarchically in the ITT analysis, are presented in Table 4.
INR values, among warfarin arm patients, were within the therapeutic range (2.0-3.0) for an average of 55% of the time on treatment (median 58%; interquartile range 43-71). When centers were divided into quartiles of equal size (p=0.74 for interaction) based on the level of TTR control (percentage of time INR is within the therapeutic range 2.0-3.0), the effect of rivaroxaban did not differ between quartiles. Within the quartile of centers with the highest control, the hazard ratio for rivaroxaban compared to warfarin was 0.74 (95% CI: 0.49-1.12).
The frequency of the primary safety endpoint (major or non-major clinically relevant bleeding) was similar in both treatment groups (see Table 5).

Table 4. Efficacy results from the Phase III ROCKET AF study

Table 5: Safety results from the Phase III ROCKET AF study

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Patient undergoing cardioversion
A prospective, randomized, open, multicenter, diagnostic study with blinded outcome assessment (X-VERT study) was conducted in 1,504 patients (previously receiving or not receiving oral anticoagulants) with non-valvular atrial fibrillation scheduled for cardioversion, to compare the efficacy of rivaroxaban with VKA in a dose-adjusted manner (randomization 2:1) for the prevention of cardiovascular events. Cardioversion strategies were based on the TEE result (1-5 days of pre-treatment) or conventional cardioversion (at least three weeks of pre-treatment). Events from the primary efficacy endpoint (any type of stroke, transient ischemic attack, systemic embolism, myocardial infarction, and cardiovascular death) occurred in 5 (0.5%) patients in the rivaroxaban group (n = 978) and in 5 (1.0%) patients in the VKA group (n = 492; relative risk 0.50; 95% CI 0.15-1.73; modified ITT population). Events from the primary safety endpoint (major bleeding) occurred in 6 (0.6%) and 4 (0.8%) patients in the rivaroxaban and VKA groups, respectively (relative risk 0.76; 95% CI 0.21-2.67; safety population). This diagnostic study demonstrated comparable efficacy and safety between the rivaroxaban and VKA groups in the context of cardioversion.
Patient with non-valvular atrial fibrillation undergoing PCI with stent placement
A randomized, open, multicenter study (PIONEER AF-PCI) was conducted in 2,124 patients with non-valvular atrial fibrillation undergoing PCI with stent placement for primary atherothrombotic disease, to compare the safety of two rivaroxaban treatment regimens and one VKA regimen. Patients were randomly assigned in a 1:1:1 ratio for 12 months of treatment. Patients with a history of stroke or TIA were excluded.
The first group received 15 mg of rivaroxaban once daily (10 mg once daily in patients with creatinine clearance of 30-49 ml/min) in combination with a P2Y12 inhibitor. The second group received 2.5 mg of rivaroxaban twice daily along with dual antiplatelet therapy (DAPT, e.g., clopidogrel 75 mg [or another P2Y12 inhibitor] in combination with low-dose aspirin [ASA]) for 1, 6, or 12 months, and then 15 mg of rivaroxaban once daily (or 10 mg in patients with creatinine clearance of 30-49 ml/min) in combination with low-dose ASA. The third group received a dose-adjusted VKA along with DAPT for 1, 6, or 12 months, and then a dose-adjusted VKA in combination with low-dose ASA.
The primary safety endpoint, clinically relevant bleeding events, occurred in 109 (15.7%), 117 (16.6%), and 167 (24.0%) patients in groups 1, 2, and 3, respectively (hazard ratio 0.59; 95% CI 0.47-0.76; p <0.001 and hazard ratio 0.63; 95% CI 0.50-0.80; p <0.001, respectively). The secondary endpoint (a composite of cardiovascular death, myocardial infarction, or stroke) occurred in 41 (5.9%), 36 (5.1%), and 36 (5.2%) patients in groups 1, 2, and 3, respectively. Each of the rivaroxaban treatment regimens showed a significant reduction in clinically relevant bleeding events compared to the VKA regimen in patients with non-valvular atrial fibrillation who underwent PCI with stent placement.
Treatment of DVT and PE and prevention of recurrent DVT and PE
The rivaroxaban clinical trial program was designed to demonstrate the efficacy of rivaroxaban for the initial and continued treatment of acute DVT and PE and for the prevention of recurrent DVT and PE.
Over 12,800 patients were studied in four randomized, controlled Phase III studies (Einstein DVT, Einstein PE, Einstein Extension, and Einstein Choice) and a prespecified pooled analysis of Einstein DVT and Einstein PE. The overall treatment duration in all studies was up to 21 months.
In the Einstein DVT study, 3,449 patients with acute DVT were studied for the treatment of DVT and prevention of recurrent DVT and PE (patients with symptomatic PE were excluded from this study). The treatment duration 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. Then, 20 mg of rivaroxaban was administered once daily.
In the Einstein PE study, 4,832 patients with acute PE were studied for the treatment of PE and prevention of recurrent DVT and PE. The treatment duration 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. Then, 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 VKA, until PT/INR values were within the therapeutic range (≥2.0). Treatment was continued with a VKA in a dose-adjusted manner to maintain PT/INR values within the therapeutic range of 2.0 to 3.0.
In the Einstein Extension study, 1,197 patients with DVT or PE were studied for the prevention of recurrent DVT and PE. The treatment duration was an additional 6 or 12 months in patients who had completed 6 or 12 months of treatment for DVT, 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 prespecified primary and secondary efficacy endpoints. The primary efficacy endpoint was symptomatic recurrent DVT or PE, defined as a composite of recurrent DVT or PE, fatal or non-fatal. The secondary efficacy endpoint was defined as a composite of recurrent DVT or PE, non-fatal PE, and all-cause mortality.
In the Einstein DVT study (see Table 6), rivaroxaban was shown to be equivalent to enoxaparin/VKA for the primary efficacy endpoint (p <0.0001 [test for equivalence]; hazard ratio: 0.680 [0.443-1.042], p = 0.076 [test for superiority]). The prespecified clinical net 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 an average of 60.3% of the time for the mean treatment duration, which was 189 days, and for 55.4%, 60.1%, and 62.8% of the time for the groups with planned treatment durations of 3, 6, and 12 months, respectively. In the enoxaparin/antagonist group, when centers were divided into tertiles of equal size, there was no clear correlation between the mean level of TTR control (percentage of time INR is within the therapeutic range 2.0-3.0) and the frequency of recurrent DVT or PE (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 frequencies of the primary safety endpoint (major or non-major clinically relevant bleeding) and the secondary safety endpoint (major bleeding) were similar in both treatment groups.

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

23

In the Einstein PE study (see Table 7), rivaroxaban was shown to be equivalent to enoxaparin/VKA for the primary efficacy endpoint (p = 0.0026 [test for equivalence]; hazard ratio: 1.123 [0.749-1.684]). The prespecified clinical net 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 an average of 63% of the time for the mean treatment duration, which was 215 days, and for 57%, 62%, and 65% of the time for the groups with planned treatment durations of 3, 6, and 12 months, respectively. In the enoxaparin/antagonist group, when centers were divided into tertiles of equal size, there was no clear correlation between the mean level of TTR control (percentage of time INR is within the therapeutic range 2-3), and the frequency of recurrent DVT or PE (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 frequencies of the primary safety endpoint (major or non-major clinically relevant bleeding) were slightly lower in the rivaroxaban group (10.3% [249/2412]) than in the enoxaparin/VKA group (11.4% [274/2405]). The frequencies 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 7: Efficacy and safety results from the Phase III Einstein PE study

24

A prespecified pooled analysis of the Einstein DVT and Einstein PE studies (see Table 8) was conducted.

Table 8: Pooled analysis of efficacy and safety results from the Phase III Einstein DVT and Einstein PE studies

25

The prespecified clinical net 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 9), rivaroxaban was superior to placebo for the primary and secondary efficacy endpoints. For the primary safety endpoint (major bleeding), a numerically non-significant higher frequency was observed in patients treated with rivaroxaban 20 mg once daily compared to placebo. The secondary safety endpoint (major or non-major clinically relevant bleeding) showed higher frequencies in patients treated with rivaroxaban 20 mg once daily compared to placebo.

5.2 Pharmacokinetic Properties

Absorption
Rivaroxaban is absorbed quickly and reaches maximum plasma concentrations (Cmax) within 2 to 4 hours after administration of the tablet.
Absorption after oral administration is almost complete, and bioavailability after oral administration is high (80-100%) for the 2.5 mg and 10 mg tablets, regardless of administration with or without food.
Taking rivaroxaban with food does not affect AUC or Cmax.
Due to reduced absorption, the bioavailability after oral administration was determined to be 66% for the 20 mg tablet when administered on an empty stomach. When rivaroxaban 20 mg tablets are taken with food, an increase in mean AUC of 39% was observed compared to administration on an empty stomach, indicating almost complete absorption and high bioavailability after oral administration. Rivaroxaban 15 mg and 20 mg should be taken with food (see section 4.2).

Pharmacokinetics of rivaroxaban is almost linear in the dose range up to about 15 mg once daily in the fasted state. When administered with food, rivaroxaban 10 mg, 15 mg, and 20 mg tablets showed dose proportionality. At higher doses, limited absorption is observed with decreased bioavailability and decreased absorption rate as the dose increases.
Variability in pharmacokinetics of rivaroxaban is moderate, with individual variability (CV%) ranging from 30% to 40%.
Absorption of rivaroxaban is dependent on the site of release in the gastrointestinal tract.
29% and 56% reduction in AUC and Cmax, respectively, were 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 associated exposure to rivaroxaban.
Systemic exposure (AUC and Cmax) was comparable for 20 mg rivaroxaban administered orally as a crushed tablet mixed with apple sauce or as an aqueous suspension administered through a gastric 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 at approximately 92% to 95%, mainly to albumin. Volume of distribution is moderate, and the volume of distribution at steady state (Vss) is approximately 50 liters.

Metabolism and Elimination
About 2/3 of the administered dose of rivaroxaban undergoes metabolic transformation, with half being excreted via the kidneys and the other half via the feces. The remaining 1/3 of the administered dose of rivaroxaban, in the form of the unchanged compound, is excreted via the kidneys in the urine, mainly through active renal secretion.

Rivaroxaban is metabolized by CYP3A4, CYP2J2, and in CYP-independent transformations. The main mechanisms of biotransformation are oxidative degradation of the morpholinone moiety 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. There is no major or active circulating metabolite. Systemic clearance is approximately 10 L/h, so rivaroxaban can be considered a low-clearance substance. After intravenous administration of a dose of 1 mg, the terminal elimination half-life is approximately 4.5 hours. After oral administration, elimination is limited by the rate of absorption.

Elimination of rivaroxaban from plasma occurs with a terminal elimination half-life of 5 to 9 hours in young individuals and 11 to 13 hours in elderly individuals.

Special Populations
Gender
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 approximately 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.

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

In patients with liver cirrhosis and moderate liver function impairment (Child-Pugh Class B), significant, 2.3-fold increase in mean AUC of rivaroxaban 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 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 clinically relevant bleeding risk, including patients with cirrhosis Child-Pugh B and C (see section 4.3).

Renal Impairment
Increased 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 activity was 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>

Due to the high degree of plasma protein binding, it is not expected that rivaroxaban will 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
At a dose of rivaroxaban 20 mg once daily in the treatment of acute venous thromboembolism, the geometric mean concentrations (90% prediction interval) at 2 to 4 hours and approximately 24 hours after administration (roughly representing maximum and minimum concentrations within the dosing interval) were 215 (22-535) μg/L and 32 (6-239) μg/L, respectively.

Pharmacokinetic/Pharmacodynamic Relationships
The pharmacokinetic/pharmacodynamic (PK/PD) relationship between rivaroxaban plasma concentration and several pharmacodynamic endpoints (inhibition of Factor Xa, PT, APTT, HepTest) was evaluated over a wide dose range (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.

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

5.3 Preclinical Safety Data

Non-clinical data from conventional studies on pharmacology, toxicity after single administration, phototoxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development do not indicate any special hazard for humans.

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 plasma concentrations were observed.

In rats, no effects on fertility were observed in either sex. In animal studies, a toxic effect on reproduction was observed, which was related to the pharmacological mechanism of action of rivaroxaban (e.g., bleeding complications). At exposure levels of clinical relevance, a toxic effect on embryo-foetal development (miscarriage, delayed or accelerated ossification, multiple, white liver spots) and an increased incidence of common developmental anomalies were observed, as well as changes in the placenta. In pre- and post-natal studies in rats, a decrease in offspring viability was observed when females were treated with toxic doses.

6. Pharmaceutical Particulars

6.1 List of Excipients

Sodium lauryl sulfate
Lactose monohydrate
Hypromellose 2910
Microcrystalline cellulose
Sodium croscarmellose
Magnesium stearate
Coating:
Hypromellose
Titanium dioxide (E 171)
Macrogol 4000

6.2 Incompatibilities

None.

6.3 Shelf Life

2 years

6.4 Special Precautions for Storage

31
Store in a temperature below 25°C.

6.5 Nature and Contents of Container

PVC/PVDC/Aluminum blister packs in a cardboard box.
Packaging: 30 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 Authorization Holder

Responsible for Batch Release

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

8. Marketing Authorization Number

Marketing Authorization Number

9. Date of First Authorization

and Date of Last Renewal

Date of first authorization:

10. Date of Revision of the Text

of the Summary of Product Characteristics

32

Information to be Included on the Outer Packaging

Carton

1. Name of the Medicinal Product

Rombidux, 20 mg, film-coated tablets
Rivaroxabanum

2. Qualitative and Quantitative Composition

Each film-coated tablet contains 20 mg of rivaroxaban.

3. List of Excipients

The medicine contains lactose monohydrate. 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. Expiration Date

Expiration Date (EXP)

9. Special Storage Conditions

Store below 25°C.
33

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

Materials, if Appropriate

11. Name and Address of the Marketing Authorization Holder

Marketing Authorization Holder:

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

12. Marketing Authorization Number

Marketing Authorization Number

13. Batch Number

Batch Number (Lot)

14. General Category of Availability

Rp - Prescription-only medicine.

15. Instructions for Use

16. Braille Information

Rombidux 20 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
34

Minimum Information to be Included on Blister Packs or Foil Strips

Blister

1. Name of the Medicinal Product

Rombidux, 20 mg, film-coated tablets
Rivaroxabanum

2. Name of the Marketing Authorization Holder

Merck Sp. z o.o.

3. Expiration Date

EXP

4. Batch Number

Lot

5. Other

35

Patient Card

Patient Card

Merck (Logo)
Rombidux
Rivaroxabanum

Rombidux 10 mg (box to mark prescribed dose)

Rombidux 15 mg (box to mark prescribed dose)

Rombidux 20 mg (box to mark prescribed dose)

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

What to know about Rombidux?

• Rombidux reduces the tendency to form blood clots, thus preventing the formation of dangerous blood clots.
• Rombidux should be taken exactly as prescribed by the doctor. To prevent blood clots, never miss a dose of Rombidux.
• Do not stop taking Rombidux without consulting a doctor, as the risk of blood clots may increase.
• Before starting Rombidux, inform the doctor about all medications currently being taken or recently taken, as well as any medications planned to be taken.
• Before any surgery or invasive procedure, inform the doctor if Rombidux is being taken.

When to consult a doctor?

During treatment with an anticoagulant like Rombidux, it is essential to be aware of possible side effects. Bleeding is the most common side effect. Do not start Rombidux without consulting a doctor if the patient knows they are at increased risk of bleeding. Inform the doctor immediately if any of the following signs of bleeding occur:

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

How to take Rombidux?

• For the prevention of blood clots in the brain (stroke) and other blood vessels in the body, the recommended dose is one Rombidux 20 mg tablet once daily. If the patient has kidney problems, the dose may be reduced to one Rombidux 15 mg tablet once daily.

Swallow the tablet with water, preferably with food. If the patient has difficulty swallowing the whole tablet, they should talk to their doctor about other ways to take Rombidux. The tablet can be crushed and mixed with water or apple sauce, just before taking. After taking the mixture, the patient should take their next meal immediately.

If necessary, the doctor may administer the crushed Rombidux tablet through a gastric tube.

When to take Rombidux?

Take one tablet every day until the doctor decides to stop treatment. It is best to take the tablet at the same time every day, as it is easier to remember. The doctor will decide how long to continue treatment.

What to do if a dose is missed?

• If the patient takes one Rombidux 20 mg or 15 mg tablet once daily and misses a dose, they should take it as soon as possible. Do not take more than one tablet in one day to make up for the missed dose. Take the next tablet the next day, and then take one tablet once daily.

41
If the patient takes one Rombidux 15 mg tablet twice daily and misses a dose, they should take it as soon as possible. Do not take more than two 15 mg tablets in one day. If the patient forgets to take a dose, they can take two 15 mg tablets at the same time to get a total of two tablets (30 mg) in one day. The next day, they should continue taking one 15 mg tablet twice daily.

What to do if a dose is taken in excess?

If the patient takes more Rombidux than prescribed, they should contact their doctor immediately. Taking too much Rombidux can increase the risk of bleeding.

What to do if treatment with Rombidux is stopped?

Do not stop taking Rombidux without consulting a doctor, as Rombidux treats and prevents serious conditions.

4. Possible Side Effects

Like all medicines, Rombidux can cause side effects, although not everybody gets them. As with other medicines with similar actions (anticoagulants), Rombidux can cause bleeding, which can be life-threatening. Excessive bleeding can lead to a sudden drop in blood pressure (shock). Not all of these will be obvious or visible signs of bleeding.

Possible Side Effects that may be a Sign of Bleeding

Tell the doctor immediatelyif any of the following side effects occur:

• prolonged or excessive bleeding,
• unusual weakness, fatigue, pallor, dizziness, headache, unexplained swelling, shortness of breath, chest pain, or angina, which may be signs of bleeding. The doctor may decide to monitor the patient closely or change the treatment.

Possible Side Effects that may be a Sign of a Skin Reaction

Tell the doctor immediatelyif the following skin reactions occur, such as:

• widespread, acute rash, blistering, or changes to the mucous membranes, e.g., mouth or eyes (Stevens-Johnson syndrome, toxic epidermal necrolysis). The frequency of these side effects is very rare (up to 1 in 10,000 patients);
• drug reaction with eosinophilia and systemic symptoms (DRESS). The frequency of these side effects is very rare (up to 1 in 10,000 patients).

Possible Side Effects that may be a Sign of a Severe Allergic Reaction

Tell the doctor immediatelyif the following side effects occur:

• swelling of the face, lips, mouth, 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 up to 1 in 10,000 patients) and not very common (angioedema and allergic edema may occur in 1 in 100 patients).

5. How to Store Rombidux

Keep this medicine out of the sight and reach of children.

6. Contents of the Pack

30 film-coated tablets

7. Further Information

For further information, see the package leaflet.

8. Marketing Authorization Holder

Merck Sp. z o.o.

9. Date of Revision of the Text

Date of revision of the text

Package Leaflet: Information for the User

Rombidux, 20 mg, film-coated tablets

Rivaroxabanum

Read the package leaflet carefully before using the medicine.

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

Contents of the Package Leaflet

• 1. What is Rombidux and what is it 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 is Rombidux and what is it used for

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

• prevent blood clots in the brain (stroke) and other blood vessels in the body, if the patient has a type of irregular heartbeat called atrial fibrillation not caused by heart valve problems;
• treat blood clots in the veins of the legs (deep vein thrombosis) and in the blood vessels of the lungs (pulmonary embolism) and prevent them from happening again.

Rombidux belongs to a group of medicines called anticoagulants. Its action is to prevent blood clots by blocking the blood clotting factor (Factor Xa).

2. Important information before taking Rombidux

When not to take Rombidux:

• -if the patient is allergic to rivaroxaban or any of the other ingredients of this medicine (listed in section 6);
• if the patient has excessive bleeding;
• if the patient has a disease or condition of an organ that increases the risk of major bleeding (e.g., stomach ulcer, injury, or recent brain, eye, or spinal surgery);
• if the patient is taking other medicines to prevent blood clotting (e.g., warfarin, dabigatran, apixaban, or heparin), except when switching from one anticoagulant to another or when heparin is used to maintain catheter patency;
• if the patient has liver disease that increases the risk of bleeding; 38
• if the patient is pregnant or breastfeeding.

Do not take Rombidux, and inform the doctorif any of the above applies to the patient. The doctor will decide whether to use Rombidux and whether the patient should be closely monitored.

Warnings and precautions

Before taking Rombidux, talk to the doctor or pharmacist.

When to be cautious with Rombidux

• if the patient has an increased risk of bleeding, such as:
• moderate or severe kidney disease, as kidney function may affect the amount of Rombidux in the body;
• if the patient is taking other medicines that prevent blood clotting (e.g., warfarin, dabigatran, apixaban, or heparin), during switching from one anticoagulant to another or when heparin is used to maintain catheter patency (see "Rombidux with other medicines");
• bleeding disorders;
• very high blood pressure that does not decrease with treatment;
• stomach or intestinal diseases that may cause bleeding, such as inflammation of the stomach and intestines or esophageal reflux disease;
• vascular disease of the retina;
• pulmonary disease with dilated bronchi and pus (bronchiectasis) or previous bleeding from the lungs;
• in patients with prosthetic heart valves;
• if the patient has abnormal blood pressure or is scheduled for a procedure to remove a blood clot from the lungs.

If any of the above applies to the patient, inform the doctorbefore taking Rombidux. The doctor will decide whether to use Rombidux and whether the patient should be closely monitored.

If the patient needs to have surgery

• It is very important to take Rombidux at the time specified by the doctor before or after surgery.
• If the patient is to undergo a procedure to remove a blood clot from the brain or spine, such as a spinal puncture or epidural anesthesia, Rombidux should be taken at the time specified by the doctor.

39

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 20 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.

What Rombidux looks like and contents of the pack

White, round, biconvex film-coated tablets with "R" embossed on one side and "20" 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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