Rombidux

CHARACTERISTICS OF THE MEDICINAL PRODUCT

1. NAME OF THE MEDICINAL PRODUCT

Rombidux, 15 mg, film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 15 mg of rivaroxaban.
Excipient with known effect
Each film-coated tablet contains 80.36 mg of lactose monohydrate, see section 4.4.
Full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet)
Brown-red, round, biconvex film-coated tablets with "R" embossed on one side and "15" 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

Dosage
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 recommended once daily intake the next day. A double dose should not be taken on the same day to make up for a missed dose.
Treatment of DVT, 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 (e.g. 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. For patients at high risk of recurrence of DVT or PE, such as patients with complicated co-morbidities 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.
Treatment duration and dose should be individualised after careful assessment of the benefit of treatment continuation versus the risk of bleeding (see section 4.4).

In case of a missed dose during the twice daily 15 mg treatment phase (days 1-21), the patient should take Rombidux as soon as possible to ensure intake of 30 mg Rombidux per day. In this case, two 15 mg tablets may be taken at the same time. The next day, the patient should continue with the regular recommended twice daily 15 mg intake.
In case of a missed dose during the once daily treatment phase, the patient should take Rombidux as soon as possible and continue with the recommended once daily intake 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
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 suitable for monitoring the anticoagulant effect 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. 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 the end of the next day. For the first two days of the transition period, standard initial dosing of VKA should be used, and subsequent dosing should be guided by INR testing. While patients are being converted from Rombidux to VKA, INR should not be tested before 24 hours after the last dose of Rombidux but prior to the next dose of VKA. After discontinuation of Rombidux, INR can be reliably measured 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 medication (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).
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 may be considered in patients at high risk of bleeding. The recommendation for dose reduction is based on pharmacokinetic modelling and has not been studied in clinical trials (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 for use in children below 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, cardioversion should be delayed until a minimum of 4 hours after administration of Rombidux to ensure adequate anticoagulation (see sections 5.1 and 5.2). In all patients, cardioversion should be performed in the presence of adequate anticoagulation, as indicated by INR or aPTT. Decisions on initiation and duration of anticoagulation should take into account the latest clinical guidelines.
Patients with non-valvular atrial fibrillation undergoing transoesophageal echocardiogram (TEE) guided cardioversion
There is limited experience with the use of 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 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 tablets may be crushed and mixed with water or apple puree, immediately before administration and taken orally. After administration of crushed Rombidux 15 mg or 20 mg film-coated tablets, the patient should be instructed to eat a meal. The crushed tablet may also be given through a gastric tube after confirmation of the correct position of the tube. The crushed tablet should be administered in a small amount of water via a gastric tube, which should then be flushed with water (see section 5.2).

• 5.2).

After administration of crushed Rombidux 15 mg or 20 mg film-coated tablets, the patient should be instructed to eat a meal (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,
Malignancy with a high risk of bleeding,
Recent intracranial haemorrhage, spinal or ocular surgery,
Recent traumatic injury,
Known or suspected oesophageal varices,
Arteriovenous malformations,
Vascular aneurysms or major bleeding in the past.
Concomitant treatment with other anticoagulants, e.g. unfractionated heparin, low molecular weight heparin (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, apixaban, dabigatran, 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, clinical monitoring is recommended, according to the standard practice for patients treated for prevention of thromboembolic events.
Bleeding risk
As with other anticoagulants, patients taking Rombidux are to be closely monitored for signs of bleeding. In case of increased bleeding risk, caution should be exercised. Rombidux should be discontinued if a severe bleeding occurs (see section 4.9).
In clinical trials, during long-term treatment with rivaroxaban compared to VKA treatment, more bleeding events were observed, such as bleeding from mucous membranes (e.g. nosebleeds, gingival, gastrointestinal, genitourinary, including abnormal vaginal or menstrual bleeding) and anaemia. Therefore, in addition to clinical monitoring, laboratory testing of haemoglobin/hematocrit may be useful in detecting occult bleeding and assessing the severity of overt bleeding, if considered appropriate.
Patients with the following conditions are at increased risk of bleeding and should be closely monitored for signs and symptoms of bleeding and anaemia after initiation of treatment (see section 4.8).
After any decrease in haemoglobin or unexplained drop in blood pressure, the source of bleeding should be investigated.
Although rivaroxaban treatment does not require routine monitoring of exposure, rivaroxaban plasma concentrations, measured with a calibrated quantitative anti-Xa assay, may be helpful in exceptional situations, such as suspected overdose and emergency surgery (see sections 5.1 and 5.2).
Patients with antiphospholipid syndrome
It is not recommended to use direct oral anticoagulants (DOACs), including rivaroxaban, in patients with a history of thrombosis and diagnosed antiphospholipid syndrome, particularly in those who are triple positive (for lupus anticoagulant, anticardiolipin and anti-β2-glycoprotein I antibodies). Treatment with DOACs may be associated with an increased risk of recurrent thrombotic events compared to anticoagulation therapy with vitamin K antagonists (see section 5.1).
Renal impairment
In patients with severe renal impairment (creatinine clearance <30 ml min), rivaroxaban plasma concentrations are significantly increased, which may lead to an increased bleeding risk. caution should be exercised when using rombidux in patients with creatinine clearance 15-29 min. is not recommended <15 min (see sections 4.2 and 5.2).
Rombidux should be used with caution in patients with renal impairment taking concomitant medications that increase rivaroxaban plasma concentrations (see section 4.5).
Interactions with other medicinal products
Rombidux should not be used concomitantly with systemic azole antifungals (such as ketoconazole, itraconazole, voriconazole, and posaconazole), or HIV protease inhibitors (such as ritonavir), as these medications are strong inhibitors of both CYP3A4 and P-glycoprotein, and may increase rivaroxaban plasma concentrations to levels that may increase the risk of bleeding (see section 4.5).
Caution should be exercised when using Rombidux in patients concomitantly treated with medications known to affect haemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid (ASA), and platelet aggregation inhibitors or selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs).
In case of patients at risk of gastrointestinal ulcers, consideration should be given to the use of prophylactic measures (see section 4.5).
Other bleeding risk factors
As with other anticoagulants, rivaroxaban is not recommended in patients with an increased bleeding risk, such as:
congenital or acquired coagulation disorders,
uncontrolled severe arterial hypertension,
other gastrointestinal diseases that may cause bleeding (e.g. inflammatory bowel disease, gastrointestinal cancer),
retinal vascular disease,
recent bleeding from the lungs or bronchiectasis.

• congenital or acquired coagulation disorders,
• uncontrolled severe arterial hypertension,
• other gastrointestinal diseases that may cause bleeding (e.g. inflammatory bowel disease, gastrointestinal cancer),
• retinal vascular disease,
• recent bleeding from the lungs or bronchiectasis.

Patients with prosthetic heart valves
Rivaroxaban should not be used in the prevention of thromboembolic events in patients who have recently undergone transaortic valve replacement (TAVR). The safety and efficacy of Rombidux have not been studied in patients with prosthetic heart valves. Therefore, there are no data to support the use of Rombidux in these patients. Treatment with Rombidux is not recommended in these patients.
Patients with non-valvular atrial fibrillation undergoing percutaneous coronary intervention (PCI) with stent placement
There is limited clinical experience with the use of 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).
There are limited data available for such patients with a history of stroke or transient ischaemic attack.
Patients with haemodynamically unstable pulmonary embolism or 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, since the safety and efficacy of Rombidux have not been established in these clinical settings.
Spinal or epidural anaesthesia/analgesia
When neuraxial anaesthesia (spinal or epidural) or spinal puncture is performed, patients treated with anticoagulants for thromboprophylaxis are at risk of developing an epidural or spinal haematoma, which may result in long-term or permanent paralysis. The risk of these complications may be increased by the concomitant use of other medications affecting haemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other anticoagulants. The risk also appears to 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.
Prior to neuraxial intervention, the physician should weigh the potential benefits versus the risk of haemorrhage in patients being treated with Rombidux.
There is no clinical experience with the use of 15 mg dose in these situations.
In order to reduce the potential risk of bleeding associated with the concurrent use of rivaroxaban and neuraxial (epidural/spinal) anaesthesia or spinal puncture, consider the pharmacokinetic profile of rivaroxaban. Placement or removal of a spinal catheter should be delayed until at least 18 hours after the last administration of rivaroxaban (see section 5.2). If traumatic puncture occurs, the administration of rivaroxaban should be delayed for 24 hours.
Re-administration of rivaroxaban should be delayed until at least 6 hours after the removal of the catheter.
Dosing recommendations before and after invasive procedures and surgical interventions
If an invasive procedure or surgical intervention is required, Rombidux 10 mg/15 mg/20 mg should be discontinued at least 24 hours before the intervention if possible, based on clinical judgement.
If a procedure cannot be delayed, the risk of bleeding should be weighed against the urgency of the intervention.
Rombidux should be restarted as soon as possible after the procedure, provided the clinical situation allows, and adequate haemostasis has been established (see section 5.2).
Elderly patients
The risk of bleeding may increase with age (see section 5.2).
Skin reactions
Severe skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS syndrome, have been reported during post-marketing use of rivaroxaban (see section 4.8). The risk of these skin reactions is probably highest during the first weeks of treatment. Most cases have been reported within the first 3 months of initiation.
Rombidux should be discontinued immediately if severe skin reactions occur (e.g. extensive, severe and/or bullous, and/or accompanied by mucosal lesions or blisters).
Information on excipients
Rombidux contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Rombidux contains less than 1 mmol sodium (23 mg) per tablet, i.e. essentially sodium-free.

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 or 2.5-fold increase in the mean rivaroxaban AUC, and a 1.7-fold or 1.6-fold increase in the mean rivaroxaban C, with significant increases in pharmacodynamic effects, which may increase the risk of bleeding. Therefore, Rombidux is not recommended in patients concomitantly treated with systemic azole antifungals, such as ketoconazole, itraconazole, voriconazole, and posaconazole, or HIV protease inhibitors (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. 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 C. The interaction with clarithromycin is likely to be clinically relevant in a limited number of patients, particularly in those with renal impairment (see section 4.4).
Erythromycin (500 mg three times daily), which is a moderate inhibitor of CYP3A4 and P-glycoprotein, resulted in a 1.3-fold increase in mean rivaroxaban AUC and C.
In patients with mild renal impairment, erythromycin (500 mg three times daily) resulted in a 1.8-fold increase in mean rivaroxaban AUC and a 1.6-fold increase in C, compared to patients with normal renal function. In patients with moderate renal impairment, erythromycin resulted in a 2.0-fold increase in mean rivaroxaban AUC and a 1.6-fold increase in C, compared to patients with normal renal function. The effect of erythromycin is additive to the effect of renal impairment (see section 4.4).
Fluconazole (400 mg once daily), considered a moderate inhibitor of CYP3A4, resulted in a 1.4-fold increase in mean rivaroxaban AUC and a 1.3-fold increase in mean rivaroxaban C. The interaction with fluconazole is likely to be clinically relevant in a limited number of patients, particularly in those with renal impairment (see section 4.4).
Considering the limited clinical data available with dronedarone, concomitant use with rivaroxaban should be avoided.
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, based on INR and aPTT.
Due to an increased bleeding risk, caution should be exercised when using Rombidux concomitantly with other anticoagulants (see sections 4.3 and 4.4).
Non-steroidal anti-inflammatory drugs (NSAIDs)/platelet aggregation inhibitors
After concomitant administration of rivaroxaban (15 mg) and naproxen (500 mg), no clinically significant increase in bleeding time was observed. However, in some patients, increased bleeding effects may occur.
After concomitant administration of rivaroxaban and acetylsalicylic acid (500 mg), no clinically significant interaction was observed, based on bleeding time, INR and aPTT.
Clopidogrel (300 mg loading dose, followed by 75 mg maintenance dose) did not have a clinically significant effect on the pharmacokinetics of rivaroxaban (15 mg). However, a significant increase in bleeding time was observed in a subset of patients, which was not correlated with platelet aggregation, P-selectin or GPIIb/IIIa receptor inhibition.
Caution should be exercised when using Rombidux concomitantly with NSAIDs (including acetylsalicylic acid) and platelet aggregation inhibitors, as these medications may increase the risk of bleeding (see section 4.4).
SSRI/SNRI
As with other anticoagulants, there is an increased risk of bleeding when rivaroxaban is co-administered with SSRIs or SNRIs. In clinical studies, concomitant use of SSRIs or SNRIs and rivaroxaban was associated with an increased risk of bleeding, including clinically significant bleeding events (see section 4.8).
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) increased PT/INR (Neoplastin) more than additively, with individual INR values up to 12, whereas effects on aPTT, inhibition of Factor Xa and endogenous thrombin generation were additive.
If it is necessary to assess the anticoagulant effect of rivaroxaban during the transition period, it is recommended to use anti-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, HepTest) reflect only rivaroxaban's effect.
If it is necessary to assess the effect of warfarin during the transition period, it is recommended to use INR as this test is minimally affected by rivaroxaban at C of rivaroxaban (24 hours after the last intake of rivaroxaban), see section 5.2.
No pharmacokinetic interaction was observed between warfarin and rivaroxaban.
CYP3A4 inducers
Concomitant use of rivaroxaban with the strong CYP3A4 inducer rifampicin led to an approximate 50% decrease in mean rivaroxaban AUC, which may decrease its anticoagulant efficacy. Concomitant use of rivaroxaban with other strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, phenobarbital or St. John's Wort (Hypericum perforatum)) may also decrease rivaroxaban plasma concentrations, which may decrease its anticoagulant efficacy. 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 medications
No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when rivaroxaban was concomitantly administered with midazolam (a CYP3A4 substrate), digoxin (a P-glycoprotein substrate), atorvastatin (a CYP3A4 and P-glycoprotein substrate) or omeprazole (a proton pump inhibitor). Rivaroxaban neither inhibits nor induces any of the major CYP isoforms in humans (CYP3A4).
Laboratory tests
Coagulation parameters (e.g. PT, aPTT, HepTest) are affected as expected, based on the mechanism of action of 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
Rivaroxaban has not been studied in human fertility studies. No effects on fertility were observed in animal studies (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: uncommon) 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 studied, 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 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

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*All bleeding events were collected, reported and adjudicated in the rivaroxaban studies
**In the COMPASS study, a low rate of anaemia was reported, as a selective approach to adverse event collection was used.
Tabular list of adverse reactions
The frequency of adverse reactions for rivaroxaban is based on the analysis of data from 53,103 patients in 13 phase III studies for the prevention of venous thromboembolism in adult patients after elective hip or knee replacement surgery, for the prevention of venous thromboembolism in hospitalised patients for acute medical conditions, for the treatment and prevention of recurrent deep vein thrombosis and pulmonary embolism, for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation, for the prevention of atherothrombotic events in patients with acute coronary syndrome, and for the prevention of atherothrombotic events in patients with coronary artery disease or peripheral artery disease (see Table 3).
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>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, an effect plateau is expected without further increase in mean plasma exposure after supratherapeutic doses of 50 mg rivaroxaban or higher.
A specific reversal agent (andexanet alfa) is available, which reverses the pharmacodynamic effects of rivaroxaban (see Summary of Product Characteristics for andexanet alfa).
In case of rivaroxaban overdose, activated charcoal may be considered to reduce absorption.
Procedure in case of bleeding
In case of bleeding complications 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 individually according 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 associated anemia or coagulopathy) or platelets.
If bleeding cannot be controlled despite 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, consideration should be given to re-administering recombinant factor VIIa and gradually increasing its dose. In case 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 benefit of using a 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

Therapeutic group: anticoagulants, direct Xa inhibitors, ATC code: B01AF01
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Mechanism of action
Rivaroxaban is a highly selective, direct inhibitor of factor Xa, with high oral bioavailability. Inhibition of factor Xa activity disrupts the coagulation cascade, inhibiting both thrombin formation and clot formation. Rivaroxaban does not inhibit thrombin (activated factor II) and has no effect on platelets.
Pharmacodynamic effects
In humans, inhibition of factor Xa activity was dose-dependent with rivaroxaban. Rivaroxaban affects prothrombin time (PT) in a dose-dependent manner. For the Neoplastin reagent, there is a close correlation with rivaroxaban plasma concentrations (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 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 rivaroxaban twice daily resulted in values from 17 to 32 seconds, and 20 mg 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 stroke prevention and systemic embolism prevention, 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 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, and in patients with moderate renal impairment treated with 15 mg once daily from 12 to 26 seconds.
In a pharmacological clinical study evaluating the reversal of rivaroxaban's pharmacodynamics in healthy adult subjects (n=22), the effects of single doses (50 IU/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 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 routine clinical practice. However, if clinically indicated, rivaroxaban plasma concentrations can be measured using a calibrated quantitative anti-Xa assay (see section 5.2)
Patients with a high risk of antiphospholipid syndrome with three positive results for marker antibodies
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In an open, randomized, multicenter study with blinded outcome assessment, rivaroxaban was compared to warfarin in patients with thrombosis and established antiphospholipid syndrome at high risk of thromboembolic events (positive results in three 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 rivaroxaban (15 mg in patients with 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. severe bleeding 4 (7%) 2 (3%) group.
Efficacy and safety
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation
not associated with valvular disease
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.
In the main, double-blind, randomized study ROCKET AF, 14,264 patients were assigned to receive 20 mg rivaroxaban once daily (15 mg once daily in patients with creatinine clearance 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 (excluding central nervous system events).
Analysis in the groups as randomized, treated, and analyzed according to the protocol, stroke or systemic embolism occurred in 188 patients treated with rivaroxaban (1.71% per year) and in 241 patients treated with warfarin (2.16% per year) (HR [hazard ratio] 0.79; 95% CI: 0.66-0.96; p <0.001 for equivalence). Among all randomized patients analyzed according to the intention-to-treat (ITT) principle, the primary endpoint occurred in 269 patients treated with rivaroxaban (2.12% per year) and in 306 patients treated with warfarin (2.42% per year) (HR [hazard ratio] 0.88; 95% CI: 0.74-1.03; p <0.001 for equivalence; p=0.117 for superiority).
Results for secondary endpoints, tested hierarchically in the ITT analysis, are presented in Table 4.
INR values, among patients in the warfarin arm, were within the therapeutic range (2.0-3.0) on average for 55% of the time on treatment (median 58%; interquartile range 43-71). When centers were divided into quartiles (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 for 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 treated or untreated with oral anticoagulants) with non-valvular atrial fibrillation scheduled for cardioversion, aiming to compare the efficacy of rivaroxaban with VKA in adjusted doses (randomization 2:1) in the prevention of cardiovascular events. The cardioversion strategy was based on the TEE result (1-5 days of pre-treatment) or conventional cardioversion (at least three weeks of pre-treatment). Patients with a history of stroke or TIA were excluded.
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 due to primary atherosclerotic changes, aiming 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 rivaroxaban once daily (10 mg once daily in patients with creatinine clearance 30-49 ml/min) in combination with a P2Y12 inhibitor. The second group received 2.5 mg rivaroxaban twice daily in combination 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, followed by 15 mg rivaroxaban (or 10 mg in patients with creatinine clearance 30-49 ml/min) once daily in combination with low-dose ASA. The third group received adjusted-dose VKA in combination with DAPT for 1, 6, or 12 months, followed by adjusted-dose VKA in combination with low-dose ASA.
The primary safety endpoint (clinically significant bleeding events) occurred in 109 (15.7%), 117 (16.6%), and 167 (24.0%) patients in groups 1, 2, and 3, respectively (HR 0.59; 95% CI: 0.47-0.76; p <0.001 and HR 0.63; 95% CI: 0.50-0.80; p <0.001, respectively). The secondary endpoint (a composite of death from cardiovascular causes, myocardial infarction, or stroke) occurred in 41 (5.9%), 36 (5.1%), and 36 (5.2%) patients, respectively, showing a significant reduction in clinically significant bleeding events compared to the VKA regimen in patients with non-valvular atrial fibrillation undergoing 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.
22
Over 12,800 patients were studied in four randomized, controlled Phase III studies (Einstein DVT, Einstein PE, Einstein Extension, and Einstein Choice) and an additional preliminary pooled analysis of Einstein DVT and Einstein PE was performed. The total 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 rivaroxaban was administered twice daily. Then, 20 mg 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 rivaroxaban was administered twice daily for three weeks. Then, 20 mg rivaroxaban was administered once daily.
In both Einstein DVT and Einstein PE studies, the comparative treatment regimen consisted of enoxaparin administered for at least 5 days in combination with a VKA, with the VKA dose adjusted to maintain a PT/INR within the therapeutic range (≥2.0). Treatment was continued with a VKA in an adjusted dose to maintain PT/INR 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 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 Choice study, 3,396 patients with confirmed symptomatic DVT and/or PE who had completed 6 to 12 months of anticoagulant treatment were studied for the prevention of recurrent VTE. Patients were excluded if they had an indication for long-term anticoagulant treatment. The treatment duration was up to 12 months, depending on individual randomization (median: 351 days). Rivaroxaban 20 mg and 10 mg once daily were compared to 100 mg aspirin once daily.
The primary efficacy endpoint was symptomatic recurrent VTE, defined as a composite of recurrent DVT or PE, fatal or non-fatal.
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 pre-defined 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 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, respectively, for groups with planned treatment durations of 3, 6, and 12 months. In the enoxaparin/antagonist group, when centers were divided into tertiles, 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 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).
23
The rates of the primary safety endpoint (major or non-major clinically relevant bleeding) as well as the secondary safety endpoint (major bleeding) were similar for both treatment groups.

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

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 pre-defined 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 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, respectively, for groups with planned treatment durations of 3, 6, and 12 months. In the enoxaparin/antagonist group, when centers were divided into tertiles, 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 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).
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The rates 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 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 7: Efficacy and safety results from the Phase III Einstein PE study

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

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

25

Została przeprowadzona wstępna analiza zbiorcza wyników badań Einstein DVT i Einstein PE (patrz tabela 8).

The pre-defined clinical benefit (primary efficacy endpoint plus major bleeding) of the pooled analysis 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 event rate 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 event rates for patients treated with rivaroxaban 20 mg once daily compared to placebo.

5.2 Pharmacokinetic Properties

Absorption
Rivaroxaban is rapidly absorbed and reaches maximum plasma concentrations (Cmax) within 2 to 4 hours after tablet intake.
After oral administration, absorption is almost complete, and bioavailability is high (80-100%) for the 2.5 mg and 10 mg tablets, regardless of food intake.
Food intake does not affect the AUC or Cmax of rivaroxaban when administered as 2.5 mg or 10 mg tablets.
Due to reduced absorption, the bioavailability of the 20 mg tablet is 66% when taken on an empty stomach. When rivaroxaban 20 mg tablets are taken with food, the mean AUC increases by 39% compared to intake on an empty stomach, indicating almost complete absorption and high bioavailability.
Rivaroxaban 15 mg and 20 mg tablets should be taken with food (see section 4.2).
Pharmacokinetics of rivaroxaban are approximately linear up to doses of about 15 mg once daily in the fasted state. When administered with food, rivaroxaban 10 mg, 15 mg, and 20 mg tablets exhibit dose proportionality.
At higher doses, absorption is limited by decreased solubility, resulting in reduced bioavailability and decreased absorption rate as the dose increases.
The variability of rivaroxaban pharmacokinetics is moderate, with individual variability (CV%) ranging from 30% to 40%.
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.
Bioavailability (AUC and Cmax) was comparable for 20 mg rivaroxaban administered orally as a crushed tablet mixed with applesauce or as a water suspension administered through a gastric tube with a subsequent liquid meal
28
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 (92% to 95%), mainly to albumin. The 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 is metabolized, 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 unchanged compound, is excreted via the kidneys into the urine, mainly through active renal secretion.
Rivaroxaban is metabolized by CYP3A4, CYP2J2, and in CYP-independent reactions. 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. The systemic clearance is approximately 10 L/h, making rivaroxaban a low-clearance substance. After intravenous administration of a 1 mg dose, the terminal half-life in the elimination phase is approximately 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 11 to 13 hours in elderly individuals.
Special Populations
Sex
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 being 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.
Renal Impairment
Exposure to rivaroxaban increased with the degree of renal impairment, as assessed by creatinine clearance. 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 1.4-, 1.5-, and 1.6-fold, respectively. In line with 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.
Given 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).
Pharmacokinetic Data in Patients
In patients receiving rivaroxaban 20 mg once daily for the treatment of acute VTE, the geometric mean concentrations (90% prediction interval) at 2 to 4 hours and approximately 24 hours after intake (roughly representing the 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 concentrations and several pharmacodynamic endpoints (inhibition of factor Xa, PT, APTT, HepTest) was evaluated over a wide range of doses (5-30 mg twice daily). The relationship between rivaroxaban concentrations and factor Xa activity was best described by an Emax model. For PT, a linear cutoff model was generally better. Depending on the reagent used to determine PT, significant differences in slope were observed.
After application of the Neoplastin reagent, the baseline PT was 13 seconds, and the slope 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.
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5.3 Preclinical Safety Data

Non-clinical data from conventional pharmacological studies on safety, single-dose toxicity, phototoxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development do not indicate any special hazard for humans.
The 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.
No effects on fertility were observed in male and female rats. 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-fetal 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, doses toxic to the dams were associated with reduced offspring viability.

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
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/Aluminum blister packs in cardboard boxes.
Pack sizes: 30 or 42 film-coated tablets.
31

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

Cardboard Box

1. Name of the Medicinal Product

Rombidux, 15 mg, film-coated tablets
Rivaroxabanum

2. Qualitative and Quantitative Composition

Each film-coated tablet contains 15 mg of rivaroxaban.

3. List of Excipients

The medicine contains lactose monohydrate. For further information, see the patient information leaflet.

4. Pharmaceutical Form and Contents of the Container

30 film-coated tablets
Code

5. Method and Route of Administration

Oral use
Read the patient information leaflet before taking the medicine.

6. Warning Regarding the 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 in a temperature not exceeding 25°C.
33

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

Materials, if Applicable

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 15 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, 15 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 (field to mark prescribed dose)

Rombidux 15 mg (field to mark prescribed dose)

Rombidux 20 mg (field to mark prescribed dose)

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

What 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 prescribed by your doctor. To prevent the formation of 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 medications you are currently taking or plan to take.
• Before any surgery or invasive procedure, inform your doctor if you are taking Rombidux.

When to consult your doctor?

During treatment with a blood thinner like Rombidux, it is essential to be aware of 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, bleeding gums, or bleeding from cuts that 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?

• For the prevention of blood clots in the brain (stroke) and other blood vessels in the body: the recommended dose is one 20 mg Rombidux tablet once daily. If you have kidney problems, the dose may be reduced to one 15 mg Rombidux tablet once daily.
• If you need a procedure to open up blood vessels in your heart (a procedure called percutaneous coronary intervention - PCI with stent placement), there is limited evidence to support a dose reduction to one 15 mg Rombidux tablet once daily (or one 10 mg Rombidux tablet once daily in case of renal impairment) in combination with an antiplatelet agent such as clopidogrel.
• For the treatment of blood clots in the veins of the legs, blood clots in the pulmonary blood vessels, and to prevent the recurrence of blood clots: the recommended dose is one 15 mg Rombidux tablet twice daily for the first 3 weeks. For treatment after 3 weeks, the recommended dose is one 20 mg Rombidux tablet once daily.
• At least 6 months after treatment for blood clots, your doctor may decide to continue treatment with either one 10 mg Rombidux tablet once daily or one 20 mg Rombidux tablet once daily. If you have kidney problems and are taking one 20 mg Rombidux tablet once daily, your doctor may decide to reduce the dose to one 15 mg Rombidux tablet once daily after 3 weeks of treatment if the risk of bleeding is higher than the risk of recurrent blood clots.

The tablet should be swallowed, preferably with water.
Rombidux should be taken with 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. After taking the mixture, you should immediately take a meal.
If necessary, your doctor may administer the crushed Rombidux tablet through a gastric tube.

When to take Rombidux?

You should take Rombidux once daily at the same time every day, as it is easier to remember.
Your doctor will decide how long you should continue treatment.
Prevention of blood clots in the brain (stroke) and other blood vessels in the body.
If your heart rhythm needs to be restored to normal using a procedure called cardioversion, Rombidux should be taken as directed by your doctor.

What to do if you take more Rombidux than you should?

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

What to do if you forget to take Rombidux?

• If you are taking one 20 mg or one 15 mg Rombidux tablet once daily and you miss a dose, 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 at the usual time the next day, and then continue taking one tablet once daily.

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

What to do if you stop taking Rombidux?

Do not stop taking Rombidux without consulting your doctor, as Rombidux treats and prevents serious conditions.
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. Excessive bleeding may lead to a sudden drop in blood pressure (shock). Not all bleeding will be obvious or visible.
42

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 given month.
Store in a temperature below 25°C.
Medicines should not be disposed of via wastewater or household waste containers. 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 is rivaroxaban. One film-coated tablet contains 15 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

Red-brown, round, biconvex film-coated tablets with “R” embossed on one side and “15” on the other side.
Blister packs of PVC/PVCD/Aluminum in a cardboard box containing 30 (3x10) or 42 (3x14) film-coated tablets.
Not all pack sizes may be marketed.

Marketing authorization holder

Merck Sp. z o.o.
Al. Jerozolimskie 142B
44
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:

45