Leaflet RIVAROXABAN VIATRIS 20mg film-coated tablets
Product code: W71743001 Quantity: 30
Indicated for: prevention and treatment of thromboembolism
Route of administration: oral
Substance: rivaroxaban (anticoagulant)
ATC: B01AF01 (Blood and blood forming organs | Antithrombotic agents | Antithrombotic agents | Direct factor xa inhibitors)
Dose adjustment may be needed in kidney disease.
This medicine may have important interactions with other medicines.
This medicine is subject to additional monitoring.
Use during breastfeeding only on medical advice.
Use during pregnancy only on medical advice.
This medicine may increase the risk of bleeding.
Rivaroxaban is a direct oral anticoagulant that inhibits factor Xa, an essential enzyme in the coagulation cascade. It is used for the prevention and treatment of deep vein thrombosis (DVT), pulmonary embolism (PE), and to reduce the risk of stroke in patients with non-valvular atrial fibrillation.
Rivaroxaban is administered orally, usually once daily, and has the advantage of not requiring regular INR (international normalized ratio) monitoring, unlike traditional anticoagulants such as warfarin. It is also indicated for the prevention of thromboembolic events following major orthopedic surgeries, such as hip or knee replacement.
Common side effects include bleeding, anemia, nausea, and dizziness. In rare cases, severe bleeding or allergic reactions may occur. It is important for patients to inform their healthcare provider about any other medications or supplements they are taking, as interactions may increase the risk of bleeding.
Rivaroxaban is a modern and effective option for the prevention and treatment of thromboembolic events, offering improved safety and convenience for patients.
General data about RIVAROXABAN VIATRIS 20mg
- Substance: rivaroxaban
- Date of latest medicines list: 01-04-2026
- Product code: W71743001
- Concentration: 20mg
- Pharmaceutical form: film-coated tablets
- Quantity: 30
- Product type: Generic medicine
- Prescription status: P-RF - Medicines dispensed with a medical prescription that is retained by the pharmacy and cannot be renewed.
Pharmaceutical forms available for rivaroxaban
Concentrations available for rivaroxaban
- 10mg
- 15mg
- 15mg+20mg
- 2.5mg
- 20mg
Leaflet RIVAROXABAN VIATRIS 20mg
Combinations with other substances
Contents of the package leaflet for the medicine RIVAROXABAN VIATRIS 20mg film-coated tablets
1. NAME OF THE MEDICINAL PRODUCT
Rivaroxaban Viatris 20 mg film-coated tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 20 mg rivaroxaban.
Excipient with known effectEach film-coated tablet contains 38.48 mg lactose (as monohydrate), see section 4.4.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Film-coated tablet (tablet)
Reddish brown coloured, film-coated, round, biconvex, beveled edge tablet (7.0 mm diameter) markedwith “RX” on one side of the tablet and “4” 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 withone or more risk factors, such as congestive heart failure, hypertension, age ≥ 75 years, diabetesmellitus, prior stroke or transient ischaemic attack.
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent
DVT and PE in adults. (See section 4.4 for haemodynamically unstable PE patients.)
Paediatric populationTreatment of venous thromboembolism (VTE) and prevention of VTE recurrence in children andadolescents aged less than 18 years and weighing more than 50 kg after at least 5 days of initialparenteral anticoagulation treatment.
4.2 Posology and method of administration
Prevention of stroke and systemic embolism in adults
The recommended dose is 20 mg once daily, which is also the recommended maximum dose.
Therapy with Rivaroxaban Viatris should be continued long term provided the benefit of prevention ofstroke and systemic embolism outweighs the risk of bleeding (see section 4.4).
If a dose is missed the patient should take Rivaroxaban Viatris immediately and continue on thefollowing day with the once daily intake as recommended. The dose should not be doubled within thesame day to make up for a missed dose.
Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE in adults
The recommended dose for the initial treatment of acute DVT or PE is 15 mg twice daily for the firstthree weeks followed by 20 mg once daily for the continued treatment and prevention of recurrent
DVT and PE.
Short duration of therapy (at least 3 months) should be considered in patients with DVT or PEprovoked by major transient risk factors (i.e. recent major surgery or trauma). Longer duration oftherapy should be considered in patients with provoked DVT or PE not related to major transient riskfactors, unprovoked DVT or PE, or a history of recurrent DVT or PE.
When extended prevention of recurrent DVT and PE is indicated (following completion of at least 6months therapy for DVT or PE), the recommended dose is 10 mg once daily. In patients in whom therisk of recurrent DVT or PE is considered high, such as those with complicated comorbidities, or whohave developed recurrent DVT or PE on extended prevention with Rivaroxaban Viatris 10 mg oncedaily, a dose of Rivaroxaban Viatris 20 mg once daily should be considered.
The duration of therapy and dose selection should be individualised after careful assessment of thetreatment benefit against the risk for bleeding (see section 4.4).
Time period Dosing schedule Total daily dose
Treatment and Day 1-21 15 mg twice daily 30 mgprevention of recurrent
DVT and PE Day 22 onwards 20 mg once daily 20 mg
Prevention of recurrent Following completion 10 mg once daily or 10 mg
DVT and PE of at least 6 months 20 mg once daily or 20 mgtherapy for DVT or PE
To support the dose switch from 15 mg to 20 mg after Day 21 a first 4 weeks treatment initiation packof Rivaroxaban Viatris for treatment of DVT/PE is available.
If a dose is missed during the 15 mg twice daily treatment phase (day 1 - 21), the patient should take
Rivaroxaban Viatris immediately to ensure intake of 30 mg Rivaroxaban Viatris per day. In this casetwo 15 mg tablets may be taken at once. The patient should continue with the regular 15 mg twicedaily intake as recommended on the following day.
If a dose is missed during the once daily treatment phase, the patient should take Rivaroxaban Viatrisimmediately, and continue on the following day with the once daily intake as recommended. The doseshould not be doubled within the same day to make up for a missed dose.
Treatment of VTE and prevention of VTE recurrence in children and adolescents
Rivaroxaban Viatris treatment in children and adolescents aged less than 18 years should be initiatedfollowing at least 5 days of initial parenteral anticoagulation treatment (see section 5.1).
The dose for children and adolescent is calculated based on body weight.
- Body weight of 50 kg or more:a once daily dose of 20 mg rivaroxaban is recommended. This is the maximum daily dose.
- Body weight from 30 to 50 kg:a once daily dose of 15 mg rivaroxaban is recommended. This is the maximum daily dose.
- For patients with body weight less 30 kg refer to the Summary of Product Characteristics ofmore suitable forms of rivaroxaban.
The weight of a child should be monitored and the dose reviewed regularly. This is to ensure atherapeutic dose is maintained. Dose adjustments should be made based on changes in body weightonly.
Treatment should be continued for at least 3 months in children and adolescents. Treatment can beextended up to 12 months when clinically necessary. There is no data available in children to support adose reduction after 6 months treatment. The benefit-risk of continued therapy after 3 months shouldbe assessed on an individual basis taking into account the risk for recurrent thrombosis versus thepotential bleeding risk.
If a dose is missed, the missed dose should be taken as soon as possible after it is noticed, but only onthe same day. If this is not possible, the patient should skip the dose and continue with the next dose asprescribed. The patient should not take two doses to make up for a missed dose.
Converting from Vitamin K Antagonists (VKA) to Rivaroxaban Viatris
- Prevention of stroke and systemic embolism:
VKA treatment should be stopped and Rivaroxaban Viatris therapy should be initiated when the
International Normalised Ratio (INR) is ≤ 3.0.
- Treatment of DVT, PE and prevention of recurrence in adults and treatment of VTE andprevention of recurrence in paediatric patients:
VKA treatment should be stopped and rivaroxaban therapy should be initiated once the INR is ≤2.5.
When converting patients from VKAs to Rivaroxaban Viatris, INR values will be falsely elevatedafter the intake ofRivaroxaban Viatris. The INR is not valid to measure the anticoagulant activity of
Rivaroxaban Viatris, and therefore should not be used (see section 4.5).
Converting from Rivaroxaban Viatris to Vitamin K antagonists (VKA)
There is a potential for inadequate anticoagulation during the transition from Rivaroxaban Viatris to
VKA. Continuous adequate anticoagulation should be ensured during any transition to an alternateanticoagulant. It should be noted that Rivaroxaban Viatris can contribute to an elevated INR.
In patients converting from Rivaroxaban Viatris to VKA, VKA should be given concurrently until the
INR is ≥ 2.0. For the first two days of the conversion period, standard initial dosing of VKA should beused followed by VKA dosing, as guided by INR testing. While patients are on both Rivaroxaban
Viatris and VKA the INR should not be tested earlier than 24 hours after the previous dose but prior tothe next dose of Rivaroxaban Viatris. Once Rivaroxaban Viatris is discontinued INR testing may bedone reliably at least 24 hours after the last dose (see sections 4.5 and 5.2).
Paediatric patients:Children who convert from Rivaroxaban Viatris to VKA need to continue Rivaroxaban Viatris for48 hours after the first dose of VKA. After 2 days of co-administration an INR should be obtainedprior to the next scheduled dose of Rivaroxaban Viatris. Co-administration of Rivaroxaban Viatris and
VKA is advised to continue until the INR is ≥ 2.0. Once Rivaroxaban Viatris is discontinued INRtesting may be done reliably 24 hours after the last dose (see above and section 4.5).
Converting from parenteral anticoagulants to Rivaroxaban Viatris
For adult and paediatric patients currently receiving a parenteral anticoagulant, discontinue theparenteral anticoagulant and start Rivaroxaban Viatris 0 to 2 hours before the time that the nextscheduled administration of the parenteral medicinal product (e.g. low molecular weight heparins)would be due or at the time of discontinuation of a continuously administered parenteral medicinalproduct (e.g. intravenous unfractionated heparin).
Converting from Rivaroxaban Viatris to parenteral anticoagulants
Discontinue Rivaroxaban Viatris and give the first dose of parenteral anticoagulant at the time the next
Rivaroxaban Viatris dose would be taken.
Special populationsRenal impairment
Adults:
Limited clinical data for patients with severe renal impairment (creatinine clearance 15 - 29 ml/min)indicate that rivaroxaban plasma concentrations are significantly increased. Therefore, Rivaroxaban
Viatris is to be used with caution in these patients. Use is not recommended in patients with creatinineclearance < 15 ml/min (see sections 4.4 and 5.2).
In patients with moderate (creatinine clearance 30 - 49 ml/min) or severe (creatinine clearance15-29 ml/min) renal impairment the following dose recommendations apply:
- For the prevention of stroke and systemic embolism in patients with non-valvular atrialfibrillation, the recommended dose is 15 mg once daily (see section 5.2).
- For the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE: patientsshould be treated with 15 mg twice daily for the first 3 weeks. Thereafter, when therecommended dose is 20 mg once daily, a reduction of the dose from 20 mg once daily to 15 mgonce daily should be considered if the patient’s assessed risk for bleeding outweighs the risk forrecurrent DVT and PE. The recommendation for the use of 15 mg is based on PK modelling andhas not been studied in this clinical setting (see sections 4.4, 5.1 and 5.2).
When the recommended dose is 10 mg once daily, no dose adjustment from the recommendeddose is necessary.
No dose adjustment is necessary in patients with mild renal impairment (creatinine clearance50-80 ml/min) (see section 5.2).
Paediatric population:- Children and adolescents with mild renal impairment (glomerular filtration rate50 - 80 mL/min/1.73 m2): no dose adjustment is required, based on data in adults and limiteddata in paediatric patients (see section 5.2).
- Children and adolescents with moderate or severe renal impairment (glomerular filtration rate< 50 mL/min/1.73 m2): Rivaroxaban Viatris is not recommended as no clinical data isavailable (see section 4.4).
Hepatic impairmentRivaroxaban Viatris is contraindicated in patients with hepatic disease associated with coagulopathyand clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C (see sections4.3 and 5.2). No clinical data is available in children with hepatic impairment.
Elderly populationNo dose adjustment (see section 5.2)
Body weightNo dose adjustment for adults (see section 5.2)
For paediatric patients the dose is determined based on body weight.
GenderNo dose adjustment (see section 5.2)
Patients undergoing cardioversionRivaroxaban Viatris can be initiated or continued in patients who may require cardioversion. Fortransesophageal echocardiogram (TEE) guided cardioversion in patients not previously treated withanticoagulants, Rivaroxaban Viatris treatment should be started at least 4 hours before cardioversion toensure adequate anticoagulation (see sections 5.1 and 5.2). For all patients, confirmation should besought prior to cardioversion that the patient has taken Rivaroxaban Viatris as prescribed. Decisionson initiation and duration of treatment should take established guideline recommendations foranticoagulant treatment in patients undergoing cardioversion into account.
Patients with non-valvular atrial fibrillation who undergo PCI (percutaneous coronary intervention)with stent placement
There is limited experience of a reduced dose of 15 mg Rivaroxaban Viatris once daily (or 10 mg
Rivaroxaban Viatris once daily for patients with moderate renal impairment [creatinine clearance30-49 ml/min]) in addition to a P2Y12 inhibitor for a maximum of 12 months in patients with non-valvular atrial fibrillation who require oral anticoagulation and undergo PCI with stent placement(see sections 4.4 and 5.1).
Paediatric populationThe safety and efficacy of Rivaroxaban Viatris in children aged 0 to < 18 years have not beenestablished in the indication prevention of stroke and systemic embolism in patients with non-valvularatrial fibrillation. No data are available. Therefore, it is not recommended for use in children below18 years of age in indications other than the treatment of VTE and prevention of VTE recurrence.
Method of administrationAdults
Rivaroxaban Viatris is for oral use.
The tablets are to be taken with food (see section 5.2).
Crushing of tablets
For patients who are unable to swallow whole tablets, Rivaroxaban Viatris tablets may be crushed andmixed with water or apple puree immediately prior to use and administered orally. After theadministration of crushed Rivaroxaban Viatris 15 mg or 20 mg film-coated tablets, the dose should beimmediately followed by food.
The crushed Rivaroxaban Viatris tablets may also be given through gastric tubes (see sections 5.2 and6.6).
Children and adolescents weighing more than 50 kg
Rivaroxaban Viatris is for oral use.
The patient should be advised to swallow the tablet with liquid. It should also be taken with food (seesection 5.2). The tablets should be taken approximately 24 hours apart.
In case the patient immediately spits up the dose or vomits within 30 minutes after receiving the dose,a new dose should be given. However, if the patient vomits more than 30 minutes after the dose, thedose should not be re-administered and the next dose should be taken as scheduled.
The tablet must not be split in an attempt to provide a fraction of a tablet dose.
Crushing of tablets
For patients who are unable to swallow whole tablets, other pharmaceutical forms such as granules fororal suspension should be used. If the oral suspension is not immediately available, when doses of15 mg or 20 mg rivaroxaban are prescribed, these could be provided by crushing the 15 mg or 20 mgtablet and mixing it with water or apple puree immediately prior to use and administering orally.
The crushed tablet may be given through a nasogastric or gastric feeding tube (see sections 5.2 and6.6)
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Active clinically significant bleeding.Lesion or condition, if considered to be a significant risk for major bleeding. This may include currentor recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recentbrain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage,known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or majorintraspinal or intracerebral vascular abnormalities.
Concomitant treatment with any other anticoagulants, e.g. unfractionated heparin (UFH), lowmolecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oralanticoagulants (warfarin, dabigatran etexilate, apixaban, etc.) except under specific circumstances ofswitching anticoagulant therapy (see section 4.2) or when UFH is given at doses necessary to maintainan open central venous or arterial catheter (see section 4.5).
Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhoticpatients 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
Clinical surveillance in line with anticoagulation practice is recommended throughout the treatmentperiod.
Haemorrhagic riskAs with other anticoagulants, patients taking Rivaroxaban Viatris are to be carefully observed forsigns of bleeding. It is recommended to be used with caution in conditions with increased risk ofhaemorrhage. Rivaroxaban Viatris administration should be discontinued if severe haemorrhageoccurs (see section 4.9).
In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinaryincluding abnormal vaginal or increased menstrual bleeding) and anaemia were seen more frequentlyduring long term rivaroxaban treatment compared with VKA treatment. Thus, in addition to adequateclinical surveillance, laboratory testing of haemoglobin/haematocrit could be of value to detect occultbleeding and quantify the clinical relevance of overt bleeding, as judged to be appropriate.
Several sub-groups of patients, as detailed below, are at increased risk of bleeding. These patients areto be carefully monitored for signs and symptoms of bleeding complications and anaemia afterinitiation of treatment (see section 4.8). Any unexplained fall in haemoglobin or blood pressure shouldlead to a search for a bleeding site.
Although treatment with rivaroxaban does not require routine monitoring of exposure, rivaroxabanlevels measured with a calibrated quantitative anti-factor Xa assay may be useful in exceptionalsituations where knowledge of rivaroxaban exposure may help to inform clinical decisions, e.g.overdose and emergency surgery (see sections 5.1 and 5.2).
Paediatric populationThere is limited data in children with cerebral vein and sinus thrombosis who have a CNS infection(see section 5.1). The risk of bleeding should be carefully evaluated before and during therapy withrivaroxaban.
Renal impairmentIn adult patients with severe renal impairment (creatinine clearance < 30 ml/min) rivaroxaban plasmalevels may be significantly increased (1.6 fold on average) which may lead to an increased bleedingrisk. Rivaroxaban Viatris is to be used with caution in patients with creatinine clearance 15 -29 ml/min. Use is not recommended in patients with creatinine clearance < 15 ml/min (see sections 4.2and 5.2).
Rivaroxaban Viatris should be used with caution in patients with renal impairment concomitantlyreceiving other medicinal products which increase rivaroxaban plasma concentrations (seesection 4.5).
Rivaroxaban Viatris is not recommended in children and adolescents with moderate or severe renalimpairment (glomerular filtration rate < 50 mL/min/1.73 m2), as no clinical data is available.
Interaction with other medicinal products
The use of Rivaroxaban Viatris is not recommended in patients receiving concomitant systemictreatment with azole-antimycotics (such as ketoconazole, itraconazole, voriconazole andposaconazole) or HIV protease inhibitors (e.g. ritonavir). These active substances are strong inhibitorsof both CYP3A4 and P-gp and therefore may increase rivaroxaban plasma concentrations to aclinically relevant degree (2.6 fold on average) which may lead to an increased bleeding risk Noclinical data is available in children receiving concomitant systemic treatment with strong inhibitors ofboth CYP 3A4 and P-gp (see section 4.5).
Care is to be taken if patients are treated concomitantly with medicinal products affecting haemostasissuch as non-steroidal anti-inflammatory medicinal products (NSAIDs), acetylsalicylic acid (ASA) andplatelet aggregation inhibitors or selective serotonin reuptake inhibitors (SSRIs) and serotoninnorepinephrine reuptake inhibitors (SNRIs). For patients at risk of ulcerative gastrointestinal diseasean appropriate prophylactic treatment may be considered (see section 4.5).
Other haemorrhagic risk factors
As with other antithrombotics, rivaroxaban is not recommended in patients with an increased bleedingrisk such as:
* congenital or acquired bleeding disorders
* uncontrolled severe arterial hypertension
* other gastrointestinal disease without active ulceration that can potentially lead to bleedingcomplications (e.g. inflammatory bowel disease, oesophagitis, gastritis and gastroesophagealreflux disease)
* vascular retinopathy
* bronchiectasis or history of pulmonary bleeding
Patients with cancer
Patients with malignant disease may simultaneously be at higher risk of bleeding and thrombosis. Theindividual benefit of antithrombotic treatment should be weighed against risk for bleeding in patientswith active cancer dependent on tumour location, antineoplastic therapy and stage of disease. Tumourslocated in the gastrointestinal or genito urinary tract have been associated with an increased risk ofbleeding during rivaroxaban therapy.
In patients with malignant neoplasms at high risk of bleeding, the use of rivaroxaban is contraindicated(see section 4.3).
Patients with prosthetic valves
Rivaroxaban should not be used for thromboprophylaxis in patients having recently undergonetranscatheter aortic valve replacement (TAVR). Safety and efficacy of Rivaroxaban Viatris have notbeen studied in patients with prosthetic heart valves; therefore, there are no data to support that
Rivaroxaban Viatris provides adequate anticoagulation in this patient population. Treatment with
Rivaroxaban Viatris is not recommended for these patients.
Patients with antiphospholipid syndromeDirect acting Oral Anticoagulants (DOACs) including rivaroxaban are not recommended for patientswith a history of thrombosis who are diagnosed with antiphospholipid syndrome. In particular forpatients that are triple positive (for lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies), treatment with DOACs could be associated with increased rates ofrecurrent thrombotic events compared with vitamin K antagonist therapy.
Patients with non-valvular atrial fibrillation who undergo PCI with stent placement
Clinical data are available from an interventional study with the primary objective to assess safety inpatients with non-valvular atrial fibrillation who undergo PCI with stent placement. Data on efficacyin this population are limited (see sections 4.2 and 5.1). No data are available for such patients with ahistory of stroke/ transient ischaemic attack.
Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonaryembolectomy
Rivaroxaban Viatris is not recommended as an alternative to unfractionated heparin in patients withpulmonary embolism who are haemodynamically unstable or may receive thrombolysis or pulmonaryembolectomy since the safety and efficacy of Rivaroxaban Viatris have not been established in theseclinical situations.
Spinal/epidural anaesthesia or punctureWhen neuraxial anaesthesia (spinal/epidural anaesthesia) or spinal/epidural puncture is employed,patients treated with antithrombotic agents for prevention of thromboembolic complications are at riskof developing an epidural or spinal haematoma which can result in long-term or permanent paralysis.
The risk of these events may be increased by the post-operative use of indwelling epidural catheters orthe concomitant use of medicinal products affecting haemostasis. The risk may also be increased bytraumatic or repeated epidural or spinal puncture. Patients are to be frequently monitored for signs andsymptoms of neurological impairment (e.g. numbness or weakness of the legs, bowel or bladderdysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Priorto neuraxial intervention the physician should consider the potential benefit versus the risk inanticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. There is no clinicalexperience with the use of 20 mg rivaroxaban in these situations.
To reduce the potential risk of bleeding associated with the concurrent use of rivaroxaban andneuraxial (epidural/spinal) anaesthesia or spinal puncture, consider the pharmacokinetic profile ofrivaroxaban. Placement or removal of an epidural catheter or lumbar puncture is best performed whenthe anticoagulant effect of rivaroxaban is estimated to be low. However, the exact timing to reach asufficiently low anticoagulant effect in each patient is not known and should be weighed against theurgency of a diagnostic procedure.
For the removal of an epidural catheter and based on the general PK characteristics at least 2x half-life, i.e. at least 18 hours in young adult patients and 26 hours in elderly patients should elapse afterthe last administration of rivaroxaban (see section 5.2). Following removal of the catheter, at least6 hours should elapse before the next rivaroxaban dose is administered.
If traumatic puncture occurs the administration of rivaroxaban is to be delayed for 24 hours.
No data is available on the timing of the placement or removal of neuraxial catheter in children whileon Rivaroxaban Viatris. In such cases, discontinue rivaroxaban and consider a short acting parenteralanticoagulant.
Dosing recommendations before and after invasive procedures and surgical intervention
If an invasive procedure or surgical intervention is required, Rivaroxaban Viatris 20 mg should bestopped at least 24 hours before the intervention, if possible and based on the clinical judgement of thephysician. If the procedure cannot be delayed the increased risk of bleeding should be assessed againstthe urgency of the intervention.
Rivaroxaban Viatris should be restarted as soon as possible after the invasive procedure or surgicalintervention provided the clinical situation allows and adequate haemostasis has been established asdetermined by the treating physician (see section 5.2).
Elderly populationIncreasing age may increase haemorrhagic risk (see section 5.2).
Dermatological reactionsSerious skin reactions, including Stevens-Johnson syndrome/toxic epidermal necrolysis and DRESSsyndrome, have been reported during post-marketing surveillance in association with the use ofrivaroxaban (see section 4.8). Patients appear to be at highest risk for these reactions early in thecourse of therapy: the onset of the reaction occurring in the majority of cases within the first weeks oftreatment. Rivaroxaban should be discontinued at the first appearance of a severe skin rash (e.g.spreading, intense and/or blistering), or any other sign of hypersensitivity in conjunction with mucosallesions.
Information about excipientsRivaroxaban Viatris contains lactose. Patients with rare hereditary problems of galactose intolerance,total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
This medicinal product contains less than 1 mmol sodium (23 mg) per dosage unit, that is to sayessentially ‘sodium-free’.
4.5 Interaction with other medicinal products and other forms of interaction
The extent of interactions in the paediatric population is not known. The below mentioned interactiondata was obtained in adults and the warnings in section 4.4 should be taken into account for thepaediatric population.
CYP3A4 and P-gp inhibitors
Co-administration of rivaroxaban with ketoconazole (400 mg once a day) or ritonavir (600 mg twice aday) led to a 2.6 fold/2.5 fold increase in mean rivaroxaban AUC and a 1.7 fold/1.6 fold increase inmean rivaroxaban Cmax, with significant increases in pharmacodynamic effects which may lead to anincreased bleeding risk. Therefore, the use of Rivaroxaban Viatris is not recommended in patientsreceiving concomitant systemic treatment with azole-antimycotics such as ketoconazole, itraconazole,voriconazole and posaconazole or HIV protease inhibitors. These active substances are stronginhibitors of both CYP3A4 and P-gp (see section 4.4).
Active substances strongly inhibiting only one of the rivaroxaban elimination pathways, either
CYP3A4 or P-gp, are expected to increase rivaroxaban plasma concentrations to a lesser extent.
Clarithromycin (500 mg twice a day), for instance, considered as a strong CYP3A4 inhibitor andmoderate P-gp inhibitor, led to a 1.5 fold increase in mean rivaroxaban AUC and a 1.4 fold increase in
Cmax. The interaction with clarithromycin is likely not clinically relevant in most patients but can bepotentially significant in high-risk patients. (For patients with renal impairment: see section 4.4)
Erythromycin (500 mg three times a day), which inhibits CYP3A4 and P-gp moderately, led to a 1.3fold increase in mean rivaroxaban AUC and Cmax. The interaction with erythromycin is likely notclinically relevant in most patients but can be potentially significant in high-risk patients.
In subjects with mild renal impairment erythromycin (500 mg three times a day) led to a 1.8 foldincrease in mean rivaroxaban AUC and 1.6 fold increase in Cmax when compared to subjects withnormal renal function. In subjects with moderate renal impairment, erythromycin led to a 2.0 foldincrease in mean rivaroxaban AUC and 1.6 fold increase in Cmax when compared to subjects withnormal renal function. The effect of erythromycin is additive to that of renal impairment (seesection 4.4).
Fluconazole (400 mg once daily), considered as a moderate CYP3A4 inhibitor, led to a 1.4 foldincrease in mean rivaroxaban AUC and a 1.3 fold increase in mean Cmax. The interaction withfluconazole is likely not clinically relevant in most patients but can be potentially significant in high-risk patients. (For patients with renal impairment: see section 4.4).
Given the limited clinical data available with dronedarone, co-administration with rivaroxaban shouldbe avoided.
Anticoagulants
After combined administration of enoxaparin (40 mg single dose) with rivaroxaban (10 mg singledose) an additive effect on anti-factor Xa activity was observed without any additional effects onclotting tests (PT, aPTT). Enoxaparin did not affect the pharmacokinetics of rivaroxaban.
Due to the increased bleeding risk care is to be taken if patients are treated concomitantly with anyother anticoagulants (see sections 4.3 and 4.4).
NSAIDs/platelet aggregation inhibitors
No clinically relevant prolongation of bleeding time was observed after concomitant administration ofrivaroxaban (15 mg) and 500 mg naproxen. Nevertheless, there may be individuals with a morepronounced pharmacodynamic response.
No clinically significant pharmacokinetic or pharmacodynamic interactions were observed whenrivaroxaban was co-administered with 500 mg acetylsalicylic acid.
Clopidogrel (300 mg loading dose followed by 75 mg maintenance dose) did not show apharmacokinetic interaction with rivaroxaban (15 mg) but a relevant increase in bleeding time wasobserved in a subset of patients which was not correlated to platelet aggregation, P-selectin or
GPIIb/IIIa receptor levels.
Care is to be taken if patients are treated concomitantly with NSAIDs (including acetylsalicylic acid)and platelet aggregation inhibitors because these medicinal products typically increase the bleedingrisk (see section 4.4).
SSRIs/SNRIs
As with other anticoagulants the possibility may exist that patients are at increased risk of bleeding incase of concomitant use with SSRIs or SNRIs due to their reported effect on platelets. Whenconcomitantly used in the rivaroxaban clinical programme, numerically higher rates of major or non-major clinically relevant bleeding were observed in all treatment groups.
WarfarinConverting patients from the vitamin K antagonist warfarin (INR 2.0 to 3.0) to rivaroxaban (20 mg) orfrom rivaroxaban (20 mg) to warfarin (INR 2.0 to 3.0) increased prothrombin time/INR (Neoplastin)more than additively (individual INR values up to 12 may be observed), whereas effects on aPTT,inhibition of factor Xa activity and endogenous thrombin potential were additive.
If it is desired to test the pharmacodynamic effects of rivaroxaban during the conversion period, anti-factor Xa activity, PiCT, and Heptest can be used as these tests were not affected by warfarin. On thefourth day after the last dose of warfarin, all tests (including PT, aPTT, inhibition of factor Xa activityand ETP) reflected only the effect of rivaroxaban.
If it is desired to test the pharmacodynamic effects of warfarin during the conversion period, INRmeasurement can be used at the Ctrough of rivaroxaban (24 hours after the previous intake ofrivaroxaban) as this test is minimally affected by rivaroxaban at this time point.
No pharmacokinetic interaction was observed between warfarin and rivaroxaban.
CYP3A4 inducersCo-administration of rivaroxaban with the strong CYP3A4 inducer rifampicin led to an approximate50% decrease in mean rivaroxaban AUC, with parallel decreases in its pharmacodynamic effects. Theconcomitant use of rivaroxaban with other strong CYP3A4 inducers (e.g. phenytoin, carbamazepine,phenobarbital or St. John’s Wort (Hypericum perforatum)) may also lead to reduced rivaroxabanplasma concentrations. Therefore, concomitant administration of strong CYP3A4 inducers should beavoided unless the patient is closely observed for signs and symptoms of thrombosis.
Other concomitant therapiesNo clinically significant pharmacokinetic or pharmacodynamic interactions were observed whenrivaroxaban was co-administered with midazolam (substrate of CYP3A4), digoxin (substrate of P-gp),atorvastatin (substrate of CYP3A4 and P-gp) or omeprazole (proton pump inhibitor). Rivaroxabanneither inhibits nor induces any major CYP isoforms like CYP3A4.
Laboratory parametersClotting parameters (e.g. PT, aPTT, Hep test) are affected as expected by the mode of action ofrivaroxaban (see section 5.1).
4.6 Fertility, pregnancy and lactation
Safety and efficacy of Rivaroxaban Viatris have not been established in pregnant women. Studies inanimals have shown reproductive toxicity (see section 5.3). Due to the potential reproductive toxicity,the intrinsic risk of bleeding and the evidence that rivaroxaban passes the placenta, Rivaroxaban
Viatris is contraindicated during pregnancy (see section 4.3).
Women of child-bearing potential should avoid becoming pregnant during treatment with rivaroxaban.
Breast-feedingSafety and efficacy of Rivaroxaban Viatris have not been established in breast-feeding women. Datafrom animals indicate that rivaroxaban is secreted into milk. Therefore Rivaroxaban Viatris iscontraindicated during breast-feeding (see section 4.3). A decision must be made whether todiscontinue breast-feeding or to discontinue/abstain from therapy.
FertilityNo specific studies with rivaroxaban in humans have been conducted to evaluate effects on fertility. Ina study on male and female fertility in rats no effects were seen (see section 5.3).
4.7 Effects on ability to drive and use machines
Rivaroxaban Viatris has minor influence on the ability to drive and use machines. Adverse reactionslike syncope (frequency: uncommon) and dizziness (frequency: common) have been reported (seesection 4.8). Patients experiencing these adverse reactions should not drive or use machines.
4.8 Undesirable effects
The safety of rivaroxaban has been evaluated in thirteen pivotal phase III studies (see Table 1).
Overall, 69,608 adult patients in nineteen phase III studies and 488 paediatric patients in two phase IIand two phase III studies were exposed to rivaroxaban.
Table 1: Number of patients studied, total daily dose and maximum treatment duration in adultand paediatric phase III studies
Indication Number of Total daily dose Maximumpatients* treatment duration
Prevention of VTE in adult 6,097 10 mg 39 dayspatients undergoing elective hipor knee replacement surgery
Prevention of VTE in medically 3,997 10 mg 39 daysill patients
Treatment of DVT, PE and 6,790 Day 1 - 21: 30 mg 21 monthsprevention of recurrence Day 22 and onwards:
20 mg After at least6 months: 10 mg or20 mg
Treatment of VTE and prevention 329 Body weight- 12 monthsof VTE recurrence in term adjusted dose toneonates and children aged less achieve a similarthan 18 years following initiation exposure as thatof standard anticoagulation observed in adultstreatment treated for DVT with20 mg rivaroxabanonce daily
Prevention of stroke and systemic 7,750 20 mg 41 monthsembolism in patients with non-valvular atrial fibrillation
Prevention of atherothrombotic 10,225 5 mg or 10 mg 31 monthsevents in patients after an ACS respectively, co-administered witheither acetylsalicylicacid oracetylsalicylic acidplus clopidogrel orticlopidine
Prevention of atherothrombotic 18,244 5 mg co- 47 monthsevents in patients with CAD/PAD administered withacetylsalicylic acidor 10 mg alone3,256** 5 mg co- 42 monthsadministered withacetylsalicylic acid∗ Patients exposed to at least one dose of rivaroxaban
** From the VOYAGER PAD study
The most commonly reported adverse reactions in patients receiving rivaroxaban were bleedings (seesection 4.4. and ‘Description of selected adverse reactions’ below) (Table 2). The most commonlyreported bleedings were epistaxis (4.5%) and gastrointestinal tract haemorrhage (3.8%).
Table 2: Bleeding* and anaemia events rates in patients exposed to rivaroxaban across thecompleted adult and paediatric phase III studies
Indication Any bleeding Anaemia
Prevention of venous thromboembolism 6.8% of patients 5.9% of patients(VTE) in adult patients undergoing electivehip or knee replacement surgery
Prevention of venous thromboembolism in 12.6% of patients 2.1% of patientsmedically ill patients
Treatment of DVT, PE and prevention of 23% of patients 1.6% of patientsrecurrence
Treatment of VTE and prevention of VTE 39.5% of patients 4.6% of patientsrecurrence in term neonates and childrenaged less than 18 years following initiationof standard anticoagulation treatment
Prevention of stroke and systemic 28 per 100 patient years 2.5 per 100 patientembolism in patients with non-valvular yearsatrial fibrillation
Prevention of atherothrombotic events in 22 per 100 patient years 1.4 per 100 patientpatients after an ACS years
Prevention of atherothrombotic events in 6.7 per 100 patient years 0.15 per 100patients with CAD/PAD patient years**8.38 per 100 patient 0.74 per 100years# patient years*** #
* For all rivaroxaban studies all bleeding events are collected, reported and adjudicated.
** In the COMPASS study, there is a low anaemia incidence as a selective approach to adverseevent collection was applied
*** A selective approach to adverse event collection was applied# From the VOYAGER PAD study
Tabulated list of adverse reactionsThe frequencies of adverse reactions reported with rivaroxaban in adult and paediatric patients aresummarised in Table 3 below by system organ class (in MedDRA) and by frequency.
Frequencies are defined as:very common (≥ 1/10)common (≥ 1/100 to < 1/10)uncommon (≥ 1/1,000 to < 1/100)rare (≥ 1/10,000 to < 1/1,000)very rare ( < 1/10,000)not known (cannot be estimated from the available data)
Table 3: All adverse reactions reported in adult patients in phase III clinical studies or throughpost-marketing use* and in two phase II and two phase III studies in paediatric patients
Common Uncommon Rare Very rare Not known
Blood and lymphatic system disordersAnaemia (incl. Thrombocytosisrespective (incl. platelet countlaboratory increased) A,parameters) Thrombocytopenia
Immune system disordersAllergic reaction, Anaphylactic
Dermatitis allergic, reactions
Angioedema and includingallergic oedema anaphylacticshock
Nervous system disordersDizziness, Cerebral and
Headache intracranialhaemorrhage,
SyncopeEye disorders
Eye haemorrhage(incl. conjunctivalhaemorrhage)
Cardiac disordersTachycardia
Vascular disorders
Hypotension,
Haematoma
Respiratory, thoracic and mediastinal disordersEpistaxis, Eosinophilic
Haemoptysis pneumonia
Gastrointestinal disordersGingival bleeding, Dry mouth
Gastrointestinaltract haemorrhage(incl. rectalhaemorrhage),
Gastrointestinal andabdominal pains,
Dyspepsia, Nausea,
ConstipationA,
Diarrhoea,
VomitingA
Hepatobiliary disordersIncrease in Hepatic Jaundice,transaminases impairment, Bilirubin
Increased bilirubin, conjugated
Increased blood increased (with oralkaline withoutphosphataseA, concomitant
Increased GGTA increase of ALT),
Cholestasis,
Hepatitis (incl.hepatocellularinjury)
Skin and subcutaneous tissue disordersCommon Uncommon Rare Very rare Not known
Pruritus (incl. Urticaria Stevens-Johnsonuncommon cases of syndrome/ Toxicgeneralised Epidermalpruritus), Necrolysis,
Rash, DRESS syndrome
Ecchymosis,
Cutaneous andsubcutaneoushaemorrhage
Musculoskeletal and connective tissue disordersPain in extremityA Haemarthrosis Muscle Compartmenthaemorrhage syndromesecondary to ableeding
Renal and urinary disordersUrogenital tract Renalhaemorrhage (incl. failure/acutehaematuria and renal failuremenorrhagiaB), secondary to a
Renal impairment bleeding(incl. blood sufficient tocreatinine causeincreased, hypoperfusion,
Blood urea Anticoagulant-increased) relatednephropathy
General disorders and administration site conditionsFeverA, Feeling unwell Localised
Peripheral oedema, (incl. malaise) oedemaA
Decreased generalstrength and energy(incl. fatigue andasthenia)
InvestigationsIncreased LDHA,
Increased lipaseA,
Increased amylaseA
Injury, poisoning and procedural complicationsPostprocedural Vascularhaemorrhage (incl. pseudoaneurysmCpostoperativeanaemia, andwoundhaemorrhage),
Contusion,
Wound secretionA
A: observed in prevention of VTE in adult patients undergoing elective hip or knee replacementsurgery
B: observed in treatment of DVT, PE and prevention of recurrence as very common in women < 55years
C: observed as uncommon in prevention of atherothrombotic events in patients after an ACS(following percutaneous coronary intervention)
* A pre-specified selective approach to adverse event collection was applied in selected phase IIIstudies. The incidence of adverse reactions did not increase and no new adverse drug reactionwas identified after analysis of these studies.
Description of selected adverse reactionsDue to the pharmacological mode of action, the use of Rivaroxaban Viatris may be associated with anincreased risk of occult or overt bleeding from any tissue or organ which may result in posthaemorrhagic anaemia. The signs, symptoms, and severity (including fatal outcome) will varyaccording to the location and degree or extent of the bleeding and/or anaemia (see section 4.9“Management of bleeding”). In the clinical studies mucosal bleedings (i.e. epistaxis, gingival,gastrointestinal, genito urinary including abnormal vaginal or increased menstrual bleeding) andanaemia were seen more frequently during long term rivaroxaban treatment compared with VKAtreatment. Thus, in addition to adequate clinical surveillance, laboratory testing ofhaemoglobin/haematocrit could be of value to detect occult bleeding and quantify the clinicalrelevance of overt bleeding, as judged to be appropriate. The risk of bleedings may be increased incertain patient groups, e.g. those patients with uncontrolled severe arterial hypertension and/or onconcomitant treatment affecting haemostasis (see section 4.4 “Haemorrhagic risk”). Menstrualbleeding may be intensified and/or prolonged. Haemorrhagic complications may present as weakness,paleness, dizziness, headache or unexplained swelling, dyspnoea and unexplained shock. In somecases as a consequence of anaemia, symptoms of cardiac ischaemia like chest pain or angina pectorishave been observed.
Known complications secondary to severe bleeding such as compartment syndrome and renal failuredue to hypoperfusion, or anticoagulant-related nephropathy have been reported for Rivaroxaban
Viatris. Therefore, the possibility of haemorrhage is to be considered in evaluating the condition inany anticoagulated patient.
Paediatric populationTreatment of VTE and prevention of VTE recurrence
The safety assessment in children and adolescents is based on the safety data from two phase II andone phase III open-label active controlled studies in paediatric patients aged birth to less than 18 years.
The safety findings were generally similar between rivaroxaban and comparator in the variouspaediatric age groups. Overall, the safety profile in the 412 children and adolescents treated withrivaroxaban was similar to that observed in the adult population and consistent across age subgroups,although assessment is limited by the small number of patients.
In paediatric patients, headache (very common, 16.7%), fever (very common, 11.7%), epistaxis (verycommon, 11.2%), vomiting (very common, 10.7%), tachycardia (common, 1.5%), increase in bilirubin(common, 1.5%) and bilirubin conjugated increased (uncommon, 0.7%) were reported more frequentlyas compared to adults. Consistent with adult population, menorrhagia was observed in 6.6% (common)of female adolescents after menarche. Thrombocytopenia as observed in the post-marketingexperience in adult population was common (4.6%) in paediatric clinical studies. The adverse drugreactions in paediatric patients were primarily mild to moderate in severity.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.
4.9 Overdose
In adults, rare cases of overdose up to 1,960 mg have been reported. In case of overdose, the patientshould be observed carefully for bleeding complications or other adverse reactions (see section“Management of bleeding”). There is limited data available in children. Due to limited absorption aceiling effect with no further increase in average plasma exposure is expected at supratherapeuticdoses of 50 mg rivaroxaban or above in adults, however, no data is available at supratherapeutic dosesin children.
A specific reversal agent (andexanet alfa) antagonising the pharmacodynamic effect of rivaroxaban isavailable for adults, but not established in children (refer to the Summary of Product Characteristics ofandexanet alfa).
The use of activated charcoal to reduce absorption in case of rivaroxaban overdose may be considered.
Management of bleeding
Should a bleeding complication arise in a patient receiving rivaroxaban, the next rivaroxabanadministration should be delayed or treatment should be discontinued as appropriate. Rivaroxaban hasa half-life of approximately 5 to 13 hours in adults. The half-life in children estimated usingpopulation pharmacokinetic (popPK) modelling approaches is shorter (see section 5.2). Managementshould be individualised according to the severity and location of the haemorrhage. Appropriatesymptomatic treatment could be used as needed, such as mechanical compression (e.g. for severeepistaxis), surgical haemostasis with bleeding control procedures, fluid replacement andhaemodynamic support, blood products (packed red cells or fresh frozen plasma, depending onassociated anaemia or coagulopathy) or platelets.
If bleeding cannot be controlled by the above measures, either the administration of a specific factor
Xa inhibitor reversal agent (andexanet alfa), which antagonises the pharmacodynamic effect ofrivaroxaban, or a specific procoagulant agent, such as prothrombin complex concentrate (PCC),activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (r-FVIIa), should beconsidered. However, there is currently very limited clinical experience with the use of thesemedicinal products in adults and children receiving rivaroxaban. The recommendation is also based onlimited non-clinical data. Re-dosing of recombinant factor VIIa shall be considered and titrateddepending on improvement of bleeding. Depending on local availability, a consultation with acoagulation expert should be considered in case of major bleedings (see section 5.1).
Protamine sulphate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban.
There is limited experience with tranexamic acid and no experience with aminocaproic acid andaprotinin in adults and children receiving rivaroxaban. There is no experience on the use of theseagents in children. There is neither scientific rationale for benefit nor experience with the use of thesystemic haemostatic desmopressin in individuals receiving rivaroxaban. Due to the high plasmaprotein binding rivaroxaban is not expected to be dialysable.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antithrombotic agents, direct factor Xa inhibitors, ATC code: B01AF01
Mechanism of actionRivaroxaban is a highly selective direct factor Xa inhibitor with oral bioavailability. Inhibition offactor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibitingboth thrombin formation and development of thrombi. Rivaroxaban does not inhibit thrombin(activated factor II) and no effects on platelets have been demonstrated.
Pharmacodynamic effectsDose-dependent inhibition of factor Xa activity was observed in humans. Prothrombin time (PT) isinfluenced by rivaroxaban in a dose dependent way with a close correlation to plasma concentrations(r value equals 0.98) if Neoplastin is used for the assay. Other reagents would provide different results.
The readout for PT is to be done in seconds, because the INR is only calibrated and validated forcoumarins and cannot be used for any other anticoagulant.
In patients receiving rivaroxaban for treatment of DVT and PE and prevention of recurrence, the 5/95percentiles for PT (Neoplastin) 2 - 4 hours after tablet intake (i.e. at the time of maximum effect) for15 mg rivaroxaban twice daily ranged from 17 to 32 s and for 20 mg rivaroxaban once daily from 15to 30 s. At trough (8 - 16 h after tablet intake) the 5/95 percentiles for 15 mg twice daily ranged from14 to 24 s and for 20 mg once daily (18 - 30 h after tablet intake) from 13 to 20 s.
In patients with non-valvular atrial fibrillation receiving rivaroxaban for the prevention of stroke andsystemic embolism, the 5/95 percentiles for PT (Neoplastin) 1 - 4 hours after tablet intake (i.e. at thetime of maximum effect) in patients treated with 20 mg once daily ranged from 14 to 40 s and inpatients with moderate renal impairment treated with 15 mg once daily from 10 to 50 s. At trough (16
- 36 h after tablet intake) the 5/95 percentiles in patients treated with 20 mg once daily ranged from 12to 26 s and in patients with moderate renal impairment treated with 15 mg once daily from 12 to 26 s.
In a clinical pharmacology study on the reversal of rivaroxaban pharmacodynamics in healthy adultsubjects (n=22), the effects of single doses (50 IU/kg) of two different types of PCCs, a 3-factor PCC(Factors II, IX and X) and a 4-factor PCC (Factors II, VII, IX and X) were assessed. The 3-factor PCCreduced mean Neoplastin PT values by approximately 1.0 second within 30 minutes, compared toreductions of approximately 3.5 seconds observed with the 4-factor PCC. In contrast, the 3-factor PCChad a greater and more rapid overall effect on reversing changes in endogenous thrombin generationthan the 4-factor PCC (see section 4.9).
The activated partial thromboplastin time (aPTT) and Hep test are also prolonged dose-dependently;however, they are not recommended to assess the pharmacodynamic effect of rivaroxaban. There is noneed for monitoring of coagulation parameters during treatment with rivaroxaban in clinical routine.
However, if clinically indicated rivaroxaban levels can be measured by calibrated quantitative anti-factor Xa tests (see section 5.2).
Paediatric populationPT (neoplastin reagent), aPTT, and anti-Xa assay (with a calibrated quantitative test) display a closecorrelation to plasma concentrations in children. The correlation between anti-Xa to plasmaconcentrations is linear with a slope close to 1. Individual discrepancies with higher or lower anti-Xavalues as compared to the corresponding plasma concentrations may occur. There is no need forroutine monitoring of coagulation parameters during clinical treatment with rivaroxaban. However, ifclinically indicated, rivaroxaban concentrations can be measured by calibrated quantitative antiFactor
Xa tests in mcg/L (see table 13 in section 5.2 for ranges of observed rivaroxaban plasmaconcentrations in children). The lower limit of quantifications must be considered when the anti-Xatest is used to quantify plasma concentrations of rivaroxaban in children. No threshold for efficacy orsafety events has been established.
Clinical efficacy and safetyPrevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation
The rivaroxaban clinical programme was designed to demonstrate the efficacy of rivaroxaban for theprevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation.
In the pivotal double-blind ROCKET AF study, 14,264 patients were assigned either to rivaroxaban20 mg once daily (15 mg once daily in patients with creatinine clearance 30 - 49 ml/min) or towarfarin titrated to a target INR of 2.5 (therapeutic range 2.0 to 3.0). The median time on treatmentwas 19 months and overall treatment duration was up to 41 months.34.9% of patients were treated with acetylsalicylic acid and 11.4% were treated with class IIIantiarrhythmic including amiodarone.
Rivaroxaban was non-inferior to warfarin for the primary composite endpoint of stroke and non-CNSsystemic embolism. In the per-protocol population on treatment, stroke or systemic embolism occurredin 188 patients on rivaroxaban (1.71% per year) and 241 on warfarin (2.16% per year) (HR 0.79;95% CI, 0.66 - 0.96; p<0.001 for non-inferiority). Among all randomised patients analysed accordingto ITT, primary events occurred in 269 on rivaroxaban (2.12% per year) and 306 on warfarin (2.42%per year) (HR 0.88; 95% CI, 0.74 - 1.03; p<0.001 for non-inferiority; p=0.117 for superiority). Resultsfor secondary endpoints as tested in hierarchical order in the ITT analysis are displayed in Table 4.
Among patients in the warfarin group, INR values were within the therapeutic range (2.0 to 3.0) amean of 55% of the time (median, 58%; interquartile range, 43 to 71). The effect of rivaroxaban didnot differ across the level of centre TTR (Time in Target INR Range of 2.0 - 3.0) in the equally sizedquartiles (p=0.74 for interaction). Within the highest quartile according to centre, the Hazard Ratio(HR) with rivaroxaban versus warfarin was 0.74 (95% CI, 0.49 - 1.12).
The incidence rates for the principal safety outcome (major and non-major clinically relevant bleedingevents) were similar for both treatment groups (see Table 5).
Table 4: Efficacy results from phase III ROCKET AF
Study population ITT analyses of efficacy in patients with non-valvular atrial fibrillation
Treatment dose Rivaroxaban Warfarin HR (95% CI)20 mg od (15 titrated to a p-value, testmg od in target INR of forpatients with 2.5 superioritymoderate (therapeuticrenal range 2.0 toimpairment) 3.0) Event
Event rate rate (100 pt-(100 pt-yr) yr)
Stroke and non-CNS systemic embolism 269 306 0.88(2.12) (2.42) (0.74 - 1.03)0.117
Stroke, non-CNS systemic embolism and 572 609 0.94vascular death (4.51) (4.81) (0.84 - 1.05)0.265
Stroke, non-CNS systemic embolism, vascular 659 709 0.93death and myocardial infarction (5.24) (5.65) (0.83 - 1.03)0.158
Stroke 253 281 0.90(1.99) (2.22) (0.76 - 1.07)0.221
Non-CNS systemic embolism 20 27 0.74(0.16) (0.21) (0.42 - 1.32)0.308
Myocardial infarction 130 142 0.91(1.02) (1.11) (0.72 - 1.16)0.464od: once daily
Table 5: Safety results from phase III ROCKET AF
Study population Patients with non-valvular atrial fibrillationa)
Treatment dose 20 mg rivaroxaban Warfarin titrated to HR (95% CI) p-valueod (15 mg od in a target INR of 2.5patients with (therapeutic rangemoderate renal 2.0 to 3.0)impairment) Event rate (100 pt-yr)
Event rate (100 pt-yr)
Major and non-major 1,475 (14.91) 1,449 (14.52) 1.03 (0.96 - 1.11)clinically relevant 0.442bleeding events
Major bleeding events 395 (3.60) 386 (3.45) 1.04 (0.90 - 1.20)0.576
Death due to bleeding* 27 (0.24) 55 (0.48) 0.50 (0.31 - 0.79)0.003
Critical organ 91 (0.82) 133 (1.18) 0.69 (0.53 - 0.91)bleeding* 0.007
Intracranial 55 (0.49) 84 (0.74) 0.67 (0.47 - 0.93)haemorrhage* 0.019
Haemoglobin drop* 305 (2.77) 254 (2.26) 1.22 (1.03 - 1.44)0.019
Transfusion of 2 or 183 (1.65) 149 (1.32) 1.25 (1.01 - 1.55)more units of packed 0.044red blood cells orwhole blood*
Non-major clinically 1,185 (11.80) 1,151 (11.37) 1.04 (0.96 - 1.13)relevant bleeding 0.345events
All-cause mortality 208 (1.87) 250 (2.21) 0.85 (0.70 - 1.02)0.073a) Safety population, on treatment
* Nominally significantod: once daily
In addition to the phase III ROCKET AF study, a prospective, single-arm, post-authorisation, non-interventional, open-label cohort study (XANTUS) with central outcome adjudication includingthromboembolic events and major bleeding has been conducted. 6,785 patients with non-valvularatrial fibrillation were enrolled for prevention of stroke and non-central nervous system (CNS)systemic embolism in clinical practice. The mean CHADS2 and HAS-BLED scores were both 2.0 in
XANTUS, compared to a mean CHADS2 and HAS-BLED score of 3.5 and 2.8 in ROCKET AF,respectively. Major bleeding occurred in 2.1 per 100 patient years. Fatal haemorrhage was reported in0.2 per 100 patient years and intracranial haemorrhage in 0.4 per 100 patient years. Stroke or non-CNSsystemic embolism was recorded in 0.8 per 100 patient years.
These observations in clinical practice are consistent with the established safety profile in thisindication.
Patients undergoing cardioversionA prospective, randomised, open-label, multicentre, exploratory study with blinded endpointevaluation (X-VERT) was conducted in 1504 patients (oral anticoagulant naive and pre-treated) withnon-valvular atrial fibrillation scheduled for cardioversion to compare rivaroxaban with dose-adjusted
VKA (randomised 2:1), for the prevention of cardiovascular events. TEE- guided (1 - 5 days of pre-treatment) or conventional cardioversion (at least three weeks of pre-treatment) strategies wereemployed. The primary efficacy outcome (all stroke, transient ischaemic attack, non-CNS systemicembolism, myocardial infarction (MI) and cardiovascular death) occurred in 5 (0.5%) patients in therivaroxaban group (n = 978) and 5 (1.0%) patients in the VKA group (n = 492; RR 0.50; 95% CI 0.15-1.73; modified ITT population). The principal safety outcome (major bleeding) occurred in 6 (0.6%)and 4 (0.8%) patients in the rivaroxaban (n = 988) and VKA (n = 499) groups, respectively (RR 0.76;95% CI 0.21-2.67; safety population). This exploratory study showed comparable efficacy and safetybetween rivaroxaban and VKA treatment groups in the setting of cardioversion.
Patients with non-valvular atrial fibrillation who undergo PCI with stent placement
A randomised, open-label, multicentre study (PIONEER AF-PCI) was conducted in 2,124 patientswith non-valvular atrial fibrillation who underwent PCI with stent placement for primaryatherosclerotic disease to compare safety of two rivaroxaban regimens and one VKA regimen. Patientswere randomly assigned in a 1:1:1 fashion for an overall 12-month-therapy. Patients with a history ofstroke or transient ischaemic attack were excluded.
Group 1 received rivaroxaban 15 mg once daily (10 mg once daily in patients with creatinineclearance 30 - 49 ml/min) plus P2Y12 inhibitor. Group 2 received rivaroxaban 2.5 mg twice daily plus
DAPT (dual antiplatelet therapy i.e. clopidogrel 75 mg [or alternate P2Y12 inhibitor] plus low-dose
ASA) for 1, 6 or 12 months followed by rivaroxaban 15 mg (or 10 mg for subjects with creatinineclearance 30 - 49 ml/min) once daily plus low-dose ASA. Group 3 received dose-adjusted VKA plus
DAPT for 1, 6 or 12 months followed by dose-adjusted VKA plus low-dose acetylsalicylic acid.
The primary safety endpoint, clinically significant bleeding events, occurred in 109 (15.7%), 117(16.6%), and 167 (24.0%) subjects in group 1, group 2 and group 3, respectively (HR 0.59; 95% CI0.47-0.76; p<0.001, and HR 0.63; 95% CI 0.50-0.80; p<0.001, respectively). The secondary endpoint(composite of cardiovascular events CV death, MI, or stroke) occurred in 41 (5.9%), 36 (5.1%), and36 (5.2%) subjects in the group 1, group 2 and group 3, respectively. Each of the rivaroxabanregimens showed a significant reduction in clinically significant bleeding events compared to the
VKA regimen in patients with non-valvular atrial fibrillation who underwent a PCI with stentplacement.
The primary objective of PIONEER AF-PCI was to assess safety. Data on efficacy (includingthromboembolic events) in this population are limited.
Treatment of DVT, PE and prevention of recurrent DVT and PE
The rivaroxaban clinical programme was designed to demonstrate the efficacy of rivaroxaban in theinitial and continued treatment of acute DVT and PE and prevention of recurrence.
Over 12,800 patients were studied in four randomised controlled phase III clinical studies (Einstein
DVT, Einstein PE, Einstein Extension and Einstein Choice) and additionally a predefined pooledanalysis of the Einstein DVT and Einstein PE studies was conducted. The overall combined treatmentduration in all studies was up to 21 months.
In Einstein DVT 3,449 patients with acute DVT were studied for the treatment of DVT and theprevention of recurrent DVT and PE (patients who presented with symptomatic PE were excludedfrom this study). The treatment duration was for 3, 6 or 12 months depending on the clinicaljudgement of the investigator.
For the initial 3 week treatment of acute DVT 15 mg rivaroxaban was administered twice daily. Thiswas followed by 20 mg rivaroxaban once daily.
In Einstein PE, 4,832 patients with acute PE were studied for the treatment of PE and the prevention ofrecurrent DVT and PE. The treatment duration was for 3, 6 or 12 months depending on the clinicaljudgement of the investigator.
For the initial treatment of acute PE 15 mg rivaroxaban was administered twice daily for three weeks.
This was followed by 20 mg rivaroxaban once daily.
In both the Einstein DVT and the Einstein PE study, the comparator treatment regimen consisted ofenoxaparin administered for at least 5 days in combination with vitamin K antagonist treatment untilthe PT/INR was in therapeutic range (≥ 2.0). Treatment was continued with a vitamin K antagonistdose-adjusted to maintain the PT/INR values within the therapeutic range of 2.0 to 3.0.
In Einstein Extension 1,197 patients with DVT or PE were studied for the prevention of recurrent
DVT and PE. The treatment duration was for an additional 6 or 12 months in patients who hadcompleted 6 to 12 months of treatment for VTE depending on the clinical judgment of theinvestigator. Rivaroxaban 20 mg once daily was compared with placebo.
Einstein DVT, PE and Extension used the same pre-defined primary and secondary efficacy outcomes.
The primary efficacy outcome was symptomatic recurrent VTE defined as the composite of recurrent
DVT or fatal or non-fatal PE. The secondary efficacy outcome was defined as the composite ofrecurrent DVT, non-fatal PE and all-cause mortality.
In Einstein Choice, 3,396 patients with confirmed symptomatic DVT and/or PE who completed 6-12months of anticoagulant treatment were studied for the prevention of fatal PE or non-fatalsymptomatic recurrent DVT or PE. Patients with an indication for continued therapeutic-dosedanticoagulation were excluded from the study. The treatment duration was up to 12 months dependingon the individual randomisation date (median: 351 days). Rivaroxaban 20 mg once daily andrivaroxaban 10 mg once daily were compared with 100 mg acetylsalicylic acid once daily.
The primary efficacy outcome was symptomatic recurrent VTE defined as the composite of recurrent
DVT or fatal or non-fatal PE.
In the Einstein DVT study (see Table 6) rivaroxaban was demonstrated to be non-inferior toenoxaparin/VKA for the primary efficacy outcome (p < 0.0001 (test for non-inferiority); HR: 0.680(0.443 - 1.042), p=0.076 (test for superiority)). The prespecified net clinical benefit (primary efficacyoutcome plus major bleeding events) was reported with a HR of 0.67 ((95% CI: 0.47 - 0.95), nominalp -value p=0.027) in favour of rivaroxaban. INR values were within the therapeutic range a mean of60.3% of the time for the mean treatment duration of 189 days, and 55.4%, 60.1%, and 62.8% of thetime in the 3-, 6-, and 12-month intended treatment duration groups, respectively. In theenoxaparin/VKA group, there was no clear relation between the level of mean centre TTR (Time in
Target INR Range of 2.0 - 3.0) in the equally sized tertiles and the incidence of the recurrent VTE(p=0.932 for interaction). Within the highest tertile according to centre, the HR with rivaroxabanversus warfarin was 0.69 (95% CI: 0.35 - 1.35).
The incidence rates for the primary safety outcome (major or clinically relevant non-major bleedingevents) as well as the secondary safety outcome (major bleeding events) were similar for bothtreatment groups.
Table 6: Efficacy and safety results from phase III Einstein DVT
Study population 3,449 patients with symptomatic acute DVT
Treatment dose and duration Rivaroxabana) Enoxaparin/VKAb)3, 6 or 12 months 3, 6 or 12 months
N=1,731 N=1,718
Symptomatic recurrent VTE* 36 (2.1%) 51 (3.0%)
Symptomatic recurrent PE 20 (1.2%) 18 (1.0%)
Symptomatic recurrent DVT 14 (0.8%) 28 (1.6%)
Symptomatic PE and DVT 1 0(0.1%)
Fatal PE/death where PE 4 (0.2%) 6 (0.3%)cannot be ruled out
Major or clinically relevant 139 (8.1%) 138 (8.1%)non-major bleeding
Major bleeding events 14 (0.8%) 20 (1.2%)a) Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once dailyb) Enoxaparin for at least 5 days, overlapped with and followed by VKA
* p < 0.0001 (non-inferiority to a prespecified HR of 2.0); HR: 0.680 (0.443 - 1.042), p=0.076(superiority)
In the Einstein PE study (see Table 7) rivaroxaban was demonstrated to be non-inferior toenoxaparin/VKA for the primary efficacy outcome (p=0.0026 (test for non-inferiority); HR: 1.123(0.749 - 1.684)). The prespecified net clinical benefit (primary efficacy outcome plus major bleedingevents) was reported with a HR of 0.849 ((95% CI: 0.633 - 1.139), nominal p -value p=0.275). INRvalues were within the therapeutic range a mean of 63% of the time for the mean treatment duration of215 days, and 57%, 62%, and 65% of the time in the 3-, 6-, and 12-month intended treatment durationgroups, respectively. In the enoxaparin/VKA group, there was no clear relation between the level ofmean centre TTR (Time in Target INR Range of 2.0 - 3.0) in the equally sized tertiles and theincidence of the recurrent VTE (p=0.082 for interaction). Within the highest tertile according tocentre, the HR with rivaroxaban versus warfarin was 0.642 (95% CI: 0.277 - 1.484).
The incidence rates for the primary safety outcome (major or clinically relevant non-major bleedingevents) were slightly lower in the rivaroxaban treatment group (10.3% (249/2412)) than in theenoxaparin/VKA treatment group (11.4% (274/2405)). The incidence of the secondary safety outcome(major bleeding events) was lower in the rivaroxaban group (1.1% (26/2412)) than in theenoxaparin/VKA group (2.2% (52/2405)) with a HR 0.493 (95% CI: 0.308 - 0.789).
Table 7: Efficacy and safety results from phase III Einstein PE
Study population 4,832 patients with an acute symptomatic PE
Treatment dose and duration Rivaroxaban a) Enoxaparin/VKAb)3, 6 or 12 months 3, 6 or 12 months
N=2,419 N=2,413
Symptomatic recurrent VTE* 50 44(2.1%) (1.8%)
Symptomatic recurrent PE 23 20(1.0%) (0.8%)
Symptomatic recurrent DVT 18 17(0.7%) (0.7%)
Symptomatic PE and DVT 0 2(<0.1%)
Fatal PE/death where PE 11 7cannot be ruled out (0.5%) (0.3%)
Major or clinically relevant 249 274non-major bleeding (10.3%) (11.4%)
Major bleeding events 26 52(1.1%) (2.2%)a) Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once dailyb) Enoxaparin for at least 5 days, overlapped with and followed by VKA
* p < 0.0026 (non-inferiority to a prespecified HR of 2.0); HR: 1.123 (0.749 - 1.684)
A prespecified pooled analysis of the outcome of the Einstein DVT and PE studies was conducted (see
Table 8).
Table 8: Efficacy and safety results from pooled analysis of phase III Einstein DVT and Einstein
PE
Study population 8,281 patients with an acute symptomatic DVT or PE
Treatment dose and duration Rivaroxabana) Enoxaparin/VKAb)3, 6 or 12 months 3, 6 or 12 months
N=4,150 N=4,131
Symptomatic recurrent VTE* 86 95(2.1%) (2.3%)
Symptomatic recurrent PE 43 38(1.0%) (0.9%)
Symptomatic recurrent DVT 32 45(0.8%) (1.1%)
Symptomatic PE and DVT 1 2(<0.1%) (<0.1%)
Fatal PE/death where PE 15 13cannot be ruled out (0.4%) (0.3%)
Major or clinically relevant 388 412non-major bleeding (9.4%) (10.0%)
Major bleeding events 40 72(1.0%) (1.7%)a) Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once dailyb) Enoxaparin for at least 5 days, overlapped with and followed by VKA
* p < 0.0001 (non-inferiority to a prespecified HR of 1.75); HR: 0.886 (0.661 - 1.186)
The prespecified net clinical benefit (primary efficacy outcome plus major bleeding events) of thepooled analysis was reported with a HR of 0.771 ((95% CI: 0.614 - 0.967), nominal p-value p=0.0244).
In the Einstein Extension study (see Table 9) rivaroxaban was superior to placebo for the primary andsecondary efficacy outcomes. For the primary safety outcome (major bleeding events) there was anon-significant numerically higher incidence rate for patients treated with rivaroxaban 20 mg oncedaily compared to placebo. The secondary safety outcome (major or clinically relevant non-majorbleeding events) showed higher rates for patients treated with rivaroxaban 20 mg once daily comparedto placebo.
Table 9: Efficacy and safety results from phase III Einstein Extension
Study population 1,197 patients continued treatment and prevention ofrecurrent VTE
Treatment dose and duration Rivaroxaban a) 6 or 12 Placebo 6 or 12 monthsmonths N=594
N=602
Symptomatic recurrent VTE* 8 (1.3%) 42 (7.1%)
Symptomatic recurrent PE 2 (0.3%) 13 (2.2%)
Symptomatic recurrent DVT 5 (0.8%) 31 (5.2%)
Fatal PE/death where PE 1 1cannot be ruled out (0.2%) (0.2%)
Major bleeding events 4 (0.7%) 0 (0.0%)
Clinically relevant non-major 32 (5.4%) 7 (1.2%)bleedinga) Rivaroxaban 20 mg once daily
* p < 0.0001 (superiority), HR: 0.185 (0.087 - 0.393)
In the Einstein Choice study (see Table 10) rivaroxaban 20 mg and 10 mg were both superior to100 mg acetylsalicylic acid for the primary efficacy outcome. The principal safety outcome (majorbleeding events) was similar for patients treated with rivaroxaban 20 mg and 10 mg once dailycompared to 100 mg acetylsalicylic acid.
Table 10: Efficacy and safety results from phase III Einstein Choice
Study population 3,396 patients continued prevention ofrecurrentVTE
Treatment dose Rivaroxaban 20 mg Rivaroxaban 10 mg Acetylsalicylic acidod od 100 mg od
N=1,107 N=1,127 N=1,131
Treatment duration 349 [189-362] days 353 [190-362] days 350 [186-362] daysmedian [interquartilerange]
Symptomatic recurrent 17 (1.5%)* 13 (1.2%)** 50 (4.4%)
VTE
Symptomatic recurrent 6 (0.5%) 6(0.5%) 19 (1.7%)
PE
Symptomatic recurrent 9 (0.8%) 8 (0.7%) 30 (2.7%)
DVT
Fatal PE/death where 2 (0.2%) 0(0.0%) 2(0.2%)
PE cannot be ruled out
Symptomatic recurrent 19 (1.7%) 18 (1.6%) 56 (5.0%)
VTE, MI, stroke, ornon-CNS systemicembolism
Major bleeding events 6 (0.5%) 5 (0.4%) 3 (0.3%)
Clinically relevant 30 (2.7) 22 (2.0) 20 (1.8)non-major bleeding
Symptomatic recurrent 23 (2.1%)+ 17 (1.5%)++ 53 (4.7%)
VTE or majorbleeding (net clinicalbenefit)od: once daily
* p<0.001(superiority) rivaroxaban 20 mg od versus acetylsalicylic acid 100 mg od; HR=0.34 (0.20-0.59)
** p<0.001 (superiority) 10 mg rivaroxaban od versus acetylsalicylic acid 100 mg od; HR=0.26 (0.14-0.47)+ rivaroxaban 20 mg od versus acetylsalicylic acid 100 mg od; HR=0.44 (0.27-0.71), p=0.0009(nominal)++ 10 mg rivaroxaban od versus acetylsalicylic acid 100 mg od; HR=0.32 (0.18-0.55), p<0.0001(nominal)
In addition to the phase III EINSTEIN programme, a prospective, non-interventional, open-labelcohort study (XALIA) with central outcome adjudication including recurrent VTE, major bleeding anddeath has been conducted. 5,142 patients with acute DVT were enrolled to investigate the long-termsafety of rivaroxaban compared with standard-of-care anticoagulation therapy in clinical practice.
Rates of major bleeding, recurrent VTE and all-cause mortality for rivaroxaban were 0.7%, 1.4% and0.5%, respectively. There were differences in patient baseline characteristics including age, cancer andrenal impairment. A pre-specified propensity score stratified analysis was used to adjust for measuredbaseline differences but residual confounding may, in spite of this, influence the results. Adjusted HRscomparing rivaroxaban and standard-of-care for major bleeding, recurrent VTE and all-cause mortalitywere 0.77 (95% CI 0.40 - 1.50), 0.91 (95% CI 0.54 - 1.54) and 0.51 (95% CI 0.24 - 1.07), respectively.
These results in clinical practice are consistent with the established safety profile in this indication.
Paediatric populationTreatment of VTE and prevention of VTE recurrence in paediatric patients
A total of 727 children with confirmed acute VTE, of whom 528 received rivaroxaban, were studied in6 open-label, multicentre paediatric studies. Body weight-adjusted dosing in patients from birth to lessthan 18 years resulted in rivaroxaban exposure similar to that observed in adult DVT patients treatedwith rivaroxaban 20 mg once daily as confirmed in the phase III study (see section 5.2).
The EINSTEIN Junior phase III study was a randomised, active-controlled, open-label multicentreclinical study in 500 paediatric patients (aged from birth to < 18 years) with confirmed acute VTE.
There were 276 children aged 12 to < 18 years, 101 children aged 6 to < 12 years, 69 children aged 2to < 6 years, and 54 children aged < 2 years.
Index VTE was classified as either central venous catheter-related VTE (CVC-VTE; 90/335 patientsin the rivaroxaban group, 37/165 patients in the comparator group), cerebral vein and sinus thrombosis(CVST; 74/335 patients in the rivaroxaban group, 43/165 patients in the comparator group), and allothers including DVT and PE (non-CVC-VTE; 171/335 patients in the rivaroxaban group, 85/165patients in the comparator group). The most common presentation of index thrombosis in childrenaged 12 to < 18 years was non-CVC-VTE in 211 (76.4%); in children aged 6 to < 12 years and aged2 to < 6 years was CVST in 48 (47.5%) and 35 (50.7%), respectively; and in children aged < 2 yearswas CVC-VTE in 37 (68.5%). There were no children < 6 months with CVST in the rivaroxabangroup. 22 of the patients with CVST had a CNS infection (13 patients in the rivaroxaban group and 9patients in comparator group).
VTE was provoked by persistent, transient, or both persistent and transient risk factors in 438 (87.6%)children.
Patients received initial treatment with therapeutic doses of UFH, LMWH, or fondaparinux for at least5 days, and were randomised 2:1 to receive either body weight-adjusted doses of rivaroxaban orcomparator group (heparins, VKA) for a main study treatment period of 3 months (1 month forchildren < 2 years with CVC-VTE). At the end of the main study treatment period, the diagnosticimaging test, which was obtained at baseline, was repeated, if clinically feasible. The study treatmentcould be stopped at this point, or at the discretion of the Investigator continued for up to 12 months(for children < 2 years with CVC-VTE up to 3 months) in total.
The primary efficacy outcome was symptomatic recurrent VTE. The primary safety outcome was thecomposite of major bleeding and clinically relevant non-major bleeding (CRNMB). All efficacy andsafety outcomes were centrally adjudicated by an independent committee blinded for treatmentallocation. The efficacy and safety results are shown in Tables 11 and 12 below.
Recurrent VTEs occurred in the rivaroxaban group in 4 of 335 patients and in the comparator group in5 of 165 patients. The composite of major bleeding and CRNMB was reported in 10 of 329 patients(3%) treated with rivaroxaban and in 3 of 162 patients (1.9%) treated with comparator. Net clinicalbenefit (symptomatic recurrent VTE plus major bleeding events) was reported in the rivaroxabangroup in 4 of 335 patients and in the comparator group in 7 of 165 patients. Normalisation of thethrombus burden on repeat imaging occurred in 128 of 335 patients with rivaroxaban treatment and in43 of 165 patients in the comparator group. These findings were generally similar among age groups.
There were 119 (36.2%) children with any treatment-emergent bleeding in the rivaroxaban group and45 (27.8%) children in the comparator group.
Table 11: Efficacy results at the end of the main treatment period
Event Rivaroxaban Comparator
N=335* N=165*
Recurrent VTE (primary efficacy outcome) 4 5(1.2%, 95% CI (3.0%, 95% CI0.4% - 3.0%) 1.2% - 6.6%)
Composite: Symptomatic recurrent VTE + 5 6asymptomatic deterioration on repeat imaging (1.5%, 95% CI (3.6%, 95% CI0.6% - 3.4%) 1.6% - 7.6%)
Composite: Symptomatic recurrent VTE + 21 19asymptomatic deterioration + no change on repeat (6.3%, 95% CI (11.5%, 95% CIimaging 4.0% - 9.2%) 7.3% - 17.4%)
Normalisation on repeat imaging 128 43(38.2%, 95% CI (26.1%, 95% CI33.0% - 43.5%) 19.8% - 33.0%)
Composite: Symptomatic recurrent VTE + major 4 7bleeding (net clinical benefit) (1.2%, 95% CI (4.2%, 95% CI0.4% - 3.0%) 2.0% - 8.4%)
Fatal or non-fatal pulmonary embolism 1 1(0.3%, 95% CI (0.6%, 95% CI0.0% - 1.6%) 0.0% - 3.1%)
*FAS= full analysis set, all children who were randomised
Table 12: Safety results at the end of the main treatment period
Rivaroxaban Comparator
N=329* N=162*
Composite: Major bleeding + CRNMB (primary safety 10 3outcome) (3.0%, 95% CI (1.9%, 95% CI1.6% - 5.5%) 0.5% - 5.3%)
Major bleeding 0 2(0.0%, 95% CI (1.2%, 95% CI0.0% - 1.1%) 0.2% - 4.3%)
Any treatment-emergent bleedings 119 (36.2%) 45 (27.8%)
* SAF= safety analysis set, all children who were randomised and received at least 1 dose ofstudy medicinal product.
The efficacy and safety profile of rivaroxaban was largely similar between the paediatric VTEpopulation and the DVT/PE adult population, however, the proportion of subjects with any bleedingwas higher in the paediatric VTE population as compared to the DVT/PE adult population.
Patients with high risk triple positive antiphospholipid syndrome
In an investigator sponsored, randomised open-label multicentre study with blinded endpointadjudication, rivaroxaban was compared to warfarin in patients with a history of thrombosis,diagnosed with antiphospholipid syndrome and at high risk for thromboembolic events (positive for all3 antiphospholipid tests: lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein Iantibodies). The study was terminated prematurely after the enrolment of 120 patients due to an excessof events among patients in the rivaroxaban arm. Mean follow-up was 569 days. 59 patients wererandomised to rivaroxaban 20 mg (15 mg for patients with creatinine clearance (CrCl) <50 mL/min)and 61 to warfarin (INR 2.0-3.0). Thromboembolic events occurred in 12% of patients randomised torivaroxaban (4 ischaemic strokes and 3 myocardial infarctions). No events were reported in patientsrandomised to warfarin. Major bleeding occurred in 4 patients (7%) of the rivaroxaban group and 2patients (3%) of the warfarin group.
Paediatric populationThe European Medicines Agency has waived the obligation to submit the results of studies withrivaroxaban in all subsets of the paediatric population in the prevention of thromboembolic events (seesection 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
The following information is based on the data obtained in adults.
Rivaroxaban is rapidly absorbed with maximum concentrations (Cmax) appearing 2 - 4 hours aftertablet intake.
Oral absorption of rivaroxaban is almost complete and oral bioavailability is high (80 - 100%) for the2.5 mg and 10 mg tablet dose, irrespective of fasting/fed conditions. Intake with food does not affectrivaroxaban AUC or Cmax at the 2.5 mg and 10 mg dose.
Due to a reduced extent of absorption an oral bioavailability of 66% was determined for the 20 mgtablet under fasting conditions. When rivaroxaban 20 mg tablets are taken together with food increasesin mean AUC by 39% were observed when compared to tablet intake under fasting conditions,indicating almost complete absorption and high oral bioavailability. Rivaroxaban 15 mg and 20 mg areto be taken with food (see section 4.2).
Rivaroxaban pharmacokinetics are approximately linear up to about 15 mg once daily in fasting state.
Under fed conditions rivaroxaban 10 mg, 15 mg and 20 mg tablets demonstrated dose-proportionality.
At higher doses rivaroxaban displays dissolution limited absorption with decreased bioavailability anddecreased absorption rate with increased dose.
Variability in rivaroxaban pharmacokinetics is moderate with inter-individual variability (CV%)ranging from 30% to 40%.
Absorption of rivaroxaban is dependent on the site of its release in the gastrointestinal tract. A 29%and 56% decrease in AUC and Cmax compared to tablet was reported when rivaroxaban granulate isreleased in the proximal small intestine. Exposure is further reduced when rivaroxaban is released inthe distal small intestine, or ascending colon. Therefore, administration of rivaroxaban distal to thestomach should be avoided since this can result in reduced absorption and related rivaroxabanexposure.
Bioavailability (AUC and Cmax) was comparable for 20 mg rivaroxaban administered orally as acrushed tablet mixed in apple puree, or suspended in water and administered via a gastric tubefollowed by a liquid meal, compared to a whole tablet. Given the predictable, dose-proportionalpharmacokinetic profile of rivaroxaban, the bioavailability results from this study are likely applicableto lower rivaroxaban doses.
Paediatric populationChildren received rivaroxaban tablet or oral suspension during or closely after feeding or food intakeand with a typical serving of liquid to ensure reliable dosing in children. As in adults, rivaroxaban isreadily absorbed after oral administration as tablet or granules for oral suspension formulation inchildren. No difference in the absorption rate nor in the extent of absorption between the tablet andgranules for oral suspension formulation was observed. No PK data following intravenousadministration to children are available so that the absolute bioavailability of rivaroxaban in children isunknown. A decrease in the relative bioavailability for increasing doses (in mg/kg bodyweight) wasfound, suggesting absorption limitations for higher doses, even when taken together with food.
Rivaroxaban 20 mg tablets should be taken with feeding or with food (see section 4.2).
DistributionPlasma protein binding in adults is high at approximately 92% to 95%, with serum albumin being themain binding component. The volume of distribution is moderate with Vss being approximately50 litres.
Paediatric populationNo data on rivaroxaban plasma protein binding specific to children is available. No PK data followingintravenous administration of rivaroxaban to children is available. Vss estimated via population PKmodelling in children (age range 0 to < 18 years) following oral administration of rivaroxaban isdependent on body weight and can be described with an allometric function, with an average of 113 Lfor a subject with a body weight of 82.8 kg.
Biotransformation and eliminationIn adults, of the administered rivaroxaban dose, approximately 2/3 undergoes metabolic degradation,with half then being eliminated renally and the other half eliminated by the faecal route. The final 1/3of the administered dose undergoes direct renal excretion as unchanged active substance in the urine,mainly via active renal secretion.
Rivaroxaban is metabolised via CYP3A4, CYP2J2 and CYP-independent mechanisms. Oxidativedegradation of the morpholinone moiety and hydrolysis of the amide bonds are the major sites ofbiotransformation. Based on in vitro investigations rivaroxaban is a substrate of the transporterproteins P-gp (P-glycoprotein) and Bcrp (breast cancer resistance protein).
Unchanged rivaroxaban is the most important compound in human plasma, with no major or activecirculating metabolites being present. With a systemic clearance of about 10 l/h, rivaroxaban can beclassified as a low-clearance substance. After intravenous administration of a 1 mg dose theelimination half-life is about 4.5 hours. After oral administration the elimination becomes absorptionrate limited. Elimination of rivaroxaban from plasma occurs with terminal half-lives of 5 to 9 hours inyoung individuals, and with terminal half-lives of 11 to 13 hours in the elderly.
Paediatric populationNo metabolism data specific to children is available. No PK data following intravenous administrationof rivaroxaban to children is available. CL estimated via population PK modelling in children (agerange 0 to < 18 years) following oral administration of rivaroxaban is dependent on body weight andcan be described with an allometric function, with an average of 8 L/h for a subject with body weightof 82.8 kg. The geometric mean values for disposition half-lives (t1/2) estimated via population PKmodelling decrease with decreasing age and ranged from 4.2 h in adolescents to approximately 3 h inchildren aged 2-12 years down to 1.9 and 1.6 h in children aged 0.5-< 2 years and less than 0.5 years,respectively.
Special populationsGender
In adults, there were no clinically relevant differences in pharmacokinetics and pharmacodynamicsbetween male and female patients. An exploratory analysis did not reveal relevant differences inrivaroxaban exposure between male and female children.
Elderly populationElderly patients exhibited higher plasma concentrations than younger patients, with mean AUC valuesbeing approximately 1.5 fold higher, mainly due to reduced (apparent) total and renal clearance. Nodose adjustment is necessary.
Different weight categories
In adults, extremes in body weight (< 50 kg or > 120 kg) had only a small influence on rivaroxabanplasma concentrations (less than 25%). No dose adjustment is necessary.
In children, rivaroxaban is dosed based on body weight. An exploratory analysis did not reveal arelevant impact of underweight or obesity on rivaroxaban exposure in children.
Inter-ethnic differences
In adults, no clinically relevant inter-ethnic differences among Caucasian, African-American,
Hispanic, Japanese or Chinese patients were observed regarding rivaroxaban pharmacokinetics andpharmacodynamics.
An exploratory analysis did not reveal relevant inter-ethnic differences in rivaroxaban exposure among
Japanese, Chinese or Asian children outside Japan and China compared to the respective overallpaediatric population.
Hepatic impairmentCirrhotic adult patients with mild hepatic impairment (classified as Child Pugh A) exhibited onlyminor changes in rivaroxaban pharmacokinetics (1.2 fold increase in rivaroxaban AUC on average),nearly comparable to their matched healthy control group. In cirrhotic patients with moderate hepaticimpairment (classified as Child Pugh B), rivaroxaban mean AUC was significantly increased by 2.3fold compared to healthy volunteers. Unbound AUC was increased 2.6 fold. These patients also hadreduced renal elimination of rivaroxaban, similar to patients with moderate renal impairment. Thereare no data in patients with severe hepatic impairment.
The inhibition of factor Xa activity was increased by a factor of 2.6 in patients with moderate hepaticimpairment as compared to healthy volunteers; prolongation of PT was similarly increased by a factorof 2.1. Patients with moderate hepatic impairment were more sensitive to rivaroxaban resulting in asteeper PK/PD relationship between concentration and PT.
Rivaroxaban is contraindicated in patients with hepatic disease associated with coagulopathy andclinically relevant bleeding risk, including cirrhotic patients with Child Pugh B and C (see section4.3).
No clinical data is available in children with hepatic impairment.
Renal impairmentIn adults, there was an increase in rivaroxaban exposure correlated to decrease in renal function, asassessed via creatinine clearance measurements. In individuals 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 and1.6 fold respectively. Corresponding increases in pharmacodynamic effects were more pronounced. Inindividuals with mild, moderate and severe renal impairment the overall inhibition of factor Xaactivity was increased by a factor of 1.5, 1.9 and 2.0 respectively as compared to healthy volunteers;prolongation of PT was similarly increased by a factor of 1.3, 2.2 and 2.4 respectively. There are nodata in patients with creatinine clearance < 15 ml/min.
Due to the high plasma protein binding rivaroxaban is not expected to be dialysable.
Use is not recommended in patients with creatinine clearance < 15 ml/min. Rivaroxaban is to be usedwith caution in patients with creatinine clearance 15 - 29 ml/min (see section 4.4).
No clinical data is available in children 1 year or older with moderate or severe renal impairment(glomerular filtration rate < 50 mL/min/1.73 m2).
Pharmacokinetic data in patients
In patients receiving rivaroxaban 20 mg once daily for treatment of acute DVT the geometric meanconcentration (90% prediction interval) 2 - 4 h and about 24 h after dose (roughly representingmaximum and minimum concentrations during the dose interval) was 215 (22 - 535) and 32 (6 - 239)mcg/l, respectively.
In paediatric patients with acute VTE receiving body weight-adjusted rivaroxaban leading to anexposure similar to that in adult DVT patients receiving a 20 mg once daily dose, the geometric meanconcentrations (90% interval) at sampling time intervals roughly representing maximum and minimumconcentrations during the dose interval are summarised in Table 13.
Table 13: Summary statistics (geometric mean (90% interval)) of rivaroxaban steady stateplasma concentrations (mcg/L) by dosing regimen and age
Timeintervalso.d. N 12 - N 6 -< 12 years< 18 years2.5-4h post 171 241.5 24 229.7(105-484) (91.5-777)20-24h post 151 20.6 24 15.9(5.69-66.5) (3.42-45.5)b.i.d. N 6 -< 12 years N 2 -< 6 years N 0.5 -< 2 years2.5-4h post 36 145.4 38 171.8 2 n.c.
(46.0-343) (70.7-438)10-16h post 33 26.0 37 22.2 3 10.7(7.99-94.9) (0.25-127) (n.c.-n.c.)t.i.d. N 2 -< 6 years N Birth - N 0.5 -< 2 years N Birth -< 2 years < 0.5 years0.5-3h post 5 164.7 25 111.2 13 114.3 12 108.0(108-283) (22.9-320) (22.9-346) (19.2-320)7-8h post 5 33.2 23 18.7 12 21.4 11 16.1(18.7-99.7) (10.1-36.5) (10.5-65.6) (1.03-33.6)o.d. = once daily, b.i.d. = twice daily, t.i.d. three times daily, n.c. = not calculated
Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculationof statistics (LLOQ = 0.5 mcg/L).
Pharmacokinetic/pharmacodynamic relationshipThe pharmacokinetic/pharmacodynamic (PK/PD) relationship between rivaroxaban plasmaconcentration and several PD endpoints (factor Xa inhibition, PT, aPTT, Heptest) has been evaluatedafter administration of a wide range of doses (5 - 30 mg twice a day). The relationship betweenrivaroxaban concentration and factor Xa activity was best described by an Emax model. For PT, thelinear intercept model generally described the data better. Depending on the different PT reagentsused, the slope differed considerably. When Neoplastin PT was used, baseline PT was about 13 s andthe slope was around 3 to 4 s/(100 mcg/l). The results of the PK/PD analyses in Phase II and III wereconsistent with the data established in healthy subjects.
Paediatric populationSafety and efficacy have not been established in the indication prevention of stroke and systemicembolism in patients with non-valvular atrial fibrillation for children and adolescents up to 18 years.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, single dose toxicity, phototoxicity, genotoxicity, carcinogenic potential and juveniletoxicity.
Effects observed in repeat-dose toxicity studies were mainly due to the exaggerated pharmacodynamicactivity of rivaroxaban. In rats, increased IgG and IgA plasma levels were seen at clinically relevantexposure levels.
In rats, no effects on male or female fertility were seen. Animal studies have shown reproductivetoxicity related to the pharmacological mode of action of rivaroxaban (e.g. haemorrhagiccomplications). Embryo-foetal toxicity (post-implantation loss, retarded/progressed ossification,hepatic multiple light coloured spots) and an increased incidence of common malformations as well asplacental changes were observed at clinically relevant plasma concentrations. In the pre- and post-natal study in rats, reduced viability of the offspring was observed at doses that were toxic to the dams.
Rivaroxaban was tested in juvenile rats up to 3 - month treatment duration starting at postnatal day 4showing a non dose-related increase in periinsular haemorrhage. No evidence of target organ-specifictoxicity was seen.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Microcrystalline cellulose
Lactose monohydrate
Croscarmellose sodium
Hypromellose
Sodium laurilsulfate
Magnesium stearate
Film-coat
Poly(vinyl alcohol)
Macrogol 3350
Talc
Titanium dioxide (E171)
Ferric oxide red (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
Bottle once opened: 180 days.
Crushed tablets
Crushed rivaroxaban tablets are stable in water and apple puree for 2 hours.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
PVC/PVdC/Aluminium foil blister packs containing 14, 28, 30, 98 or 100 film-coated tablets orperforated unit dose blisters in cartons of 14 × 1, 28 × 1, 30 × 1, 50 × 1, 90 × 1, 98 × 1 or 100 × 1 film-coated tablets or calendar packs of 14, 28 or 98 film-coated tablets.
White HDPE bottles with white opaque PP screw cap with aluminium induction sealing liner wadcontaining 30, 98,100 or 250 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.
Crushing of tablets
Rivaroxaban Viatris tablets may be crushed and suspended in 50 mL of water and administered via anasogastric tube or gastric feeding tube after confirming gastric placement of the tube. Afterwards, thetube should be flushed with water. Since rivaroxaban absorption is dependent on the site of activesubstance release, administration of rivaroxaban distal to the stomach should be avoided, as this canresult in reduced absorption and thereby, reduced active substance exposure. Enteral feeding isrequired immediately after administration of the 15 mg or 20 mg tablets.
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu.