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

Posology
Prevention of stroke and systemic embolism
The recommended dose is 20 mg once daily, which is also the recommended maximum
dose.
Therapy with Banoriv should be continued long term provided the benefit of prevention
of stroke and systemic embolism outweighs the risk of bleeding (see section 4.4).
If a dose is missed the patient should take Banoriv immediately and continue on the
following day with the once daily intake as recommended. The dose should not be
doubled within the same day to make up for a missed dose.
 

Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE
The recommended dose for the initial treatment of acute DVT or PE is 15 mg twice daily
for the first three 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 PE provoked by major transient risk factors (i.e. recent major surgery or trauma).
Longer duration of therapy should be considered in patients with provoked DVT or PE

not related to major transient risk factors, 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 6 months therapy for DVT or PE), the recommended dose is 10 mg once daily.
In patients in whom the risk of recurrent DVT or PE is considered high, such as those
with complicated comorbidities, or who have developed recurrent DVT or PE on
extended prevention with Banoriv 10 mg once daily, a dose of Banoriv 20 mg once daily
should be considered.

The duration of therapy and dose selection should be individualised after careful
assessment of the treatment benefit against the risk for bleeding (see section 4.4).

	Time Period	Dosing schedule	Total daily dose
Treatment and prevention of recurrent DVT and PE	Day 1 - 21	15 mg twice daily	30 mg
	Day 22 onwards	20 mg once daily	20 mg
Prevention of recurrent DVT and PE	Prevention of recurrent DVT and PE	10 mg once daily or 20 mg once daily	10 mg or 20 mg

To support the dose switch from 15 mg to 20 mg after Day 21 a first 4 weeks treatment
initiation pack of Banoriv for treatment of DVT/PE is available (see section 6.5).
If a dose is missed during the 15 mg twice daily treatment phase (day 1 - 21), the patient
should take Banoriv immediately to ensure intake of 30 mg Banoriv per day. In this case
two 15 mg tablets may be taken at once. The patient should continue with the regular 15
mg twice daily intake as recommended on the following day.
If a dose is missed during the once daily treatment phase, the patient should take Banoriv
immediately, and continue on the following day with the once daily intake as
recommended. The dose should not be doubled within the same day to make up for a
missed dose.

Converting from Vitamin K Antagonists (VKA) to Banoriv
For patients treated for prevention of stroke and systemic embolism, VKA treatment
should be stopped and Banoriv therapy should be initiated when the International
Normalized Ratio (INR) is ≤ 3.0.
For patients treated for DVT, PE and prevention of recurrence, VKA treatment should be
stopped and Banoriv therapy should be initiated once the INR is ≤ 2.5.
When converting patients from VKAs to Banoriv, INR values will be falsely elevated
after the intake of Banoriv. The INR is not valid to measure the anticoagulant activity of
Banoriv, and therefore should not be used (see section 4.5).

Converting from Banoriv to Vitamin K antagonists (VKA)
There is a potential for inadequate anticoagulation during the transition from Banoriv to
VKA. Continuous adequate anticoagulation should be ensured during any transition to an
alternate anticoagulant. It should be noted that Banoriv can contribute to an elevated INR.
In patients converting from Banoriv 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 be used followed by VKA dosing, as guided by INR testing. While patients
are on both Banoriv and VKA the INR should not be tested earlier than 24 hours after the
previous dose but prior to the next dose of Banoriv. Once Banoriv is discontinued INR
testing may be done reliably at least 24 hours after the last dose (see sections 4.5 and 5.2).

Converting from parenteral anticoagulants to Banoriv
For patients currently receiving a parenteral anticoagulant, discontinue the parenteral
anticoagulant and start Banoriv 0 to 2 hours before the time that the next scheduled
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
medicinal product (e.g. intravenous unfractionated heparin).

Converting from Banoriv to parenteral anticoagulants
Give the first dose of parenteral anticoagulant at the time the next Banoriv dose would be
taken.
 

Special populations
Renal impairment
Limited clinical data for patients with severe renal impairment (creatinine clearance 15 -
29 ml/min) indicate that rivaroxaban plasma concentrations are significantly increased.
Therefore, Banoriv is to be used with caution in these patients. Use is not recommended
in patients with creatinine clearance < 15 ml/min (see sections 4.4 and 5.2).
In patients with moderate (creatinine clearance 30 - 49 ml/min) or severe (creatinine
clearance 15 - 29 ml/min) renal impairment the following dosage recommendations
apply:
- For the prevention of stroke and systemic embolism in patients with non-valvular atrial
fibrillation, the recommended dose is 15 mg once daily (see section 5.2).
- For the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE:
patients should be treated with 15 mg twice daily for the first 3 weeks. Thereafter, when
the recommended dose is 20 mg once daily, a reduction of the dose from 20 mg once
daily to 15 mg once daily should be considered if the patient's assessed risk for bleeding
outweighs the risk for recurrent DVT and PE. The recommendation for the use of 15 mg
is based on PK modelling and has 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
recommended dose is necessary.
No dose adjustment is necessary in patients with mild renal impairment (creatinine
clearance 50 - 80 ml/min) (see section 5.2).

Hepatic impairment
Banoriv is contraindicated in patients with hepatic disease associated with coagulopathy
and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C
(see sections 4.3 and 5.2).

Elderly population
No dose adjustment (see section 5.2).

Body weight
No dose adjustment (see section 5.2).

Gender
No dose adjustment (see section 5.2).

Paediatric population
The safety and efficacy of Banoriv in children aged 0 to 18 years have not been
established. No data are available. Therefore, Banoriv is not recommended for use in
children below 18 years of age.

Patients undergoing cardioversion
Banoriv can be initiated or continued in patients who may require cardioversion.
For transesophageal echocardiogram (TEE) guided cardioversion in patients not
previously treated with anticoagulants, Banoriv treatment should be started at least 4
hours before cardioversion to ensure adequate anticoagulation (see sections 5.1 and
5.2). For all patients, confirmation should be sought prior to cardioversion that the
patient has taken Banoriv as prescribed. Decisions on initiation and duration of treatment
should take established guideline recommendations for anticoagulant 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 Banoriv once daily (or 10 mg
Banoriv once daily for patients with moderate renal impairment [creatinine clearance 30
– 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).

Method of administration
For oral use.
Banoriv 20 mg tablets are to be taken with food (see section 5.2).
For patients who are unable to swallow whole tablets, Banoriv tablet may be crushed and
mixed with water or apple puree immediately prior to use and administered orally. After
the administration of crushed Banoriv 15 mg or 20 mg film-coated tablets, the dose
should be immediately followed by food.

The crushed Banoriv tablet may also be given through gastric tubes after confirmation of
the correct gastric placement of the tube. The crushed tablet should be administered in a
small amount of water via a gastric tube after which it should be flushed with water.
After the administration of crushed Banoriv 15 mg or 20 mg film-coated tablets, the dose
should then be immediately followed by enteral feeding (see section 5.2).

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 current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities. Concomitant treatment with any other anticoagulants e.g. unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, dabigatran etexilate, apixaban, etc.) except under specific circumstances of switching anticoagulant therapy (see section 4.2) or when UFH is given at doses necessary to maintain an open central venous or arterial catheter (see section 4.5). Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C (see section 5.2). Pregnancy and breast feeding (see section 4.6).

Clinical surveillance in line with anticoagulation practice is recommended throughout the
treatment period.

Haemorrhagic risk
As with other anticoagulants, patients taking Banoriv are to be carefully observed for
signs of bleeding. It is recommended to be used with caution in conditions with increased
risk of haemorrhage. Banoriv administration should be discontinued if severe
haemorrhage occurs.

In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito
urinary including abnormal vaginal or increased menstrual bleeding) and anaemia were
seen more frequently during long term rivaroxaban treatment compared with VKA
treatment. Thus, in addition to adequate clinical surveillance, laboratory testing of
haemoglobin/haematocrit could be of value to detect occult bleeding 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 are to be carefully monitored for signs and symptoms of bleeding complications
and anaemia after initiation of treatment (see section 4.8).
Any unexplained fall in haemoglobin or blood pressure should lead to a search for a
bleeding site.

Although treatment with rivaroxaban does not require routine monitoring of exposure,
rivaroxaban levels measured with a calibrated quantitative anti-factor Xa assay may be
useful in exceptional situations where knowledge of rivaroxaban exposure may help to
inform clinical decisions, e.g., overdose and emergency surgery (see sections 5.1 and
5.2).
 

Renal impairment
In patients with severe renal impairment (creatinine clearance < 30 ml/min) rivaroxaban
plasma levels may be significantly increased (1.6 fold on average) which may lead to an

increased bleeding risk. Banoriv 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 4.2 and 5.2).
Banoriv should be used with caution in patients with renal impairment concomitantly
receiving other medicinal products which increase rivaroxaban plasma concentrations
(see section 4.5).

Interaction with other medicinal products
The use of Banoriv is not recommended in patients receiving concomitant systemic
treatment with azole-antimycotics (such as ketoconazole, itraconazole, voriconazole and
posaconazole) or HIV protease inhibitors (e.g. ritonavir). These active substances are
strong inhibitors of both CYP3A4 and P-gp and therefore may increase rivaroxaban
plasma concentrations to a clinically relevant degree (2.6 fold on average) which may
lead to an increased bleeding risk (see section 4.5).

Care is to be taken if patients are treated concomitantly with medicinal products affecting
haemostasis such as non-steroidal anti-inflammatory medicinal products (NSAIDs),
acetylsalicylic acid and platelet aggregation inhibitors or selective serotonin reuptake
inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs). For
patients at risk of ulcerative gastrointestinal disease an 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 bleeding risk such as:
• congenital or acquired bleeding disorders
• uncontrolled severe arterial hypertension
• other gastrointestinal disease without active ulceration that can potentially lead to
bleeding complications (e.g. inflammatory bowel disease, oesophagitis, gastritis and
gastroesophageal reflux disease)
• vascular retinopathy
• bronchiectasis or history of pulmonary bleeding

Patients with prosthetic valves
Safety and efficacy of Banoriv have not been studied in patients with prosthetic heart
valves; therefore, there are no data to support that Banoriv provides adequate
anticoagulation in this patient population. Treatment with Banoriv is not recommended
for these patients.

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 in patients with non-valvular atrial fibrillation who undergo PCI with stent
placement. Data on efficacy in this population are limited (see sections 4.2 and 5.1). No
data are available for such patients with a history of stroke/TIA.

Haemodynamically unstable PE patients or patients who require thrombolysis or
pulmonary embolectomy

Banoriv is not recommended as an alternative to unfractionated heparin in patients with
pulmonary embolism who are haemodynamically unstable or may receive thrombolysis
or pulmonary embolectomy since the safety and efficacy of Banoriv have not been
established in these clinical situations.

Spinal/epidural anaesthesia or puncture
When neuraxial anaesthesia (spinal/epidural anaesthesia) or spinal/epidural puncture is
employed, patients treated with antithrombotic agents for prevention of thromboembolic
complications are at risk of 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 or the concomitant use of medicinal
products affecting haemostasis. The risk may also be increased by traumatic or repeated
epidural or spinal puncture. Patients are to be frequently monitored for signs and
symptoms of neurological impairment (e.g. numbness or weakness of the legs, bowel or
bladder dysfunction). If neurological compromise is noted, urgent diagnosis and
treatment is necessary. Prior to neuraxial intervention the physician should consider the
potential benefit versus the risk in anticoagulated patients or in patients to be
anticoagulated for thromboprophylaxis. There is no clinical experience with the use of 20
mg rivaroxaban in these situations.

To reduce the potential risk of bleeding associated with the concurrent use of rivaroxaban
and neuraxial (epidural/spinal) anaesthesia or spinal puncture, consider the
pharmacokinetic profile of rivaroxaban. Placement or removal of an epidural catheter or
lumbar puncture is best performed when the anticoagulant effect of rivaroxaban is
estimated to be low. However, the exact timing to reach a sufficiently low anticoagulant
effect in each patient is not known.

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 patients and 26 hours in elderly patients
should elapse after the last administration of rivaroxaban (see section 5.2). Following
removal of the catheter, at least 6 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.

Dosing recommendations before and after invasive procedures and surgical intervention
If an invasive procedure or surgical intervention is required, Banoriv 20 mg should be
stopped at least 24 hours before the intervention, if possible and based on the clinical
judgement of the physician.
If the procedure cannot be delayed the increased risk of bleeding should be assessed
against the urgency of the intervention.

Banoriv should be restarted as soon as possible after the invasive procedure or surgical
intervention provided the clinical situation allows and adequate haemostasis has been
established as determined by the treating physician (see section 5.2).

Elderly population
Increasing age may increase haemorrhagic risk (see section 5.2).

Dermatological reactions
Serious skin reactions, including Stevens-Johnson syndrome/Toxic Epidermal
Necrolysis, have been reported during post-marketing surveillance in association with the
use of rivaroxaban (see section 4.8). Patients appear to be at highest risk for these
reactions early in the course of therapy: the onset of the reaction occurring in the majority
of cases within the first weeks of treatment. 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 mucosal lesions.

Information about excipients
Banoriv contains lactose. Patients with rare hereditary problems of galactose intolerance,
the Lapp lactase deficiency or glucose-galactose malabsorption should not take this
medicinal product.

CYP3A4 and P-gp inhibitors
Co-administration of rivaroxaban with ketoconazole (400 mg once a day) or ritonavir
(600 mg twice a day) led to a 2.6 fold / 2.5 fold increase in mean rivaroxaban AUC and a
1.7 fold / 1.6 fold increase in mean rivaroxaban Cmax, with significant increases in
pharmacodynamic effects which may lead to an increased bleeding risk. Therefore, the
use of Banoriv is not recommended in patients receiving concomitant systemic treatment
with azole-antimycotics such as ketoconazole, itraconazole, voriconazole and
posaconazole or HIV protease inhibitors. These active substances are strong inhibitors 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 and moderate P-gp inhibitor, led to a 1.5 fold increase in mean
rivaroxaban AUC and a 1.4 fold increase in Cmax. This increase is not considered
clinically relevant. (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 1.3 fold increase in mean rivaroxaban AUC and Cmax. This increase is not
considered clinically relevant.

In subjects with mild renal impairment erythromycin (500 mg three times a day) led to a
1.8 fold increase in mean rivaroxaban AUC and 1.6 fold increase in Cmax when compared
to subjects with normal renal function. In subjects with moderate renal impairment,
erythromycin led to a 2.0 fold increase in mean rivaroxaban AUC and 1.6 fold increase in
Cmax when compared to subjects with normal renal function. The effect of erythromycin
is additive to that of renal impairment (see section 4.4).

Fluconazole (400 mg once daily), considered as a moderate CYP3A4 inhibitor, led to a
1.4 fold increase in mean rivaroxaban AUC and a 1.3 fold increase in mean Cmax. This
increase is not considered clinically relevant. (For patients with renal impairment: see
section 4.4).

Given the limited clinical data available with dronedarone, co-administration with
rivaroxaban should be avoided.

Anticoagulants
After combined administration of enoxaparin (40 mg single dose) with rivaroxaban (10
mg single dose) an additive effect on anti-factor Xa activity was observed without any
additional effects on clotting 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 any other anticoagulants (see sections 4.3 and 4.4).

NSAIDs/platelet aggregation inhibitors
No clinically relevant prolongation of bleeding time was observed after concomitant
administration of rivaroxaban (15 mg) and 500 mg naproxen. Nevertheless, there may be
individuals with a more pronounced pharmacodynamic response.

No clinically significant pharmacokinetic or pharmacodynamic interactions were
observed when rivaroxaban was co-administered with 500 mg acetylsalicylic acid.

Clopidogrel (300 mg loading dose followed by 75 mg maintenance dose) did not show a
pharmacokinetic interaction with rivaroxaban (15 mg) but a relevant increase in bleeding
time was observed 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 bleeding risk (see section 4.4).

SSRIs/SNRIs
As with other anticoagulants the possibility may exist that patients are at increased risk of
bleeding in case of concomitant use with SSRIs or SNRIs due to their reported effect on
platelets. When concomitantly used in the rivaroxaban clinical program, numerically
higher rates of major or non-major clinically relevant bleeding were observed in all
treatment groups.

Warfarin
Converting patients from the vitamin K antagonist warfarin (INR 2.0 to 3.0) to
rivaroxaban (20 mg) or from 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 the fourth day after the last dose of warfarin, all tests (including
PT, aPTT, inhibition of factor Xa activity and ETP) reflected only the effect of
rivaroxaban.

If it is desired to test the pharmacodynamic effects of warfarin during the conversion
period, INR measurement can be used at the Ctrough of rivaroxaban (24 hours after the
previous intake of rivaroxaban) as this test is minimally affected by rivaroxaban at this
time point.

No pharmacokinetic interaction was observed between warfarin and rivaroxaban.

CYP3A4 inducers
Co-administration of rivaroxaban with the strong CYP3A4 inducer rifampicin led to an
approximate 50 % decrease in mean rivaroxaban AUC, with parallel decreases in its
pharmacodynamic effects. The concomitant 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 rivaroxaban plasma
concentrations. Therefore, concomitant administration of strong CYP3A4 inducers
should be avoided unless the patient is closely observed for signs and symptoms of
thrombosis.

Other concomitant therapies
No clinically significant pharmacokinetic or pharmacodynamic interactions were
observed when rivaroxaban 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). Rivaroxaban neither inhibits nor induces any major CYP
isoforms like CYP3A4.

Laboratory parameters
Clotting parameters (e.g. PT, aPTT, HepTest) are affected as expected by the mode of
action of rivaroxaban (see section 5.1).

Pregnancy
Safety and efficacy of Banoriv have not been established in pregnant women. Studies in
animals 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, Banoriv is contraindicated during pregnancy (see section 4.3).
Women of child-bearing potential should avoid becoming pregnant during treatment with
rivaroxaban.

Breast feeding
Safety and efficacy of Banoriv have not been established in breast feeding women. Data
from animals indicate that rivaroxaban is secreted into milk. Therefore Banoriv is
contraindicated during breast feeding (see section 4.3). A decision must be made whether
to discontinue breast feeding or to discontinue/abstain from therapy.

Fertility
No specific studies with rivaroxaban in humans have been conducted to evaluate effects
on fertility. In a study on male and female fertility in rats no effects were seen (see
section 5.3).

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

Summary of the safety profile
The safety of rivaroxaban has been evaluated in twelve phase III studies including 34,859
patients exposed to rivaroxaban (see Table 1).
Table 1: Number of patients studied, total daily dose and maximum treatment
duration in phase III studies

Indication	Number of patients*	Total daily dose	Maximum treatment duration
Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery	6,097	10 mg	39 days
Prevention of venous thromboembolism in medically ill patients	3,997	10 mg	39 days
Treatment of DVT, PE and prevention of recurrence	6,790	Day 1 - 21: 30 mg Day 22 and onwards: 20 mg After at least 6 months: 10 mg or 20mg	21 months
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation	7,750	20 mg	41 months
Prevention of atherothrombotic events in patients after an ACS	10,225	5 mg or 10 mg respectively, coadministered with either ASA or ASA plus clopidogrel or ticlopidine	31 months

*Patients exposed to at least one dose of rivaroxaban
The most commonly reported adverse reactions in patients receiving rivaroxaban were
bleedings (see section 4.4. and 'Description of selected adverse reactions' below) (Table
2). The most commonly reported bleedings (≥4 %) were epistaxis (5.8 %) and
gastrointestinal tract haemorrhage (4.1 %).
In total about 65% of patients exposed to at least one dose of rivaroxaban were reported
with treatment emergent adverse events. About 21% of the patients experienced adverse
events considered related to treatment as assessed by itors.
Table 2 Bleeding and anaemia events rates in patients exposed to rivaroxaban
across the completed phase III studies:

Indication	Any Bleeding	Anaemia
Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery	6.8% of patients	5.9% of patients
Prevention of venous thromboembolism in medically ill patients	12.6% of patients	2.1% of patients
Treatment of DVT, PE and prevention of recurrence	23% of patients	1.6% of patients
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation	28 per 100 patient years	2.5 per 100 patient years
Prevention of atherothrombotic events in patients after an ACS	22 per 100 patient years	1.4 per 100 patient years

Tabulated list of adverse reactions
The frequencies of adverse reactions reported with Banoriv are summarised 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 treatment-emergent adverse reactions reported in patients in phase III
studies

Common	Uncommon	Rare	Not known
Blood and lymphatic system disorders
Anaemia (incl. respective laboratory parameters)	Thrombocythemia (incl. platelet count increased)A
Immune system disorders
	Allergic reaction, dermatitis allergic
Nervous system disorders
Dizziness, headache	Cerebral and intracranial haemorrhage, syncope
Eye disorders
Eye haemorrhage (incl. conjunctival haemorrhage)
Cardiac disorders
	Tachycardia
Vascular disorders
Hypotension, haematoma
Respiratory, thoracic and mediastinal disorders
Epistaxis, haemoptysis
Gastrointestinal disorders
Gingival bleeding, gastrointestinal tract haemorrhage (incl. rectal haemorrhage), gastrointestinal and abdominal pains, dyspepsia, nausea, constipationA, diarrhoea, vomitingA	Dry mouth
Hepatobiliary disorders
	Hepatic function abnormal	Jaundice
Skin and subcutaneous tissue disorders
Pruritus (incl. uncommon cases of generalised pruritus), rash, ecchymosis, cutaneous and subcutaneous haemorrhage	Urticaria
Musculoskeletal and connective tissue disorders
Pain in extremityA	Haemarthrosis	Muscle haemorrhage	Compartment syndrome secondary to a bleeding
Renal and urinary disorders
Urogenital tract haemorrhage (incl. haematuria and menorrhagiaB), renal impairment (incl. blood creatinine increased, blood urea increased)A			Renal failure/acute renal failure secondary to a bleeding sufficient to cause hypoperfusion
General disorders and administration site conditions
FeverA, peripheral oedema, decreased general strength and energy (incl. fatigue and asthenia)	Feeling unwell (incl. malaise)	Localised oedemaA
Investigations
Increase in transaminases	Increased bilirubin, increased blood alkaline phosphataseA, increased LDHA, increased lipaseA, increased amylaseA, increased GGTA	Bilirubin conjugated increased (with or without concomitant increase of ALT)
Injury, poisoning and procedural complications
Postprocedural haemorrhage (incl. postoperative anaemia, and wound haemorrhage), contusion, wound secretionA		Vascular pseudoaneurysmC

 

A: observed in prevention of venous thromboembolism (VTE) in adult patients
undergoing elective hip or knee replacement surgery
B: observed in treatment of DVT, PE and prevention of recurrence as very common in
women < 55 years
C: observed as uncommon in prevention of atherothrombotic events in patients after an
ACS (following percutaneous coronary intervention)

Description of selected adverse reactions
Due to the pharmacological mode of action, the use of Banoriv may be associated with an
increased risk of occult or overt bleeding from any tissue or organ which may result in
post haemorrhagic anaemia. The signs, symptoms, and severity (including fatal outcome)
will vary according 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) and anaemia were seen more frequently during long term
rivaroxaban treatment compared with VKA treatment. Thus, in addition to adequate
clinical surveillance, laboratory testing of haemoglobin/haematocrit could be of value to
detect occult bleeding and quantify the clinical relevance of overt bleeding, as judged to
be appropriate. The risk of bleedings may be increased in certain patient groups e.g. those
patients with uncontrolled severe arterial hypertension and/or on concomitant treatment
affecting haemostasis (see Haemorrhagic risk in section 4.4). Menstrual bleeding may be
intensified and/or prolonged. Haemorrhagic complications may present as weakness,
paleness, dizziness, headache or unexplained swelling, dyspnoea and unexplained shock.
In some cases as a consequence of anaemia, symptoms of cardiac ischaemia like chest
pain or angina pectoris have been observed.
Known complications secondary to severe bleeding such as compartment syndrome and
renal failure due to hypoperfusion have been reported for Banoriv. Therefore, the
possibility of haemorrhage is to be considered in evaluating the condition in any
anticoagulated patient.

Post-marketing observations
The following adverse reactions have been reported post-marketing in temporal
association with the use of Banoriv. The frequency of these adverse reactions reported
from post-marketing experience cannot be estimated.
Immune system disorders: Angioedema and allergic oedema (In the pooled phase III
trials, these events were uncommon (≥ 1/1,000 to < 1/100)).
Hepatobiliary disorders: Cholestasis, Hepatitis (incl. hepatocellular injury) (In the pooled
phase III trials, these events were rare (≥ 1/10,000 to < 1/1,000)).
Blood and lymphatic system disorders: Thrombocytopenia (In the pooled phase III trials,
these events were uncommon (≥ 1/1,000 to < 1/100)).
Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome/Toxic Epidermal
Necrolysis (In the pooled phase III trials, these events were estimated as very rare
(<1/10,000)).

Reporting of suspected adverse reactions

To report any side effect(s): ·         The National Pharmacovigilance and Drug Safety Centre (NPC) Fax: +966-11-205-7662 Call NPC at:      +966-11-2038222          Exts: 2317-2356-2353-2354-2334-2340. Toll free phone: 8002490000 E-mail: npc.drug@sfda.gov.sa Website: www.sfda.gov.sa/npc

Rare cases of overdose up to 600 mg have been reported without bleeding complications
or other adverse reactions. Due to limited absorption a ceiling effect with no further
increase in average plasma exposure is expected at supratherapeutic doses of 50 mg
rivaroxaban or above.
A specific antidote antagonising the pharmacodynamic effect of rivaroxaban is not
available.
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
rivaroxaban administration should be delayed or treatment should be discontinued as
appropriate. Rivaroxaban has a half-life of approximately 5 to 13 hours (see section 5.2).
Management should be individualised according to the severity and location of the
haemorrhage. Appropriate symptomatic treatment could be used as needed, such as
mechanical compression (e.g. for severe epistaxis), surgical haemostasis with bleeding
control procedures, fluid replacement and haemodynamic support, blood products

(packed red cells or fresh frozen plasma, depending on associated anaemia or
coagulopathy) or platelets.

If bleeding cannot be controlled by the above measures, administration of a specific
procoagulant reversal agent should be considered, such as prothrombin complex
concentrate (PCC), activated prothrombin complex concentrate (APCC) or recombinant
factor VIIa (r-FVIIa). However, there is currently very limited clinical experience with
the use of these products in individuals receiving rivaroxaban. The recommendation is
also based on limited non-clinical data. Re-dosing of recombinant factor VIIa shall be
considered and titrated depending on improvement of bleeding. Depending on local
availability, a consultation with a coagulation expert should be considered in case of
major bleedings (see section 5.1).

Protamine sulfate 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 and aprotinin in individuals receiving rivaroxaban. There is neither
scientific rationale for benefit nor experience with the use of the systemic haemostatic
desmopressin in individuals receiving rivaroxaban. Due to the high plasma protein
binding rivaroxaban is not expected to be dialysable.

Pharmacotherapeutic group: Direct factor Xa inhibitors, ATC code: B01AF01
Mechanism of action
Rivaroxaban is a highly selective direct factor Xa inhibitor with oral bioavailability.
Inhibition of factor Xa interrupts the intrinsic and extrinsic pathway of the blood
coagulation cascade, inhibiting both thrombin formation and development of thrombi.
Rivaroxaban does not inhibit thrombin (activated factor II) and no effects on platelets
have been demonstrated.

Pharmacodynamic effects
Dose-dependent inhibition of factor Xa activity was observed in humans. Prothrombin
time (PT) is influenced 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 (International Normalised Ratio) is only calibrated and validated for
coumarins and cannot be used for any other anticoagulant.
In patients receiving rivaroxaban for treatment of DVT and PE and prevention of
recurrence, the 5/95 percentiles for PT (Neoplastin) 2 - 4 hours after tablet intake (i.e. at
the time of maximum effect) for 15 mg rivaroxaban twice daily ranged from 17 to 32 s
and for 20 mg rivaroxaban once daily from 15 to 30 s. At trough (8 - 16 h after tablet
intake) the 5/95 percentiles for 15 mg twice daily ranged from 14 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 and systemic embolism, the 5/95 percentiles for PT (Neoplastin) 1 - 4 hours after
tablet intake (i.e. at the time of maximum effect) in patients treated with 20 mg once daily
ranged from 14 to 40 s and in patients 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 12 to 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 adult subjects (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 PCC reduced mean Neoplastin PT values by
approximately 1.0 second within 30 minutes, compared to reductions of approximately
3.5 seconds observed with the 4-factor PCC. In contrast, the 3-factor PCC had a greater
and more rapid overall effect on reversing changes in endogenous thrombin generation
than the 4-factor PCC (see section 4.9).
The activated partial thromboplastin time (aPTT) and HepTest are also prolonged dosedependently;
however, they are not recommended to assess the pharmacodynamic effect
of rivaroxaban. There is no need 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).

Clinical efficacy and safety
Prevention of stroke and systemic embolism in patients with non-valvular atrial
fibrillation
The Banoriv clinical program was designed to demonstrate the efficacy of Banoriv for
the prevention 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
Banoriv 20 mg once daily (15 mg once daily in patients with creatinine clearance 30 - 49
ml/min) or to warfarin titrated to a target INR of 2.5 (therapeutic range 2.0 to 3.0). The
median time on treatment was 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 III antiarrhythmic including amiodarone.
Banoriv was non-inferior to warfarin for the primary composite endpoint of stroke and
non-CNS systemic embolism. In the per-protocol population on treatment, stroke or
systemic embolism occurred in 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 according to 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). Results for
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) a mean of 55% of the time (median, 58%; interquartile range, 43 to 71). The effect
of rivaroxaban did not differ across the level of centre TTR (Time in Target INR Range
of 2.0 - 3.0) in the equally sized quartiles (P=0.74 for interaction). Within the highest
quartile according to centre, the hazard ratio 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 bleeding events) 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 dosage	Banoriv 20 mg od (15 mg od in patients with moderate renal impairment) Event rate (100 pt-yr)	Warfarin titrated to a target INR of 2.5 (therapeutic range 2.0 to 3.0) Event rate (100 pt-yr)	Hazard ratio (95% CI) p-value, test for superiority
Stroke and non-CNS systemic embolism	269 (2.12)	306 (2.42)	0.88 (0.74 - 1.03) 0.117
Stroke, non-CNS systemic embolism and vascular death	572 (4.51)	609 (4.81)	0.94 (0.84 - 1.05) 0.265
Stroke, non-CNS systemic embolism, vascular death and myocardial infarction	659 (5.24)	709 (5.65)	0.93 (0.83 - 1.03) 0.158
Stroke	253 (1.99)	281 (2.22)	0.90 (0.76 - 1.07) 0.221
Non-CNS systemic embolism	20 (0.16)	27 (0.21)	0.74 (0.42 - 1.32) 0.308
Myocardial infarction	130 (1.02)	142 (1.11)	0.91 (0.72 - 1.16) 0.464

 

Table 5: Safety results from phase III ROCKET AF

Study population	Patients with non-valvular atrial fibrillationa)
Treatment dosage	Banoriv 20 mg once a day (15 mg once a day in patients with moderate renal impairment) Event rate (100 pt-yr)	Warfarin titrated to a target INR of 2.5 (therapeutic range 2.0 to 3.0)   Event rate (100 pt-yr)	Hazard ratio (95% CI) p-value
Major and non-major clinically relevant bleeding events	1,475 (14.91)	1,449 (14.52)	1.03 (0.96 - 1.11) 0.442
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 bleeding*	91 (0.82)	133 (1.18)	0.69 (0.53 - 0.91) 0.007
Intracranial haemorrhage*	55 (0.49)	84 (0.74)	0.67 (0.47 - 0.93) 0.019
Haemoglobin drop*	305 (2.77)	254 (2.26)	1.22 (1.03 - 1.44) 0.019
Transfusion of 2 or more units of packed red blood cells or whole blood*	183 (1.65)	149 (1.32)	1.25 (1.01 - 1.55) 0.044
Non-major clinically relevant bleeding events	1,185 (11.80)	1,151 (11.37)	1.04 (0.96 - 1.13) 0.345
All cause mortality	208 (1.87)	250 (2.21)	0.85 (0.70 - 1.02) 0.073
a) Safety population, on treatment * Nominally significant

In addition to the phase III ROCKET AF study, a prospective, single-arm, postauthorization,
non-interventional, open-label cohort study (XANTUS) with central
outcome adjudication including thromboembolic events and major bleeding has been
conducted. 6,785 patients with non-valvular atrial 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 in 0.2 per 100 patient years and intracranial haemorrhage in 0.4 per 100
patient years. Stroke or non-CNS systemic embolism was recorded in 0.8 per 100 patient
years.

These observations in clinical practice are consistent with the established safety profile in
this indication.

Patients undergoing cardioversion
A prospective, randomized, open-label, multicenter, exploratory study with blinded
endpoint evaluation (X-VERT) was conducted in 1504 patients (oral anticoagulant naive
and pre-treated) with non-valvular atrial fibrillation scheduled for cardioversion to
compare rivaroxaban with dose-adjusted VKA (randomized 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 were employed. The
primary efficacy outcome (all stroke, transient ischemic attack, non-CNS systemic
embolism, MI and cardiovascular death) occurred in 5 (0.5 %) patients in the rivaroxaban
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 safety between rivaroxaban and VKA
treatment groups in the setting of cardioversion.

Patients with non-valvular atrial fibrillation who undergo PCI with stent placement
A randomized, open-label, multicenter study (PIONEER AF-PCI) was conducted in 2124
patients with non-valvular atrial fibrillation who underwent PCI with stent placement for
primary atherosclerotic disease to compare safety of two rivaroxaban regimens and one
VKA regimen. Patients were randomly assigned in a 1:1:1 fashion for an overall 12-
month-therapy. Patients with a history of stroke or TIA were excluded.
Group 1 received rivaroxaban 15 mg once daily (10 mg once daily in patients with
creatinine clearance 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 acetylsalicylic acid [ASA]) for 1, 6 or 12
months followed by rivaroxaban 15 mg (or 10 mg for subjects with creatinine clearance
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 ASA.
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% CI 0.47-0.76; p<0.001, and HR 0.63; 95% CI 0.50-0.80;
p<0.001, respectively). The secondary endpoint (composite of cardiovascular events CV
death, MI, or stroke) occurred in 41 (5.9%), 36 (5.1%), and 36 (5.2%) subjects in the
group 1, group 2 and group 3, respectively. Each of the rivaroxaban regimens 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 stent
placement.
The primary objective of PIONEER AF-PCI was to assess safety. Data on efficacy
(including thromboembolic events) in this population are limited.

Treatment of DVT, PE and prevention of recurrent DVT and PE
The Banoriv clinical program was designed to demonstrate the efficacy of Banoriv in the
initial 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 pooled analysis of the Einstein DVT and Einstein PE studies was conducted.
The overall combined treatment duration 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 the prevention of recurrent DVT and PE (patients who presented with symptomatic
PE were excluded from this study). The treatment duration was for 3, 6 or 12 months
depending on the clinical judgement of the investigator.

For the initial 3 week treatment of acute DVT 15 mg rivaroxaban was administered twice
daily. This was 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 of recurrent DVT and PE. The treatment duration was for 3, 6 or 12 months
depending on the clinical judgement 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 of enoxaparin administered for at least 5 days in combination with vitamin K
antagonist treatment until the PT/INR was in therapeutic range (≥ 2.0). Treatment was
continued with a vitamin K antagonist dose-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 had completed 6 to 12 months of treatment for venous thromboembolism

depending on the clinical judgment of the investigator. Banoriv 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 of recurrent DVT, non-fatal PE and all
cause mortality.
In Einstein Choice, 3,396 patients with confirmed symptomatic DVT and/or PE who
completed 6-12 months of anticoagulant treatment were studied for the prevention of
fatal PE or non-fatal symptomatic recurrent DVT or PE. Patients with an indication for
continued therapeutic-dosed anticoagulation were excluded from the study. The treatment
duration was up to 12 months depending on the individual randomization date (median :
351 days). Banoriv 20 mg once daily and Banoriv 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
to enoxaparin/VKA for the primary efficacy outcome (p < 0.0001 (test for noninferiority);
hazard ratio: 0.680 (0.443 - 1.042), p=0.076 (test for superiority)). The
prespecified net clinical benefit (primary efficacy outcome plus major bleeding events)
was reported with a hazard ratio of 0.67 ((95% CI: 0.47 - 0.95), nominal p value p=0.027)
in favour of rivaroxaban. INR values were within the therapeutic range a mean of 60.3%
of the time for the mean treatment duration of 189 days, and 55.4%, 60.1%, and 62.8% of
the time in the 3-, 6-, and 12-month intended treatment duration groups, respectively. In
the enoxaparin/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 hazard ratio with rivaroxaban versus warfarin was 0.69 (95% CI:
0.35 - 1.35).

The incidence rates for the primary safety outcome (major or clinically relevant nonmajor
bleeding events) as well as the secondary safety outcome (major bleeding events)
were similar for both treatment groups.

Table 6: Efficacy and safety results from phase III Einstein DVT
Study population	3,449 patients with symptomatic acute deep vein thrombosis
Treatment dosage and duration	Banoriva) 3, 6 or 12 months N=1,731	Enoxaparin/VKAb) 3, 6 or 12 months 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 (0.1%)	0
Fatal PE/Death where PE cannot be ruled out	4 (0.2%)	6 (0.3%)
Major or clinically relevant non-major bleeding	139 (8.1%)	138 (8.1%)
Major bleeding events	14 (0.8%)	20 (1.2%)
a) Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily b) Enoxaparin for at least 5 days, overlapped with and followed by VKA * p < 0.0001 (non-inferiority to a prespecified hazard ratio of 2.0); hazard ratio: 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 to
enoxaparin/VKA for the primary efficacy outcome (p=0.0026 (test for non-inferiority);
hazard ratio: 1.123 (0.749 – 1.684)). The prespecified net clinical benefit (primary
efficacy outcome plus major bleeding events) was reported with a hazard ratio of 0.849
((95% CI: 0.633 - 1.139), nominal p value p= 0.275). INR values were within the
therapeutic range a mean of 63% of the time for the mean treatment duration of 215 days,
and 57%, 62%, and 65% of the time in the 3-, 6-, and 12-month intended treatment
duration groups, respectively. In the enoxaparin/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=0.082 for interaction).
Within the highest tertile according to centre, the hazard ratio 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 nonmajor
bleeding events) were slightly lower in the rivaroxaban treatment group (10.3%
(249/2412)) than in the enoxaparin/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 the enoxaparin/VKA group (2.2% (52/2405))
with a hazard ratio 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 dosage and duration	Banoriva) 3, 6 or 12 months N=2,419	Enoxaparin/VKAb) 3, 6 or 12 months N=2,413
Symptomatic recurrent VTE*	50 (2.1%)	44 (1.8%)
Symptomatic recurrent PE	23 (1.0%)	20 (0.8%)
Symptomatic recurrent DVT	18 (0.7%)	17 (0.7%)
Symptomatic PE and DVT	0	2 (<0.1%)
Fatal PE/Death where PE cannot be ruled out	11 (0.5%)	7 (0.3%)
Major or clinically relevant non-major bleeding	249 (10.3%)	274 (11.4%)
Major bleeding events	26 (1.1%)	52 (2.2%)
a) Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily b) Enoxaparin for at least 5 days, overlapped with and followed by VKA * p < 0.0026 (non-inferiority to a prespecified hazard ratio of 2.0); hazard ratio: 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 dosage and duration	Banoriva) 3, 6 or 12 months N=4,150	Enoxaparin/VKAb) 3, 6 or 12 months N=4,131
Symptomatic recurrent VTE*	86 (2.1%)	95 (2.3%)
Symptomatic recurrent PE	43 (1.0%)	38 (0.9%)
Symptomatic recurrent DVT	32 (0.8%)	45 (1.1%)
Symptomatic PE and DVT	1 (<0.1%)	2 (<0.1%)
Fatal PE/Death where PE cannot be ruled out	15 (0.4%)	13 (0.3%)
Major or clinically relevant non-major bleeding	388 (9.4%)	412 (10.0%)
Major bleeding events	40 (1.0%)	72 (1.7%)
a) Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily b) Enoxaparin for at least 5 days, overlapped with and followed by VKA * p < 0.0001 (non-inferiority to a prespecified hazard ratio of 1.75); hazard ratio: 0.886 (0.661 – 1.186)

The prespecified net clinical benefit (primary efficacy outcome plus major bleeding
events) of the pooled analysis was reported with a hazard ratio 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 and secondary efficacy outcomes. For the primary safety outcome (major
bleeding events) there was a non-significant numerically higher incidence rate for
patients treated with rivaroxaban 20 mg once daily compared to placebo. The secondary
safety outcome (major or clinically relevant non-major bleeding events) showed higher
rates for patients treated with rivaroxaban 20 mg once daily compared to placebo.

Table9: Efficacy and safety results from phase III Einstein Extension
Study population	1,197 patients continued treatment and prevention of recurrent venous thromboembolism
Treatment dosage and duration	Banoriva) 6 or 12 months N=602	Placebo 6 or 12 months N=594
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 cannot be ruled out	1 (0.2%)	1 (0.2%)
Major bleeding events	4 (0.7%)	0 (0.0%)
Clinically relevant non-major bleeding	32 (5.4%)	7 (1.2%)
a) Rivaroxaban 20 mg once daily * p < 0.0001 (superiority), hazard ratio: 0.185 (0.087 - 0.393)

 

In the Einstein Choice study (see Table 10) Banoriv 20 mg and 10 mg were both superior
to 100 mg acetylsalicylic acid for the primary efficacy outcome. The principal safety
outcome (major bleeding events) was similar for patients treated with Banoriv 20 mg and
10 mg once daily compared to 100 mg acetylsalicylic acid.

3,396 patients continued prevention of recurrent venous thromboembolism
Study population	3,396 patients continued prevention of recurrent venous thromboembolism
Treatment dosage	Banoriv 20 mg od N=1,107	Banoriv 10 mg od N=1,127	ASA 100 mg od N=1,131
Treatment duration median [interquartile range]	349 [189-362] days	353 [190-362] days	350 [186-362] days
Symptomatic recurrent VTE	17 (1.5%)*	13 (1.2%)**	50 (4.4%)
Symptomatic recurrent PE	6 (0.5%)	6 (0.5%)	19 (1.7%)
Symptomatic recurrent DVT	9 (0.8%)	8 (0.7%)	30 (2.7%)
Fatal PE/Death where PE cannot be ruled out	2 (0.2%)	0 (0.0%)	2 (0.2%)
Symptomatic recurrent VTE, MI, stroke, or non-CNS systemic embolism	19 (1.7%)	18 (1.6%)	56 (5.0%)
Major bleeding events	6 (0.5%)	5 (0.4%)	3 (0.3%)
Clinically relevant non-major bleeding	30 (2.7)	22 (2.0)	20 (1.8)
Symptomatic recurrent VTE or major bleeding (net clinical benefit)	23 (2.1%)+	17 (1.5%)++	53 (4.7%)
* p<0.001(superiority) Banoriv 20 mg od vs ASA 100 mg od; HR=0.34 (0.20–0.59) ** p<0.001 (superiority) Banoriv 10 mg od vs ASA 100 mg od; HR=0.26 (0.14–0.47) + Banoriv 20 mg od vs. ASA 100 mg od; HR=0.44 (0.27–0.71), p=0.0009 (nominal) ++ Banoriv 10 mg od vs. ASA 100 mg od; HR=0.32 (0.18–0.55), p<0.0001 (nominal)

In addition to the phase III EINSTEIN program, a prospective, non-interventional, openlabel
cohort study (XALIA) with central outcome adjudication including recurrent VTE,
major bleeding and death has been conducted. 5,142 patients with acute DVT were
enrolled to investigate the long-term safety of rivaroxaban compared with standard-ofcare
anticoagulation therapy in clinical practice. Rates of major bleeding, recurrent VTE
and all-cause mortality for rivaroxaban were 0.7%, 1.4% and 0.5%, respectively. There
were differences in patient baseline characteristics including age, cancer and renal
impairment. A pre-specified propensity score stratified analysis was used to adjust for
measured baseline differences but residual confounding may, in spite of this, influence
the results. Adjusted hazard ratios comparing rivaroxaban and standard-of-care for major
bleeding, recurrent VTE and all-cause mortality were 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 population
The European Medicines Agency has deferred the obligation to submit the results of
studies with Banoriv in one or more subsets of the paediatric population in the treatment
of thromboembolic events. The European Medicines Agency has waived the obligation to
submit the results of studies with Banoriv in all subsets of the paediatric population in the
prevention of thromboembolic events (see section 4.2 for information on paediatric use).

Absorption
Rivaroxaban is rapidly absorbed with maximum concentrations (Cmax) appearing 2 - 4
hours after tablet intake.
Oral absorption of rivaroxaban is almost complete and oral bioavailability is high (80 -
100%) for the 2.5 mg and 10 mg tablet dose, irrespective of fasting/fed conditions. Intake
with food does not affect rivaroxaban 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 mg tablet under fasting conditions. When Banoriv 20 mg tablets are taken together
with food increases in mean AUC by 39% were observed when compared to tablet intake
under fasting conditions, indicating almost complete absorption and high oral
bioavailability. Banoriv 15 mg and 20 mg are to 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 Banoriv 10 mg, 15 mg and 20 mg tablets demonstrated
dose-proportionality. At higher doses rivaroxaban displays dissolution limited absorption
with decreased bioavailability and decreased 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 is released in the proximal small intestine. Exposure is further
reduced when rivaroxaban is released in the distal small intestine, or ascending colon.
Therefore, administration of rivaroxaban distal to the stomach should be avoided since
this can result in reduced absorption and related rivaroxaban exposure.

Bioavailability (AUC and Cmax) was comparable for 20 mg rivaroxaban administered
orally as a crushed tablet mixed in apple puree, or suspended in water and administered
via a gastric tube followed by a liquid meal, compared to a whole tablet. Given the
predictable, dose-proportional pharmacokinetic profile of rivaroxaban, the bioavailability
results from this study are likely applicable to lower rivaroxaban doses.

Distribution
Plasma protein binding in humans is high at approximately 92 % to 95 %, with serum
albumin being the main binding component. The volume of distribution is moderate with
Vss being approximately 50 litres.

Biotransformation and elimination
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 1/3 of 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.
Oxidative degradation of the morpholinone moiety and hydrolysis of the amide bonds are
the major sites of biotransformation. Based on in vitro investigations rivaroxaban is a
substrate of the transporter proteins P-gp (P-glycoprotein) and Bcrp (breast cancer
resistance protein).
Unchanged rivaroxaban is the most important compound in human plasma, with no major
or active circulating metabolites being present. With a systemic clearance of about 10 l/h,
rivaroxaban can be classified as a low-clearance substance. After intravenous
administration of a 1 mg dose the elimination half-life is about 4.5 hours. After oral
administration the elimination becomes absorption rate limited. Elimination of
rivaroxaban from plasma occurs with terminal half-lives of 5 to 9 hours in young
individuals, and with terminal half-lives of 11 to 13 hours in the elderly.

Special populations
Gender
There were no clinically relevant differences in pharmacokinetics and pharmacodynamics
between male and female patients.

Elderly population
Elderly patients exhibited higher plasma concentrations than younger patients, with mean
AUC values being approximately 1.5 fold higher, mainly due to reduced (apparent) total
and renal clearance. No dose adjustment is necessary.

Different weight categories
Extremes in body weight (< 50 kg or > 120 kg) had only a small influence on rivaroxaban
plasma concentrations (less than 25 %). No dose adjustment is necessary.

Inter-ethnic differences
No clinically relevant inter-ethnic differences among Caucasian, African-American,
Hispanic, Japanese or Chinese patients were observed regarding rivaroxaban
pharmacokinetics and pharmacodynamics.

Hepatic impairment
Cirrhotic patients with mild hepatic impairment (classified as Child Pugh A) exhibited
only minor 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 hepatic impairment (classified as Child Pugh B), rivaroxaban
mean AUC was significantly increased by 2.3 fold compared to healthy volunteers.
Unbound AUC was increased 2.6 fold. These patients also had reduced renal elimination
of rivaroxaban, similar to patients with moderate renal impairment. There are 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 hepatic impairment as compared to healthy volunteers; prolongation of PT was
similarly increased by a factor of 2.1. Patients with moderate hepatic impairment were

more sensitive to rivaroxaban resulting in a steeper PK/PD relationship between
concentration and PT.
Banoriv is contraindicated in patients with hepatic disease associated with coagulopathy
and clinically relevant bleeding risk, including cirrhotic patients with Child Pugh B and C
(see section 4.3).

Renal impairment
There was an increase in rivaroxaban exposure correlated to decrease in renal function, as
assessed 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 and 1.6 fold respectively. Corresponding
increases in pharmacodynamic effects were more pronounced. In individuals with mild,
moderate and severe renal impairment the overall inhibition of factor Xa activity 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 no data 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. Banoriv is to
be used with caution in patients with creatinine clearance 15 - 29 ml/min (see section
4.4).

Pharmacokinetic data in patients
In patients receiving rivaroxaban for treatment of acute DVT 20 mg once daily the
geometric mean concentration (90% prediction interval) 2 - 4 h and about 24 h after dose
(roughly representing maximum and minimum concentrations during the dose interval)
was 215 (22 - 535) and 32 (6 - 239) μg/l, respectively.

Pharmacokinetic/pharmacodynamic relationship
The pharmacokinetic/pharmacodynamic (PK/PD) relationship between rivaroxaban
plasma concentration and several PD endpoints (factor Xa inhibition, PT, aPTT, Heptest)
has been evaluated after administration of a wide range of doses (5 - 30 mg twice a day).
The relationship between rivaroxaban concentration and factor Xa activity was best
described by an Emax model. For PT, the linear intercept model generally described the
data better. Depending on the different PT reagents used, the slope differed considerably.
When Neoplastin PT was used, baseline PT was about 13 s and the slope was around 3 to
4 s/(100 μg/l). The results of the PK/PD analyses in Phase II and III were consistent with
the data established in healthy subjects.

Paediatric population
Safety and efficacy have not been established for children and adolescents up to 18 years.

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

Effects observed in repeat-dose toxicity studies were mainly due to the exaggerated
pharmacodynamic activity of rivaroxaban. In rats, increased IgG and IgA plasma levels
were seen at clinically relevant exposure levels.

In rats, no effects on male or female fertility were seen. Animal studies have shown
reproductive toxicity related to the pharmacological mode of action of rivaroxaban (e.g.
haemorrhagic complications). Embryo-foetal toxicity (post-implantation loss,
retarded/progressed ossification, hepatic multiple light coloured spots) and an increased
incidence of common malformations as well as placental 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.

	20mg Quantity (mg)
Active Ingredients
Rivaroxaban	20.000
Excipients
Lactose BP 200	178.000
Avicel PH 101	160.000
Hydroxypropyl Methylcellulose	16.000
Sodium Lauryl Sulphate	12.000
Croscarmellose Sodium Type-A	12.000
Magnesium Stearate	2.000
Coating Materials
Hydroxypropyl Methyl Cellulose	7.680
Titanium Dioxide Pharma Grade	2.400
Purified Talc	0.480
Polyethylene Glycol MW 6000	1.200
Iron Oxide Red	0.240
Purified Water BP	Qs.

Not applicable.

24 Months/2 Years

Store below 30°C

Reel PVC/PE/PVDC
Each pack contains 28 film coated tablets.
Not all pack sizes may be marketed.

No special requirements for disposal.