XARELTO 20 MG

Israel - English - Ministry of Health

Buy It Now

Active ingredient:
RIVAROXABAN MICRONIZED
Available from:
BAYER ISRAEL LTD
ATC code:
B01AX06
Pharmaceutical form:
FILM COATED TABLETS
Composition:
RIVAROXABAN MICRONIZED 20 MG
Administration route:
PER OS
Prescription type:
Required
Manufactured by:
BAYER AG., GERMANY
Therapeutic group:
RIVAROXABAN
Therapeutic area:
RIVAROXABAN
Therapeutic indications:
Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors, such as congestive heart failure, hypertension, age≥75 years, diabetes 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.
Authorization number:
147 45 33579 00
Authorization date:
2017-01-31

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

18-01-2021

Patient Information leaflet Patient Information leaflet - Hebrew

19-02-2020

דומע

ךותמ

ראורבפ

2019

ה/אפור

,ה/דבכנ

,ה/דבכנ ת/חקור

:ןודנה

Xarelto 15 mg, Xarelto 20 mg

וטלרסק

15

וטלרסק ,ג"מ

20

ג"מ

Film coated tablets

Rivaroxaban

םישקבמ ונא םכעידוהל

ולעהש םינ

ןכרצל ןולעהו אפור רישכתה לש םי

.ונכדוע

תויוותה

רישכתל תורשואמ םי

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.

ה םילולכ וז העדוהב םינוכדיע

דבלב םייתוהמה

עיפומ ןלהלש טוריפב

הנושש קרפ לכ ךותמ ,םינולעב

קר תנמוסמ טסקט תפסות .ןכדעתהש עדימה ןותחת וקב ט תקיחמ , תנמוסמ טסק

הצוח וקב

וכדעה םינ

אפורל ןולעב

רישכתה לש

Xarelto 15 mg

3.

PHARMACEUTICAL FORM

Prescriber guide

Patient safety information card

This product is marketed with patient safety information card (patient card).

The marketing of Xarelto 15 mg is subject to a risk management plan (RMP) including a

'patient safety information card' (Patient card). Please provide a patient card to each patient

who is prescribed with Xarelto 15 mg. The 'patient safety information card', emphasizes

important safety information that the patient should be aware of before and during treatment.

Please explain to the patient the need to review the card before starting treatment and the

implications of this treatment including the need for compliance. Please also explain the

signs of important adverse events and instruct the patient when to seek medical care.

דומע

ךותמ

(Minor change in the black box warning):

WARNING: (A) PREMATURE DISCONTINUATION OF XARELTO INCREASES

THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA

B. SPINAL/EPIDURAL HEMATOMA

[see special warnings and precautions for use (4.4) and undesirable effects (4.8)].

4.2

Posology and method of administration

Posology

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, as indicated in the table below.

Dosing schedule

Maximum daily dose

Day 1 - 21

15 mg twice daily

30 mg

Day 22 and onwards

20 mg once daily

20 mg

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).

and longer durations should be based on permanent risk factors or idiopathic 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.

The safety and efficacy of treatment duration beyond 12 months has not been established. It

should be considered whether to continue treatment beyond 12 months.

The duration of therapy should be individualised after careful assessment of the treatment

benefit against the risk for bleeding (see section 4.4). Short duration of therapy (at least

3 months) should be based on transient risk factors (e.g. recent surgery, trauma,

immobilisation) and longer durations should be based on permanent risk factors or idiopathic

DVT or PE.

Time Period

Dosing schedule

Total daily dose

Treatment and

prevention of

recurrent DVT and

Day 1 - 21

15 mg twice daily

30 mg

Day 22 onwards

20 mg once daily

20 mg

Prevention of

recurrent DVT and

PE

Following completion

of at least 6 months

therapy for DVT or

10 mg once daily

10 mg

דומע

ךותמ

Special populations

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 Xarelto once daily 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

There is no data regarding chewing or halving the tablets.

4.4

Special warnings and precautions for use

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/transient ischaemic attack (TIA).

Dermatological reactions

Serious skin reactions, including Stevens-Johnson syndrome/ toxic epidermal necrolysis and

DRESS syndrome, 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

Xarelto contains lactose. Patients with rare hereditary problems of galactose intolerance, the

Lapp total lactase deficiency or glucose-galactose malabsorption should not take this

medicinal product.

דומע

ךותמ

4.5

Interaction with other medicinal products and other forms of interaction

CYP3A4 and P-gp inhibitors

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 C

. This increase is not considered clinically relevant. The

interaction with clarithromycin 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).

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 C

. This increase is not considered

clinically relevant. The interaction with erythromycin is likely not clinically 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 fold increase in mean rivaroxaban AUC and 1.6 fold increase in C

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

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 C

. This

increase is not considered clinically relevant. The interaction with fluconazole 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).

4.8

Undesirable effects

Summary of the safety profile

The safety of rivaroxaban has been evaluated in twelve thirteen phase III studies including

34,859 53,103 patients exposed to rivaroxaban (see Table 1).

דומע

ךותמ

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 atherothrombotic

events in patients with CAD/PAD

18,244

5 mg co-

administered with

ASA or 10 mg

alone

47 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 (4.5% 5.8%) and

gastrointestinal tract haemorrhage (4.1% 3.8%).

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 investigators.

Table 2: Bleeding* and anaemia events rates in patients exposed to rivaroxaban

across the completed phase III studies

Indication

Any bleeding

Anaemia

Prevention of atherothrombotic

events in patients with CAD/PAD

6.7 per 100

patient years

0.15 per 100

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

adverse event collection was applied

Table 3: All treatment-emergent adverse reactions reported in patients in phase III

studies clinical trials or through post-marketing use*

דומע

ךותמ

Common

Uncommon

Rare

Very rare

Not known

Blood and lymphatic system disorders

Anaemia (incl.

respective

laboratory

parameters)

Thrombocytosis

(incl. platelet count

increased)

Thrombocytopenia

Immune system disorders

Allergic reaction,

dermatitis allergic,

Angioedema and

allergic oedema

Anaphylactic

reactions

including

anaphylactic

shock

...

Hepatobiliary disorders

Increase in

transaminases

Hepatic

impairment,

Increased bilirubin,

increased blood

alkaline

phosphatase

increased GGT

Jaundice,

Bilirubin

conjugated

increased (with

or without

concomitant

increase of

ALT),

Cholestasis,

Hepatitis (incl.

hepatocellular

injury)

Skin and subcutaneous tissue disorders

Pruritus (incl.

uncommon cases

of generalised

pruritus), rash,

ecchymosis,

cutaneous and

subcutaneous

haemorrhage

Urticaria

Stevens-Johnson

syndrome/ Toxic

Epidermal

Necrolysis

DRESS

syndrome

Investigations

דומע

ךותמ

Common

Uncommon

Rare

Very rare

Not known

Increase in

transaminases

Increased bilirubin,

increased blood

alkaline

phosphatase

Increased LDH

increased lipase

increased

amylase

increased GGT

Bilirubin

conjugated

increased (with

or without

concomitant

increase of

ALT)

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)

* A pre-specified selective approach to adverse event collection was applied. As incidence of

adverse reactions did not increase and no new adverse reaction was identified, COMPASS

study data were not included for frequency calculation in this table.

Post-marketing observations

The following adverse reactions have been reported post-marketing in temporal association

with the use of Xarelto. 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)).

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Antithrombotic agents, direct factor Xa inhibitors, ATC code:

B01AF01

דומע

ךותמ

Clinical efficacy and safety

Patients with non-valvular atrial fibrillation who undergo PCI with stent placement

A randomized, open-label, multicentre study (PIONEER AF-PCI) was conducted in

2,124 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 Xarelto clinical program programme was designed to demonstrate the efficacy of Xarelto

in the initial and continued treatment of acute DVT and PE and prevention of recurrence.

Over 9,400 12,800 patients were studied in three four randomised controlled phase III clinical

studies (Einstein DVT , Einstein PE, and 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 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 randomisation date (median: 351 days). Xarelto

20 mg once daily and Xarelto 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.

דומע

ךותמ

In the Einstein Choice study (see Table 10) Xarelto 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 Xarelto 20 mg and 10 mg once

daily compared to 100 mg acetylsalicylic acid.

Table 10: Efficacy and safety results from phase III Einstein Choice

Study population

3,396 patients continued prevention of

recurrent venous thromboembolism

Treatment dose

Xarelto 20 mg od

N=1,107

Xarelto 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

(1.5%)*

(1.2%)**

(4.4%)

Symptomatic

recurrent PE

(0.5%)

(0.5%)

(1.7%)

Symptomatic

recurrent DVT

(0.8%)

(0.7%)

(2.7%)

Fatal PE/death where

PE cannot be ruled

(0.2%)

(0.0%)

(0.2%)

Symptomatic recurrent

VTE, MI, stroke, or non-

CNS systemic embolism

(1.7%)

(1.6%)

(5.0%)

Major bleeding events

(0.5%)

(0.4%)

(0.3%)

Clinically relevant non-

major bleeding

(2.7%)

(2.0%)

(1.8%)

Symptomatic recurrent

VTE or major bleeding

(net clinical benefit)

(2.1%)

(1.5%)

(4.7%)

* p<0.001(superiority) Xarelto 20 mg od vs ASA 100 mg od; HR=0.34 (0.20–0.59)

** p<0.001 (superiority) Xarelto 10 mg od vs ASA 100 mg od; HR=0.26 (0.14–0.47)

Xarelto 20 mg od vs. ASA 100 mg od; HR=0.44 (0.27–0.71), p=0.0009 (nominal)

Xarelto 10 mg od vs. ASA 100 mg od; HR=0.32 (0.18–0.55), p<0.0001 (nominal)

דומע

ךותמ

אפורל ןולעב םינוכדעה

רישכתה לש

20 mg

Xarelto

3.

PHARMACEUTICAL FORM

Prescriber guide

Patient safety information card

This product is marketed with patient safety information card(patient card).

The marketing of Xarelto 20 mg is subject to a risk management plan (RMP) including a

'patient safety information card' (Patient card). Please provide a patient card to each patient

who is prescribed with Xarelto 20 mg. The 'patient safety information card', emphasizes

important safety information that the patient should be aware of before and during treatment.

Please explain to the patient the need to review the card before starting treatment and the

implications of this treatment including the need for compliance. Please also explain the

signs of important adverse events and instruct the patient when to seek medical care.

(Minor change in the black box warning):

WARNING: (A) PREMATURE DISCONTINUATION OF XARELTO INCREASES

THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA

B. SPINAL/EPIDURAL HEMATOMA

[see special warnings and precautions for use (4.4) and undesirable effects (4.8)].

4.2 Posology and method of administration

Posology

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, as indicated in the table below.

Dosing schedule

Maximum daily dose

Day 1 - 21

15 mg twice daily

30 mg

Day 22 and onwards

20 mg once daily

20 mg

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).

דומע

ךותמ

and longer durations should be based on permanent risk factors or idiopathic 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.

The safety and efficacy of treatment duration beyond 12 months has not been established. It

should be considered whether to continue treatment beyond 12 months.

The duration of therapy should be individualised after careful assessment of the treatment

benefit against the risk for bleeding (see section 4.4). Short duration of therapy (at least

3 months) should be based on transient risk factors (e.g. recent surgery, trauma,

immobilisation) and longer durations should be based on permanent risk factors or idiopathic

DVT or PE.

Time Period

Dosing schedule

Total daily dose

Treatment and

prevention of

recurrent DVT and

Day 1 - 21

15 mg twice daily

30 mg

Day 22 onwards

20 mg once daily

20 mg

Prevention of

recurrent DVT and

PE

Following completion

of at least 6 months

therapy for DVT or

10 mg once daily

10 mg

Method of administration

There is no data regarding chewing or halving the tablets.

4.4

Special warnings and precautions for use

Dermatological reactions

Serious skin reactions, including Stevens-Johnson syndrome/ toxic epidermal necrolysis and

DRESS syndrome, 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

Xarelto contains lactose. Patients with rare hereditary problems of galactose intolerance, the

Lapp total lactase deficiency or glucose-galactose malabsorption should not take this

medicinal product.

דומע

ךותמ

4.5

Interaction with other medicinal products and other forms of interaction

CYP3A4 and P-gp inhibitors

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 C

. This increase is not considered clinically relevant. The

interaction with clarithromycin 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).

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 C

. This increase is not considered

clinically relevant. The interaction with erythromycin is likely not clinically 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 fold increase in mean rivaroxaban AUC and 1.6 fold increase in CRmax 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

CRmax 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 C

. This

increase is not considered clinically relevant. The interaction with fluconazole 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).

4.8

Undesirable effects

Summary of the safety profile

The safety of rivaroxaban has been evaluated in twelve thirteen phase III studies including

34,859 53,103 patients exposed to rivaroxaban (see Table 1).

דומע

ךותמ

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 atherothrombotic

events in patients with CAD/PAD

18,244

5 mg co-

administered with

ASA or 10 mg

alone

47 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 4.5%) and gastrointestinal

tract haemorrhage (4.1 3.8%).

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 investigators.

Table 2: Bleeding* and anaemia events rates in patients exposed to rivaroxaban

across the completed phase III studies:

Indication

Any bleeding

Anaemia

Prevention of atherothrombotic

events in patients with CAD/PAD

6.7 per 100

patient years

0.15 per 100

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

adverse event collection was applied

דומע

ךותמ

Table 3: All treatment-emergent adverse reactions reported in patients in phase III

studies clinical trials or through post-marketing use*

Common

Uncommon

Rare

Very rare

Not known

Blood and lymphatic system disorders

Anaemia (incl.

respective

laboratory

parameters)

Thrombocytosis

(incl. platelet count

increased)

Thrombocytopenia

Immune system disorders

Allergic reaction,

dermatitis allergic,

Angioedema and

allergic oedema

Anaphylactic

reactions

including

anaphylactic

shock

Hepatobiliary disorders

Increase in

transaminases

Hepatic

impairment,

Increased bilirubin,

increased blood

alkaline

phosphatase

increased GGT

Jaundice, Bilirubin

conjugated

increased (with or

without

concomitant

increase of ALT),

Cholestasis,

Hepatitis (incl.

hepatocellular

injury)

Skin and subcutaneous tissue disorders

Pruritus (incl.

uncommon cases

of generalised

pruritus), rash,

ecchymosis,

cutaneous and

subcutaneous

haemorrhage

Urticaria

Stevens-

Johnson

syndrome/ Toxic

Epidermal

Necrolysis,

DRESS

syndrome

Investigations

Increase in

transaminases

Increased bilirubin,

increased blood

alkaline

phosphatase

Increased LDH

increased lipase

increased

amylase

increased GGT

Bilirubin conjugated

increased (with or

without

concomitant

increase of ALT)

דומע

ךותמ

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)

* A pre-specified selective approach to adverse event collection was applied. As incidence of

adverse reactions did not increase and no new adverse reaction was identified, COMPASS

study data were not included for frequency calculation in this table.

Post-marketing observations

The following adverse reactions have been reported post-marketing in temporal association

with the use of Xarelto. 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)).

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Antithrombotic agents, direct factor Xa inhibitors, ATC code:

B01AF01

Clinical efficacy and safety

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 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

דומע

ךותמ

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 Xarelto clinical program

programme was designed to demonstrate the efficacy of Xarelto

in the initial and continued treatment of acute DVT and PE and prevention of recurrence.

Over 9,400 12,800 patients were studied in three four randomised controlled phase III clinical

studies (Einstein DVT, Einstein PE, and 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 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 randomisation date (median : 351 days).

Xarelto 20 mg once daily and Xarelto 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 Choice study (see Table 10) Xarelto 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 Xarelto 20 mg and 10 mg once

daily compared to 100 mg acetylsalicylic acid

דומע

ךותמ

Table 10: Efficacy and safety results from phase III Einstein Choice

Study population

3,396 patients continued prevention of

recurrent venous thromboembolism

Treatment dose

Xarelto 20 mg od

N=1,107

Xarelto 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

(1.5%)*

(1.2%)**

(4.4%)

Symptomatic recurrent

(0.5%)

(0.5%)

(1.7%)

Symptomatic recurrent

(0.8%)

(0.7%)

(2.7%)

Fatal PE/death where

PE cannot be ruled

(0.2%)

(0.0%)

(0.2%)

Symptomatic recurrent

VTE, MI, stroke, or non-

CNS systemic embolism

(1.7%)

(1.6%)

(5.0%)

Major bleeding events

(0.5%)

(0.4%)

(0.3%)

Clinically relevant non-

major bleeding

(2.7%)

(2.0%)

(1.8%)

Symptomatic recurrent

VTE or major bleeding

(net clinical benefit)

(2.1%)

(1.5%)

(4.7%)

* p<0.001(superiority) Xarelto 20 mg od vs ASA 100 mg od; HR=0.34 (0.20–0.59)

** p<0.001 (superiority) Xarelto 10 mg od vs ASA 100 mg od; HR=0.26 (0.14–0.47)

Xarelto 20 mg od vs. ASA 100 mg od; HR=0.44 (0.27–0.71), p=0.0009 (nominal)

Xarelto 10 mg od vs. ASA 100 mg od; HR=0.32 (0.18–0.55), p<0.0001 (nominal)

דומע

ךותמ

וכדעה םינ ןכרצל ןולעב

םירישכתל ףתושמה

Xarelto 15 mg + Xarelto 20 mg

ףיעס האר :םינגרלאו םיליעפ יתלב םירמוח

"ףסונ עדימ" ףיעסבו

לש םיביכרמהמ קלח לע בושח עדימ" ."הפורתה

לפוטמל יתוחיטב עדימ סיטרכ

ףסונב

,ןולעל

רישכתל

םייק וטלרסק

סיטרכ

עדימ יתוחיטב

מל סיטרכ .לפוט

הז

ליכמ

עדימ

בושח

ךילעש

תעדל

ינפל רישכתה תליטנ

.ויפ לע לועפלו וטלרסקב לופיטה ךלהמבו לופיטה תלחתה

שי

ןייעל

סיטרכב

עדימ

יתוחיטב לפוטמל ןכרצל ןולעבו

םרטב הילבטה תליטנ

.רישכתב שומישה תליחת

ךרוצה תדימב ףסונ ןויעל ןולעהו סיטרכה תא רומשל שי

2

(

הפורתב שומישה ינפל

שמתשהל ןיא

ב

:םא הפורת

.ךילע לח הלעמ םיראותמה םיבצמהמ דחא םא ךלש אפורל רפסו וטלרסק לוטית לא

תויצקארטניא

/

תובוגת

ןיב

תויתפורת

ותו םשרמ אלל תופורת ללוכ תורחא תופורת ,הנורחאל תחקל םא וא ,חקול התא םא לע רפס ,הנוזת יפס חקורל וא אפורל ךכ

.

:חקול התא םא דחוימב

:ןוגכ) םייתיירטפ םימוהיז דגנ תומייוסמ תופורת לוזאנוקוטק

,לוזאנוקולפ

,לוזנוקארטיא

,לוזאנוקירוו .רועה לע החירמל קר תודעוימש ולאל טרפ ,(לוזאנוקאסופ

גנישוק תנומסתב לופיטל לוזאנוקוטק תוליכמה תוילבט

צמ .(לוזיטרוק לש ףדוע רציימ ףוגה וב ב

.(ןיצימורתירא ,ןיצימורתיראלק :ןוגכ) םייקדייח םימוהיזב לופיטל תומיוסמ תופורת

ןסקורפנ :ןוגכ) באכ תוככשמו תקלד תודגונ תופורת

וא ] תיליצילסליטצא הצמוח ןיריפסא

לופיטל תומיוסמ תופורת דב

ןואכ

רזוח הגיפס לש םיביטקלס םיבכעמ) ) ןינוטורס לש ת

(SSRIs

וא

םיבכעמ םיביטקלס

ןירפניפארונו ןינוטורס לש תרזוח הגיפס לש

((SNRIs

שי םאהו וטלרסק םע ךב לפטל םאה טילחי ךלש אפורה .וטלרסק תוליעפ תרבגהל םורגל תולולע ולא תופורת .הדומצ תיאופר החגשהב ךרוצ

רתה לש םיביכרמהמ קלח לע בושח עדימ הפו

זוטקל הליכמ הפורתה

ןרתנו

.

לע ךל רמאנ םא

התאש ינפל אפורל הנפ ,םימייוסמ םירכוסל תוליבס יאמ לבוס ךנהש אפורה ידי

לוטיל ליחתמ .וטלרסק

דומע

ךותמ

מ תוחפ הליכמ הפורתה

) ןרתנ לומילימ

."ןרתנ תלוטנ" התוהמב תבשחנ ןכ לעו הילבט לכב (ג"מ

3

(

?הפורתב שמתשת דציכ

ןונימה לע ועבקי לופיטה ןפואו

.דבלב אפורה ידי

ףוגב םירחא םד ילכבו (ץבש) חומב םד ישירק תעינמל

אוה ללכ ךרדב לבוקמה ןונימה

בט לש תחא היל

.םויב םעפ ג"מ

לבוס ךנהו הדימב ,תוילכה דוקפתב יוקילמ

ימהו ןכתי לש תחא הילבטל תחפוי ןונ

.םויב םעפ ג"מ

ךילה רובעל ךירצ התא םא

תירועלמ תילילכ תוברעתה :םשב ךילה) בלב םדה ילכב המיסחב לופיטל

וטלרסק לש תחא הילבטל ןונימה תתחפה לע לבגומ עדימ םייק ,(ןכמות תרדחה םע

םעפ ג"מ ,תויסט תבכעמ הפורתל ףסונב םויב תחא

.לרגודיפולק :ןוגכ

תואירה לש םדה ילכבו םיילגרה ידירוב םד ישירקב לופיטל םד ישירק לש תרזוח העפוה תעינמלו

לש תחא הילבט אוה ללכ ךרדב לבוקמה ןונימה

ךשמל םויב םיימעפ ג"מ

,םינושארה תועובשה לש תחא הילבט ךשמהבו

.םויב םעפ ג"מ תוחפל תמלשה רחאל

ןכתיי ,לופיט לש םישדוח וטלרסקב לופיטה תא ךישמהל טילחי אפורהו

.םויב תחא הילבט ג"מ

תוילכה דוקפתב יוקילמ לבוס ךנהו הדימב

וטלרסק לטונו

םויב תחא םעפ ג"מ

טילחי אפורהש ןכתיי תיחפהל ןונימה תא אל רח

תועובש

לש תחא הילבטל

פ ג"מ ,םויב םע

תאז

ןוכיסהש הדימב דוע תורצוויהל ןוכיסהמ רתוי לודג םומידל

שירק

הליטנה תרוצ

...

יצח יבגל עדימ ןיא .הסיעל /ה

4

(

יאוול תועפות

ןמיס תווהל תולוכי רשא תוירשפא יאוול תועפות

:הרומח תירוע הבוגתל

םא אפורל דימ תונפל שי

הווח התא תירוע הבוגת

תוירוע תובוגת

:ןוגכ

םייניעב וא הפב לשמל ,תיריר המקרב םיעצפ וא תויחופלש ,רועה לע תטשפתמ תיביסניטניא החירפ

Toxic Epidermal Necrolysis/ Stevens-Johnson syndrome)

וז יאוול תעפות לש תורידתה .( ) דואמ הרידנ הניה דחא שמתשממ תוחפ

שמתשמ דע

ךותמ

10,000

(םדה לש) תויגולוטמה תוגירח ,םיימינפ םירביא לש תקלד ,םוח ,החירפל תמרוגה הפורתל הבוגת תנומסת) יתכרעמ ילוחו

DRESS

ות לש תורידתה שמתשמ דע) דואמ הרידנ הניה וז יאוול תעפ

ךותמ

10,000

ןמיס תווהל תולוכי רשא תוירשפא יאוול תועפות

:הרומח תיגרלא הבוגתל

םא אפורל דימ תונפל שי

תואבה יאוולה תועפותמ תחא לכ הווח התא

העילב יישק ;ןורגה וא ןושלה ,הפה ,םייתפשה ,םינפה תוחפנתה

;המישנ יישקו תדפרס החינצ ,תויטקליפאנא תובוגת) דואמ תורידנ ןניה הלא יאוול תועפות לש תויורידתה .םדה ץחל לש תימואתפ שמתשמ דע לע עיפשהל תולולע ;יטקליפאנא קוש ללוכ

ךותמ

10,000

המדאויגנא) תוחיכש ןניאו שמתשמ דע לע עיפשהל תולולע ;תיגרלא תקצבו

ךותמ

דומע

ךותמ

תופסונ יאוול תועפות

ות ) תוחיכש ןניאש יאוול תועפ

Uncommon

עיפשהל תולולעש תועפות רתויה לכל לע דע

שמתשמ דחא

ךותמ

(םדה תשירקל םיעייסמש םיאת ןהש ,םד תויסט לש ךומנ רפסמ) הינפוטיצובמורט

) תורידנ יאוול תועפות

Rare

עיפשהל תולולעש תועפות רתויה לכל לע דע

שמתשמ דחא

ךותמ

1000

דבכ) דבכה יאתב העיגפ ללוכ (סיטיטאפה) דבכה תקלד ,(הרמ לש תתחפומ המירז) סיזאטסלוכ (תידבכ העיגפ ללוכ יתקלד

:קווישל רישכתה רשוא זאמ וחווד ןלהל תועיפומה יאוולה תועפות

.(עולה וא ןושלה ,הפה ,םייתפשה ,םינפה לש תוחפנתה) תיגרלא תקצבו המדאויגנא

יתקלד דבכ) דבכה יאתב העיגפ תללוכה (תבהצ) דבכ תקלד ,(הרמ לש תתחפומ המירז) סיזטסלוכ (תידבכ העיגפ ללוכ

םד תויסט לש ךומנ רפסמ) הינפוטיצובמורט

(םד תשירקב םיעייסמש םיאת ןהש

ולעה םינ

אפורל

ןולעה ןכרצל

חלשנ

םוסרפל

רגאמב

תופורתה

רתאבש

דרשמ

תואירבה

https://www.old.health.gov.il/units/pharmacy/trufot/index.asp

ןתינ

לבקל

ספדומ םי

"

הינפ

תרבחל

רייאב

לארשי

חר

שרחה

דוה

ןורשה :ןופלט ,

09-7626700

,הכרבב

לארשי רייאב

1.

NAME OF THE MEDICINAL PRODUCT

Xarelto 20 mg

Film coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 20 mg rivaroxaban.

Excipient with known effect:

Each film-coated tablet contains 22.9 mg lactose monohydrate, see section 4.4.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablet (tablet).

Brown-red, round biconvex tablets (6 mm diameter, 9 mm radius of curvature) marked with the

BAYER-cross on one side and “20” and a triangle on the other side.

Prescriber guide

This product is marketed with prescriber guide providing recommendations for the risk

minimization in the use of Xarelto 20

mg. Please ensure you are familiar with this material as

it contains important safety information.

Patient safety information card

. The marketing of Xarelto 20 mg is subject to a risk management plan (RMP) including a

'patient safety information card' (Patient card). Please provide a patient card to each patient

who is prescribed with Xarelto 20 mg. The 'patient safety information card', emphasizes

important safety information that the patient should be aware of before and during treatment.

Please explain to the patient the need to review the card before starting treatment and the

implications of this treatment including the need for compliance. Please also explain the signs

of important adverse events and instruct the patient when to seek medical care.

WARNING: (A) PREMATURE DISCONTINUATION OF XARELTO INCREASES THE

RISK OF THROMBOTIC EVENTS,

(B) SPINAL/EPIDURAL HEMATOMA

A.

PREMATURE DISCONTINUATION OF XARELTO INCREASES THE RISK OF

THROMBOTIC EVENTS

Premature discontinuation of any oral anticoagulant, including XARELTO, increases the

risk of thrombotic events. If anticoagulation with XARELTO is discontinued for a reason

other than pathological bleeding or completion of a course of therapy, consider coverage

with another anticoagulant [see posology and method of administration (4.2), and special

warnings and precautions for use(4.4)].

B.

SPINAL/EPIDURAL HEMATOMA

Epidural or spinal hematomas have occurred in patients treated with XARELTO who are

receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may

result in long-term or permanent paralysis. Consider these risks when scheduling patients

for spinal procedures. Factors that can increase the risk of developing epidural or spinal

hematomas in these patients include:

use of indwelling epidural catheters

concomitant

use

of

other

drugs

that

affect

hemostasis,

such

as

non-steroidal

anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants

a history of traumatic or repeated epidural or spinal punctures

a history of spinal deformity or spinal surgery

optimal timing between the administration of XARELTO and neuraxial procedures is

not known

[see special warnings and precautions for use (4.4) and Undesirable effects (4.8)].

Monitor

patients

frequently

for

signs

and

symptoms

of

neurological

impairment.

If

neurological compromise is noted, urgent treatment is necessary [see special Warnings and

Precautions for use (4.4)].

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or

to be anticoagulated for thromboprophylaxis [see special Warnings and Precautions for use

(4.4)].

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation

with one or more risk factors, such as congestive heart failure, hypertension, age≥75 years, diabetes

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.)

4.2

Posology and method of administration

Posology

Prevention of stroke and systemic embolism

The recommended dose is 20 mg once daily, which is also the recommended maximum dose.

Therapy with Xarelto 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 Xarelto 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). and longer durations

should be based on permanent risk factors or idiopathic 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.

The safety and efficacy of treatment duration beyond 12 months has not been established. It should

be considered whether to continue treatment beyond 12 months.

The duration of therapy 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

Following completion

of at least 6 months

therapy for DVT or PE

10 mg once daily

10 mg

If a dose is missed during the 15 mg twice daily treatment phase (day 1 - 21), the patient should

take Xarelto immediately to ensure intake of 30 mg Xarelto 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 Xarelto

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 Xarelto

For patients treated for prevention of stroke and systemic embolism, VKA treatment should be

stopped and Xarelto therapy should be initiated when the International Normalised Ratio (INR) is

≤ 3.0.

For patients treated for DVT, PE and prevention of recurrence, VKA treatment should be stopped

and Xarelto therapy should be initiated once the INR is ≤ 2.5.

When converting patients from VKAs to Xarelto, INR values will be falsely elevated after the

intake of Xarelto. The INR is not valid to measure the anticoagulant activity of Xarelto, and

therefore should not be used (see section 4.5).

Converting from Xarelto to Vitamin K antagonists (VKA)

There is a potential for inadequate anticoagulation during the transition from Xarelto to VKA.

Continuous adequate anticoagulation should be ensured during any transition to an alternate

anticoagulant. It should be noted that Xarelto can contribute to an elevated INR.

In patients converting from Xarelto 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 Xarelto and

VKA the INR should not be tested earlier than 24 hours after the previous dose but prior to the next

dose of Xarelto. Once Xarelto 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 Xarelto

For patients currently receiving a parenteral anticoagulant, discontinue the parenteral anticoagulant

and start Xarelto 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 Xarelto to parenteral anticoagulants

Give the first dose of parenteral anticoagulant at the time the next Xarelto 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, Xarelto 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 dose recommendations apply:

For the prevention of stroke and systemic embolism in patients with non-valvular atrial

fibrillation, the recommended dose is 15 mg once daily (see section 5.2).

For the treatment of DVT, 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).

No dose adjustment is necessary in patients with mild renal impairment (creatinine clearance

50 - 80 ml/min) (see section 5.2).

Hepatic impairment

Xarelto 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 Xarelto in children aged 0 to 18 years have not been established. No data

are available. Therefore, Xarelto is not recommended for use in children below 18 years of age.

Patients undergoing cardioversion

Xarelto can be initiated or continued in patients who may require cardioversion.

For transesophageal echocardiogram (TEE) guided cardioversion in patients not previously treated

with anticoagulants, Xarelto 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 Xarelto as prescribed. Decisions on initiation

and duration of treatment should take established guideline recommendations for anticoagulant

treatment in patients undergoing cardioversion into account.

Method of administration

Xarelto is for oral use.

The tablets are to be taken with food (see section 5.2).

For patients who are unable to swallow whole tablets, Xarelto tablet may be crushed and mixed

with water or apple puree immediately prior to use and administered orally. After the administration

of crushed Xarelto 15 mg or 20 mg film-coated tablets, the dose should be immediately followed by

food.

The crushed Xarelto 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

Xarelto 15 mg or 20 mg film-coated tablets, the dose should then be immediately followed by

enteral feeding (see section 5.2).

There is no data regarding chewing or halving the tablets.

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

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).

4.4

Special warnings and precautions for use

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

period.

Haemorrhagic risk

As with other anticoagulants, patients taking Xarelto are to be carefully observed for signs of

bleeding. It is recommended to be used with caution in conditions with increased risk of

haemorrhage. Xarelto 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. Xarelto 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).

Xarelto 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 Xarelto 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

Rivaroxaban should not be used for thromboprophylaxis in patients having recently undergone

transcatheter aortic valve replacement (TAVR).Safety and efficacy of Xarelto have not been studied

in patients with prosthetic heart valves; therefore, there are no data to support that Xarelto provides

adequate anticoagulation in this patient population. Treatment with Xarelto is not recommended for

these patients.

Patients with antiphospholipid syndrome

Direct acting Oral Anticoagulants (DOACs) including rivaroxaban are not recommended for

patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome. In

particular for patients 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 of recurrent thrombotic events compared with vitamin K antagonist therapy.

Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary

embolectomy

Xarelto 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 Xarelto 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 [See boxed warning].

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, Xarelto 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.

Xarelto 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 and

DRESS syndrome, 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

Xarelto contains lactose. Patients with rare hereditary problems of galactose intolerance, total

lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Increased Risk of Thrombotic Events after Premature Discontinuation

Premature discontinuation of any oral anticoagulant, including Xarelto, in the absence of adequate

alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was

observed during the transition from Xarelto to warfarin in clinical trials in atrial fibrillation patients.

If Xarelto is discontinued for a reason other than pathological bleeding or completion of a course of

therapy, consider coverage with another anticoagulant [for conversion instructions see Dosage and

Administration (4.2)]

4.5

Interaction with other medicinal products and other forms of interaction

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 C

, with significant increases in pharmacodynamic effects which

may lead to an increased bleeding risk. Therefore, the use of Xarelto 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 C

. The interaction with clarithromycin 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).

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 C

. The interaction with erythromycin is likely

not clinically 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 fold

increase in mean rivaroxaban AUC and 1.6 fold increase in C

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 C

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 C

. The interaction with

fluconazole 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

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.

לע העדוה לע העדוה לע העדוה ( הרמחה ( הרמחה ( הרמחה

עדימ עדימ עדימ ןכרצל ןולעב )תוחיטב ןכרצל ןולעב )תוחיטב ןכרצל ןולעב )תוחיטב

ןכדועמ( ןכדועמ( ןכדועמ(

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___ ךיראת

_________

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תילגנאב רישכת םש

םושירה רפסמו

Xarelto 15 , Xarelto 20 mg

00/01

-

33579

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45

-

147

,

00/01

-

33576

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147

םושירה לעב םש

מ"עב לארשי רייאב

ה טורפל דעוימ הז ספוט דבלב תורמחה

תורמחהה שקובמה תו

ןולעב קרפ

יחכונ טסקט

שדח טסקט

תויוותה

שמתשהל ןיא יתמ ?רישכתב

תודחוימ תורהזא שומישל תועגונה :הפורתב

שמתשהל ןיא ילבמ הפורתב ינפל אפורב ץעוויהל :לופיטה תלחתה

ןיב תובוגת :תויתופורת

:הקנהו ןוירה

שמתשת דציכ :הפורתב

א

חותינ רובעל ןנכותמ התא

ם

וא תינשלופ הרודצורפ

ירחאו ינפל וטלרסק לוטיל רתויב בושח תינשלופה הרודצורפה וא חותינה .אפורה ךל עבקש םינמזב קוידב

חותינ רובעל ןנכותמ התא םא

וא ךילה

ינשלופ

ינפל וטלרסק לוטיל רתויב בושח ינשלופה ךילהה וא חותינה ירחאו בקש םינמזב קוידב .אפורה ךל ע

יתרדיש ךות הקירז וא רתנצ ם םי

ןוגכ יתרדיש וא ילרודיפא שוחלאל חותינב םיברועמ )באכ ךוכישל וא :ךלש

בושח לוטיל רתויב ינפל וטלרסק רתנצה תרסה וא הקירזה ירחאו .אפורה ךל עבקש םינמזב קוידב

הנפ תא םא לפטמה אפורל דימ

השלוח וא השוחת רסוחמ לבוס

םיילגרב וא יעמב תויעבמ וא

תיחופלשב

ןתשה רחאל

שיש רחאמ ,שוחלאה תוגגופתה הפוחד תיאופר תוברעתהב ךרוצ

:יאוול תועפות

וחווד ןלהל תועיפומה יאוולה תועפות :קווישל רישכתה רשוא זאמ

תימוקמ תקצב לש םיפקתה תרידח בקע

םילזונ לש רתי םד ילכל ץוחמ

המדאויגנא

זאמ וחווד ןלהל תועיפומה יאוולה תועפות :קווישל רישכתה רשוא

המדאויגנא

תיגרלא תקצבו ,םייתפשה ,םינפה לש תוחפנתה( .)עולה וא ןושלה ,הפה

פנתה( תיגרלא תקצבו תוח ,הפה ,םייתפשה ,םינפה לש .)עולה וא ןושלה

סיזטסלוכ

לש תתחפומ המירז( )הרמ העיגפ תללוכה תבהצ , ללוכ יתקלד דבכ( דבכה יאתב העיגפ

)תידבכ

( הינפוטיצובמורט לש ךומנ רפסמ תויסט

םד

םיעייסמש םיאת ןהש םד תשירקב

אפורל ןולעב )תוחיטב עדימ ( הרמחה לע העדוה אפורל ןולעב )תוחיטב עדימ ( הרמחה לע העדוה אפורל ןולעב )תוחיטב עדימ ( הרמחה לע העדוה

ןכדועמ( ןכדועמ( ןכדועמ(

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םושירה רפסמו תילגנאב רישכת םש

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44

-

Xarelto 15 mg 147

םושירה לעב םש לארשי רייאב מ"עב

! דבלב תורמחהה טורפל דעוימ הז ספוט

תושקובמה תורמחהה

ןולעב קרפ

יחכונ טסקט

שדח טסקט

Indication

contraindications

Posology, dosage &

administration

Special Warnings and

Special Precautions for

Use

Interaction with Other

Medicaments and Other

Forms of Interaction

Fertility,

pregnancy

and Lactation

Adverse events

Post-marketing

observations

Angioedema

allergic

oedema

have

been

reported post-marketing in

temporal association with

Xarelto.

frequency of these adverse

reactions

reported

from

post-marketing experience

cannot be estimated. In the

pooled

phase

trials,

these

events

were

uncommon

(≥ 1/1,000

< 1/100)

Post-marketing observations

The following adverse reactions have

been reported post-marketing in

temporal association with the use of

Xarelto. 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)).

אפורל ןולעב )תוחיטב עדימ ( הרמחה לע העדוה אפורל ןולעב )תוחיטב עדימ ( הרמחה לע העדוה אפורל ןולעב )תוחיטב עדימ ( הרמחה לע העדוה

ןכדועמ( ןכדועמ( ןכדועמ(

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םושירה רפסמו תילגנאב רישכת םש

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33579

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45

-

Xarelto 20 mg 147

םושירה לעב םש י רייאב מ"עב לארש

! דבלב תורמחהה טורפל דעוימ הז ספוט

תושקובמה תורמחהה

ןולעב קרפ

יחכונ טסקט

שדח טסקט

Indication

contraindications

Posology, dosage &

administration

Special Warnings and

Special Precautions for

Use

Interaction with Other

Medicaments and Other

Forms of Interaction

Fertility,

pregnancy

and Lactation

Adverse events

Angioedema

allergic

oedema

have

been

reported post-marketing in

temporal association with

Xarelto.

frequency of these adverse

reactions

reported

from

post-marketing experience

cannot be estimated. In the

pooled

phase

trials,

these

events

were

uncommon

(≥ 1/1,000

< 1/100)

marketing observations

Post

The following adverse reactions have

been reported post-marketing in

temporal association with the use of

Xarelto. 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)

III trials, these

(In the pooled phase

1/10,000 to

events were rare (≥

1/1,000)).

<

Blood and lymphatic system

disorders: Thrombocytopenia (In the

rials, these events

III t

pooled phase

1/1,000 to

were uncommon (≥

1/100)).

<

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