Xarelto 20mg film-coated tablets

  • Name:

    Xarelto 20mg film-coated tablets

  • Company:
    info
  • Active Ingredients:

    Rivaroxaban

  • Legal Category:

    Product subject to medical prescription which may be renewed (B)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 17/07/19

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Summary of Product Characteristics last updated on medicines.ie: 8/11/2019
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

Click on this link to Download PDF directly

Bayer Limited

Bayer Limited

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When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 8 November 2019 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.9 - Overdose

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

This variation was to update sections 4.4 Special warnings and precautions for use and 4.9 Management of bleeding of Xarelto’s SmPC in order to provide reference to the EU-approved specific reversal agent Ondexxya (Andexanet).

Updated on 6 November 2019 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.9 - Overdose

Legal category: Product subject to medical prescription which may be renewed (B)

Updated on 24 July 2019 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use

Legal category: Product subject to medical prescription which may be renewed (B)

Updated on 17 July 2019 PIL

Reasons for updating

  • Change to section 3 - how to take/use
  • Change to section 6 - date of revision

Updated on 17 July 2019 SmPC

Reasons for updating

  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

  • SmPC section 4.8: deletion of a footnote in the adverse event table for the system organ class “renal and urinary disorders”

Updated on 21 June 2019 PIL

Reasons for updating

  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 6 - date of revision

Updated on 21 June 2019 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

APS PRAC UPDATE

Updated on 21 June 2019 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

APS PRAC update

Updated on 17 May 2019 SmPC

Reasons for updating

  • Correction of spelling/typing errors

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

SPC began to duplicate from the begining again after section 4.8 - this version corrects this and so now section 4.9 follows immediately after section 4.8 without extra duplicate text inbetween

Updated on 29 January 2019 Ed-HCP

Reasons for updating

  • Add New Doc

Updated on 29 January 2019 Ed-Both

Reasons for updating

  • Add New Doc

Updated on 22 January 2019 PIL

Reasons for updating

  • Change to section 2 - interactions with other medicines, food or drink
  • Change to section 3 - how to take/use

Updated on 21 January 2019 SmPC

Reasons for updating

  • Change to section 4.8 - Undesirable effects

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Section 4.8 - Update to the data for bleeding and anaemia events rates in patients exposed to rivaroxaban across completed phase III studies.

Section 10 - Update to date of revision of the text.

Updated on 18 June 2018 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Section 4.2 - Minor typographical updates

Section 4.3 - Minor typographical updates


Section 4.4 - Minor typographical updates

Section 4.5 - Minor typographical updates

Section 4.8 - Minor typographical updates

Section 4.9 - minor typographical updates

Section 5.1 - Minor typographical updates

Section 5.2 - Minor typeographical udpates


Section 10 - Date of revision of the text has been updated to 05/2018

Updated on 18 June 2018 PIL

Reasons for updating

  • Change to section 2 - driving and using machines
  • Change to section 2 - excipient warnings
  • Change to section 4 - possible side effects
  • Change to section 6 - what the product contains
  • Change to section 6 - manufacturer
  • Change to section 6 - date of revision

Updated on 29 March 2018 PIL

Reasons for updating

  • New PIL for new product

Updated on 2 November 2017 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

In section 4.2 - update to the posology on treatment of DVT, treatment of PE and prevention of recurrent DVT and PE
In section 4.4 - update regarding use with SSRIs and SNRIs
In section 4.5 - update regarding use with SSRIs/SNRIs
In section 4.8 - update to the information
In section 5.1-  addition of the results from the clinical study Einstein Choice

Updated on 2 November 2017 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may be renewed (B)

Updated on 2 November 2017 PIL

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties

Free text change information supplied by the pharmaceutical company

In section 4.2 - update to the posology on treatment of DVT, treatment of PE and prevention of recurrent DVT and PE
In section 4.4 - update regarding use with SSRIs and SNRIs
In section 4.5 - update regarding use with SSRIs/SNRIs
In section 4.8 - update to the information
In section 5.1-  addition of the results from the clinical study Einstein Choice

Updated on 29 August 2017 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

In section 4.2 - Addition of information of patients with non-valvular atrial fibrillation who undergo PCI (percutaneous coronary intervention) with stent placement
In section 4.4 - Addition of information of patient with non-valvular atrial fibrillation who undergo PCI with stent placement
In section 5.1 - Addition of the results from the multicentre study PIONEER AF-PCI
In section 10 - Change of the date of revision of the text

Updated on 29 August 2017 PIL

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Free text change information supplied by the pharmaceutical company

In section 4.2 - Addition of information of patients with non-valvular atrial fibrillation who undergo PCI (percutaneous coronary intervention) with stent placement
In section 4.4 - Addition of information of patient with non-valvular atrial fibrillation who undergo PCI with stent placement
In section 5.1 - Addition of the results from the multicentre study PIONEER AF-PCI
In section 10 - Change of the date of revision of the text

Updated on 8 August 2017 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Present

New

Section 4.4

 

Elderly population

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

Section 4.4

 

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.

Section 4.8

 

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)).

Section 4.8

 

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)).

Updated on 8 August 2017 PIL

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Free text change information supplied by the pharmaceutical company

Present

New

Section 4.4

 

Elderly population

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

Section 4.4

 

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.

Section 4.8

 

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)).

Section 4.8

 

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)).

Updated on 18 May 2017 SmPC

Reasons for updating

  • Change to section 10 - Date of revision of the text
  • Change to section 7 - Marketing authorisation holder

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Name and address of MAH has changed from Bayer Pharma AG, 13342 Berlin, Germany to Bayer AG, 51368 Leverkusen, Germany.

Updated on 18 May 2017 PIL

Reasons for updating

  • Change to section 10 - Date of revision of the text
  • Change to section 7 - Marketing authorisation holder

Free text change information supplied by the pharmaceutical company

Name and address of MAH has changed from Bayer Pharma AG, 13342 Berlin, Germany to Bayer AG, 51368 Leverkusen, Germany.

Updated on 9 March 2017 SmPC

Reasons for updating

  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Section 4.6 - Update to heading to align with QRD template
Update to date of revision of the text.

Updated on 9 March 2017 PIL

Reasons for updating

  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 10 - Date of revision of the text

Free text change information supplied by the pharmaceutical company

Section 4.6 - Update to heading to align with QRD template
Update to date of revision of the text.

Updated on 7 November 2016 SmPC

Reasons for updating

  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Update to Section 5.1 of the SmPC to add the results of Xantus: A prospective, single-arm, non interventional, open-label cohort study conducted in patients with non-valvular atrial fibrillation to investigate the safety and effectiveness in a real-world setting.

Update to Section 5.1 of the SmPC to add the results of Xalia: A prospective, non-interventional, open-label cohort study conducted in patients with acute DVT to investigate the safety and effectiveness in a real-world setting.

Updated on 7 November 2016 PIL

Reasons for updating

  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Free text change information supplied by the pharmaceutical company

Update to Section 5.1 of the SmPC to add the results of Xantus: A prospective, single-arm, non interventional, open-label cohort study conducted in patients with non-valvular atrial fibrillation to investigate the safety and effectiveness in a real-world setting.

Update to Section 5.1 of the SmPC to add the results of Xalia: A prospective, non-interventional, open-label cohort study conducted in patients with acute DVT to investigate the safety and effectiveness in a real-world setting.

Updated on 20 July 2016 PIL

Reasons for updating

  • Change to section 6.5 - Nature and contents of container
  • Change to section 8 - MA number
  • Change to section 10 - Date of revision of the text

Free text change information supplied by the pharmaceutical company

Addition of pack size of 10, to Section 6.5, Nature and Contents of Container.

Marketing Authorisation Number, Section 8, addition of EU/1/08/472/039 MA Number.

Update of Revision of Text Date.

Updated on 20 July 2016 SmPC

Reasons for updating

  • Change to section 6.5 - Nature and contents of container
  • Change to section 8 - MA number
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Addition of pack size of 10, to Section 6.5, Nature and Contents of Container.

Marketing Authorisation Number, Section 8, addition of EU/1/08/472/039 MA Number.

Update of Revision of Text Date.

Updated on 14 July 2015 PIL

Reasons for updating

  • Change to section 6.5 - Nature and contents of container
  • Change to section 8 - MA number
  • Change to section 10 - Date of revision of the text

Free text change information supplied by the pharmaceutical company



Xarelto 20mg – EU/1/08/472/018
EMEA/H/C/944/IB/40/G
www.medicines.ie

(Inserted Text; Deleted Text)

 

6.5       Nature and contents of container

PP/Aluminium foil blisters in cartons of 14, 28, 42 or 98 film-coated tablets or perforated unit dose blisters in cartons of 10 x 1, or 100 x 1 or in multipacks containing 100 (10 packs of 10 x 1) film-coated tablets.
HDPE bottles of 100 film-coated tablets with a PP screw cap.

Not all pack sizes may be marketed

 

8          Marketing authorization number(s)

EU/1/08/472/017-021, EU/1/08/472/024, EU/1/08/472/037.

 

10           Date of revision of the text

05/2015 07/2015

Updated on 14 July 2015 SmPC

Reasons for updating

  • Change to section 6.5 - Nature and contents of container
  • Change to section 8 - MA number
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company



Xarelto 20mg – EU/1/08/472/018
EMEA/H/C/944/IB/40/G
www.medicines.ie

(Inserted Text; Deleted Text)

 

6.5       Nature and contents of container

PP/Aluminium foil blisters in cartons of 14, 28, 42 or 98 film-coated tablets or perforated unit dose blisters in cartons of 10 x 1, or 100 x 1 or in multipacks containing 100 (10 packs of 10 x 1) film-coated tablets.
HDPE bottles of 100 film-coated tablets with a PP screw cap.

Not all pack sizes may be marketed

 

8          Marketing authorization number(s)

EU/1/08/472/017-021, EU/1/08/472/024, EU/1/08/472/037.

 

10           Date of revision of the text

05/2015 07/2015

Updated on 18 June 2015 PIL

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Free text change information supplied by the pharmaceutical company



Xarelto 20mg – EU/1/08/472/018
EMEA/H/C/944/11/37
www.medicines.ie

(Inserted Text; Deleted Text)

 

4.4          Special warnings and precautions for use

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 15 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).
At least 18 hours should elapse after the last administration of rivaroxaban before removal of an epidural catheter.
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.

 

4.8       Undesirable effects

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 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. (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)).

 

10           Date of revision of the text

12/2014 05/2015

Updated on 18 June 2015 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company



Xarelto 20mg – EU/1/08/472/018
EMEA/H/C/944/11/37
www.medicines.ie

(Inserted Text; Deleted Text)

 

4.4          Special warnings and precautions for use

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 15 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).
At least 18 hours should elapse after the last administration of rivaroxaban before removal of an epidural catheter.
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.

 

4.8       Undesirable effects

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 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. (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)).

 

10           Date of revision of the text

12/2014 05/2015

Updated on 28 January 2015 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company



In section 4.2 Posology and method of administration

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.

 

In section 4.4 Special warnings and precautions for use the following text has been inserted:

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. At least 18 hours should elapse after the last administration of rivaroxaban before removal of an epidural catheter. 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.

In section 4.4 Special warnings and precautions within the paragraph ”Dosing recommendations before and after invasive procedures and surgical intervention” minor changes have been made to improve the readability of the section.

In section 4.9 Overdose under “Management of bleeding”

·         “There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving rivaroxaban” now reads as “There is limited experience with tranexamic acid and no experience with aminocaproic acid and aprotinin in individuals receiving rivaroxaban”

·         Aprotinin has been deleted as a haemostatic

 

In section 5.1 Pharmacodynamic properties the following text has been inserted under “Pharmacodynamic effects”:

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).

 

 

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.

 

 

 

 

Updated on 28 January 2015 PIL

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties

Free text change information supplied by the pharmaceutical company



In section 4.2 Posology and method of administration

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.

 

In section 4.4 Special warnings and precautions for use the following text has been inserted:

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. At least 18 hours should elapse after the last administration of rivaroxaban before removal of an epidural catheter. 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.

In section 4.4 Special warnings and precautions within the paragraph ”Dosing recommendations before and after invasive procedures and surgical intervention” minor changes have been made to improve the readability of the section.

In section 4.9 Overdose under “Management of bleeding”

·         “There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving rivaroxaban” now reads as “There is limited experience with tranexamic acid and no experience with aminocaproic acid and aprotinin in individuals receiving rivaroxaban”

·         Aprotinin has been deleted as a haemostatic

 

In section 5.1 Pharmacodynamic properties the following text has been inserted under “Pharmacodynamic effects”:

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).

 

 

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.

 

 

 

 

Updated on 9 September 2014 PIL

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Free text change information supplied by the pharmaceutical company

·  In section 4.2, the following change was made:

Converting from parenteral anticoagulants to XareltoFor patients currently receiving a parenteral anticoagulant, discontinue the parenteral anticoagulant and start Xarelto should be started 0 to 2 hours before the time of 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).

·  In section 4.3, the following change was made: 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 the specific circumstances of switching anticoagulant therapy to or from rivaroxaban (see section 4.2) or when UFH is given atdoses necessary to maintain an open central venous or arterial catheter (see section 4.5).

 

·  In section 4.8, the updated HPRA details were added in place of  IMB.

Updated on 9 September 2014 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

·  In section 4.2, the following change was made:

Converting from parenteral anticoagulants to XareltoFor patients currently receiving a parenteral anticoagulant, discontinue the parenteral anticoagulant and start Xarelto should be started 0 to 2 hours before the time of 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).

·  In section 4.3, the following change was made: 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 the specific circumstances of switching anticoagulant therapy to or from rivaroxaban (see section 4.2) or when UFH is given atdoses necessary to maintain an open central venous or arterial catheter (see section 4.5).

 

·  In section 4.8, the updated HPRA details were added in place of  IMB.

Updated on 19 December 2013 PIL

Reasons for updating

  • Addition of black triangle
  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 10 - Date of revision of the text

Free text change information supplied by the pharmaceutical company

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

 

 

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Excipients with known effect:

Each 20 mg film-coated tablet contains 21.76 mg lactose (as monohydrate), see section 4.4.

 

 

4.2         Posology and method of administration

 

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. thereforeTherefore, 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).

 

Method of administration

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 Xarelto15 mg or 20 mg film-coated tablets, the dose should then be immediately followed by enteral feeding (see section 5.2).

 

 

4.4     Special warnings and precautions for use

 

Although treatment with rivaroxaban does not require routine monitoring of exposure, rivaroxaban levels measured with a calibrated quantitative anti-Factor 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)that are potent inhibitors of CYP3A4 (e.g. clarithromycin, telithromycin) as PK modelling shows increased rivaroxaban concentrations in these patients.

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)active ulcerative gastrointestinal disease

·    vascular retinopathy

·    bronchiectasis or history of pulmonary bleeding

 

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 5.1 and 5.2).

 

4.5     Interaction with other medicinal products and other forms of interaction

 

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 CRmaxR. This increase is not considered clinically relevant. (For patients with renal impairment: see section 4.4).

 

 

Anticoagulants

After combined administration of enoxaparin (40 mg single dose) with rivaroxaban (10 mg single dose) an additive effect on anti-Factor 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).

 

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 sStrong CYP3A4 inducers should be avoided unless the patient is closely observed for signs and symptoms of thrombosis.co-administered with caution.

 

 

4.8         Undesirable effects

 

Table 1: Number of patients studied, maximum daily dose and treatment duration in phase III studies

Indication

Number of patients*

Maximum 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

4,556

Day 1 ‑ 21: 30 mg

Day 22 and onwards: 20 mg

21 months

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

7,750

20 mg

41 months

Prevention of atherothrombotic eventscardiovascular death and myocardial infarction in patients after an acute coronary syndrome (ACS)

10,225

5 mg or 10 mg respectively, on top ofco-administered 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). The most commonly reported bleedings (≥4 %) were epistaxis (5.9 %) and gastrointestinal tract haemorrhage (4.2 %).

 

 

Table 2: All treatment-emergent adverse reactions reported in patients in phase III studies  

 

C: observed as uncommon in prevention of atherothrombotic events cardiovascular death and MI in patients after an ACS (following percutaneous coronary intervention)

 

 

Post-marketing observations

Angioedema and allergic oedema 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. In the pooled phase III trials, these events were uncommon (≥ 1/1,000 to < 1/100).

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions preferably through the online reporting option accessible from the IMB homepage. A downloadable report form is also accessible from the IMB website, which may be completed manually and submitted to the IMB via ‘freepost’, in addition to the traditional post-paid ‘yellow card’ option.

 

FREEPOST

Pharmacovigilance Section

Irish Medicines Board

Kevin O’Malley House

Earlsfort Centre

Earlsfort Terrace

Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

 

 

5.1     Pharmacodynamic properties

 

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 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 factor II) and no effects on platelets have been demonstrated.

 

Pharmacodynamic effects

Dose-dependent inhibition of Factor factor Xa activity was observed in humans

 

 

However, if clinically indicated rivaroxaban levels can be measured by calibrated quantitative anti-Factor factor Xa tests (see section 5.2).

 

 

5.2     Pharmacokinetic properties

 

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 CRmaxR at the 2.5 mg and 10 mg dose.

 

 

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.

 

Hepatic impairment

 

The inhibition of Factor 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.

 

Pharmacokinetic/pharmacodynamic relationship

 

The pharmacokinetic/pharmacodynamic (PK/PD) relationship between rivaroxaban plasma concentration and several PD endpoints (Factor 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 factor Xa activity was best described by an ERmaxR model.

 

 

5.3     Preclinical safety data

 

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

 

10.       DATE OF REVISION OF THE TEXT

 

November 2013

 

Updated on 19 December 2013 SmPC

Reasons for updating

  • Addition of black triangle
  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

 

 

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Excipients with known effect:

Each 20 mg film-coated tablet contains 21.76 mg lactose (as monohydrate), see section 4.4.

 

 

4.2         Posology and method of administration

 

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. thereforeTherefore, 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).

 

Method of administration

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 Xarelto15 mg or 20 mg film-coated tablets, the dose should then be immediately followed by enteral feeding (see section 5.2).

 

 

4.4     Special warnings and precautions for use

 

Although treatment with rivaroxaban does not require routine monitoring of exposure, rivaroxaban levels measured with a calibrated quantitative anti-Factor 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)that are potent inhibitors of CYP3A4 (e.g. clarithromycin, telithromycin) as PK modelling shows increased rivaroxaban concentrations in these patients.

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)active ulcerative gastrointestinal disease

·    vascular retinopathy

·    bronchiectasis or history of pulmonary bleeding

 

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 5.1 and 5.2).

 

4.5     Interaction with other medicinal products and other forms of interaction

 

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 CRmaxR. This increase is not considered clinically relevant. (For patients with renal impairment: see section 4.4).

 

 

Anticoagulants

After combined administration of enoxaparin (40 mg single dose) with rivaroxaban (10 mg single dose) an additive effect on anti-Factor 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).

 

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 sStrong CYP3A4 inducers should be avoided unless the patient is closely observed for signs and symptoms of thrombosis.co-administered with caution.

 

 

4.8         Undesirable effects

 

Table 1: Number of patients studied, maximum daily dose and treatment duration in phase III studies

Indication

Number of patients*

Maximum 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

4,556

Day 1 ‑ 21: 30 mg

Day 22 and onwards: 20 mg

21 months

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

7,750

20 mg

41 months

Prevention of atherothrombotic eventscardiovascular death and myocardial infarction in patients after an acute coronary syndrome (ACS)

10,225

5 mg or 10 mg respectively, on top ofco-administered 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). The most commonly reported bleedings (≥4 %) were epistaxis (5.9 %) and gastrointestinal tract haemorrhage (4.2 %).

 

 

Table 2: All treatment-emergent adverse reactions reported in patients in phase III studies  

 

C: observed as uncommon in prevention of atherothrombotic events cardiovascular death and MI in patients after an ACS (following percutaneous coronary intervention)

 

 

Post-marketing observations

Angioedema and allergic oedema 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. In the pooled phase III trials, these events were uncommon (≥ 1/1,000 to < 1/100).

 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions preferably through the online reporting option accessible from the IMB homepage. A downloadable report form is also accessible from the IMB website, which may be completed manually and submitted to the IMB via ‘freepost’, in addition to the traditional post-paid ‘yellow card’ option.

 

FREEPOST

Pharmacovigilance Section

Irish Medicines Board

Kevin O’Malley House

Earlsfort Centre

Earlsfort Terrace

Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

 

 

5.1     Pharmacodynamic properties

 

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 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 factor II) and no effects on platelets have been demonstrated.

 

Pharmacodynamic effects

Dose-dependent inhibition of Factor factor Xa activity was observed in humans

 

 

However, if clinically indicated rivaroxaban levels can be measured by calibrated quantitative anti-Factor factor Xa tests (see section 5.2).

 

 

5.2     Pharmacokinetic properties

 

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 CRmaxR at the 2.5 mg and 10 mg dose.

 

 

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.

 

Hepatic impairment

 

The inhibition of Factor 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.

 

Pharmacokinetic/pharmacodynamic relationship

 

The pharmacokinetic/pharmacodynamic (PK/PD) relationship between rivaroxaban plasma concentration and several PD endpoints (Factor 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 factor Xa activity was best described by an ERmaxR model.

 

 

5.3     Preclinical safety data

 

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

 

10.       DATE OF REVISION OF THE TEXT

 

November 2013

 

Updated on 12 August 2013 PIL

Reasons for updating

  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.9 - Overdose
  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text

Free text change information supplied by the pharmaceutical company

Red text = deleted text

Blue text = inserted text

Section 4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Active clinically significant bleeding Clinically significant active bleeding.

Lesion or condition, if considered to be a at significant risk of for major bleeding. This may include

such as 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 anticoagulant agent s e.g. unfractionated heparin (UFH), low

molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral

anticoagulants (warfarin, apixaban, dabigatran, etexilate, apixaban,etc.) except under the

circumstances of switching therapy to or from rivaroxaban (see section 4.2) or when UFH is given at

doses necessary to maintain a patentan open central venous or arterial catheter (see section 4.5).

……………………………….

Section 4.4 Special warnings and precautions for use

……………………………….

Xarelto should be restarted after the invasive procedure or surgical intervention as soon as possible

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).

Section 4.5 Interaction with other medicinal products and other forms of interaction

……………………………….

This increase is not considered clinically relevant. (For patients with renal impairment: see

section 4.4).

……………………………….

Section 4.9 Overdose

……………………………….

Depending on local availability, a consultation with a coagulation expert should be considered in case

of major bleedings.

……………………………….

Section 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 30 September 2008

Date of latest renewal: 22 May 2013

Section 10. DATE OF REVISION OF THE TEXT

June 2013{MM/YYYY}

 

Updated on 12 August 2013 SmPC

Reasons for updating

  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.9 - Overdose
  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Red text = deleted text

Blue text = inserted text

Section 4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Active clinically significant bleeding Clinically significant active bleeding.

Lesion or condition, if considered to be a at significant risk of for major bleeding. This may include

such as 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 anticoagulant agent s e.g. unfractionated heparin (UFH), low

molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral

anticoagulants (warfarin, apixaban, dabigatran, etexilate, apixaban,etc.) except under the

circumstances of switching therapy to or from rivaroxaban (see section 4.2) or when UFH is given at

doses necessary to maintain a patentan open central venous or arterial catheter (see section 4.5).

……………………………….

Section 4.4 Special warnings and precautions for use

……………………………….

Xarelto should be restarted after the invasive procedure or surgical intervention as soon as possible

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).

Section 4.5 Interaction with other medicinal products and other forms of interaction

……………………………….

This increase is not considered clinically relevant. (For patients with renal impairment: see

section 4.4).

……………………………….

Section 4.9 Overdose

……………………………….

Depending on local availability, a consultation with a coagulation expert should be considered in case

of major bleedings.

……………………………….

Section 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 30 September 2008

Date of latest renewal: 22 May 2013

Section 10. DATE OF REVISION OF THE TEXT

June 2013{MM/YYYY}

 

Updated on 28 January 2013 PIL

Reasons for updating

  • Change to section 10 - Date of revision of the text

Free text change information supplied by the pharmaceutical company

Section 10 - date of revision of text changed from November 2012 to January 2013

Updated on 28 January 2013 SmPC

Reasons for updating

  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Section 10 - date of revision of text changed from November 2012 to January 2013

Updated on 18 January 2013 PIL

Reasons for updating

  • Change to section 5.1 - Pharmacodynamic properties

Free text change information supplied by the pharmaceutical company

Section 5.1:

From:

Pharmacotherapeutic group: Other antithrombotic agents, ATC code: B01AX06


To:

Pharmacotherapeutic group: Direct factor Xa inhibitors, ATC code: B01AF01


Updated on 18 January 2013 SmPC

Reasons for updating

  • Change to section 5.1 - Pharmacodynamic properties

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Section 5.1:

From:

Pharmacotherapeutic group: Other antithrombotic agents, ATC code: B01AX06


To:

Pharmacotherapeutic group: Direct factor Xa inhibitors, ATC code: B01AF01


Updated on 5 December 2012 SmPC

Reasons for updating

  • New individual SPC (was previously included in combined SPC)

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Previously, a combined SPC was used for both Xarelto 15mg and Xarelto 20mg. The purpose of this submission is to upload an individual SPC for Xarelto 20mg film-coated tablets.

Updated on 5 December 2012 PIL

Reasons for updating

  • New individual SPC (was previously included in combined SPC)

Free text change information supplied by the pharmaceutical company

Previously, a combined SPC was used for both Xarelto 15mg and Xarelto 20mg. The purpose of this submission is to upload an individual SPC for Xarelto 20mg film-coated tablets.