Xarelto 10 mg film-coated tablets

  • Name:

    Xarelto 10 mg 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: 21/06/19

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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.

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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 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 29 January 2019 Ed-HCP

Reasons for updating

  • Add New Doc

Updated on 29 January 2019 Ed-Ptnt

Reasons for updating

  • Add New Doc

Updated on 29 January 2019 Ed-HCP

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

Updated on 21 January 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

Section 4.8 Undesirable effects: new data added regarding bleeding and anaemia events.

Section 10: Date of revision of the text has been updated to August 2018

Updated on 18 June 2018 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 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic 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

Section 4.2 - 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 - 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 29 March 2018 PIL

Reasons for updating

  • Change to section 1 - what the product is used for
  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 2 - interactions with other medicines, food or drink
  • Change to section 3 - how to take/use
  • Change to section 6 - what the product looks like and pack contents

Updated on 26 October 2017 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - 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 4.1 - addition of the indication "Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults."

In section 4.2 - addition of the posology for Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE

In section 4.4 - Updated information on Haemorrhagic risk, patients with prosthetic valves, and Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary embolectomy

In Section 5.1 - addition of the results of the Einstein Choice clinical study

Updated on 26 October 2017 SmPC

Reasons for updating

  • New SmPC for new product

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

Updated on 30 August 2017 PIL

Reasons for updating

  • Change to section 6 - date of revision

Updated on 30 August 2017 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

In section 10, update to 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 2 August 2017 PIL

Reasons for updating

  • Change to section 4 - possible side effects
  • Change to section 4 - how to report a side effect
  • Change to section 6 - date of revision

Updated on 18 May 2017 SmPC

Reasons for updating

  • Change to section 7 - Marketing authorisation holder
  • 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

MAH has been changed from Bayer Pharma AG, 13342 Berlin, Germany to Bayer AG 51368 Leverkusen, Germany

Updated on 17 May 2017 PIL

Reasons for updating

  • Change to section 6 - marketing authorisation number
  • Change to section 6 - manufacturer
  • Change to section 6 - date of revision

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

Update to section 4.6 - Title of section aligned with QRD
Update to date of revision of the text

Updated on 15 July 2015 PIL

Reasons for updating

  • Change to date of revision
  • Change to MA holder contact details

Updated on 14 July 2015 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



Xarelto 10mg – EU/1/08/472/007
EMEA/H/C/944/IB/40/G
www.medicines.ie

(Inserted Text; Deleted Text)

 

10           Date of revision of the text

05/2015 07/2015

 

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 - how to report a side effect
  • 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 10mg – EU/1/08/472/007
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.
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 (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 PIL

Reasons for updating

  • Change to side-effects
  • Change to date of revision

Updated on 27 January 2015 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to improve clarity and readability

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

Free text change information supplied by the pharmaceutical company



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).

Updated on 12 September 2014 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Addition of information on reporting a side effect.

Updated on 10 September 2014 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • 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 4.4 Special warnings and precautions for use under the sub-heading 'Hip fracture surgery' the inclusion of  interventional to describe the clinical trial and the direct recommendation not to use Rivaroxaban in these patients has been removed.
"Rivaroxaban has not been studied in interventional clinical trials in patients undergoing hip fracture surgery to evaluate efficacy and safety." and deletion of "in these patients. Therefore, rivaroxaban is not recommended in these patients"

In section 4.8 Undesirable effects under the sub-heading Reporting of suspected adverse reactions the contact details for the IMB have been replaced with the respective details of teh HPRA as follows:
"Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517.
Website:www.hpra.ie; E-mail: medsafety@hpra.ie."

In section 5. PHARMACOLOGICAL PROPERTIES  under the sub-heading Clinical efficacy and safety the following paragraph was introduced
In addition to the phase III RECORD program, a post-authorization, non-interventional, open-label cohort study (XAMOS) has been conducted in 17,413 patients undergoing major orthopaedic surgery of the hip or knee, to compare rivaroxaban with other pharmacological thromboprophylaxis (standard-of-care) under real-life setting. Symptomatic VTE occurred in 57 (0.6%) patients in the rivaroxaban group (n=8,778) and 88 (1.0%) of patients in the standard-of-care group (n=8,635; HR 0.63; 95% CI 0.43-0.91); safety population). Major bleeding occurred in 35 (0.4%) and 29 (0.3%) of patients in the rivaroxaban and standard-of-care groups (HR 1.10; 95% CI 0.67-1.80). Thus, the results were consistent with the results of the pivotal randomised studies.

 

 

 

Updated on 19 August 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 - how to report a side effect
  • 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 Xarelto

     

    For 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 SmPC

    Reasons for updating

    • Addition of black triangle
    • 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 4.7 - Effects on ability to drive and use machines
    • 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.

     

    4.2         Posology and method of administration

     

    Method of administration

    For oral use.

    Xarelto can be taken with or without food (see sections 4.5 and 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.

    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 (see section 5.2).

     

    4.4     Special warnings and precautions for use

     

    Haemorrhagic risk

    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). This may be done by regular physical examination of the patients, close observation of the surgical wound drainage and periodic measurements of haemoglobin.

    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 is to be used with caution iIn patients with moderate renal impairment (creatinine clearance 30 - 49 ml/min) concomitantly receiving other medicinal products which increase rivaroxaban plasma concentrations Xarelto is to be used with caution (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 (ASA) and, platelet aggregation inhibitors or other antithrombotic agents. For patients at risk of ulcerative gastrointestinal disease an appropriate prophylactic treatment may be considered (see section 4.5).

     

     

    Xarelto is to be used with caution in In patients with moderate renal impairment (creatinine clearance 30 ‑ 49 ml/min) concomitantly receiving other medicinal products which increase rivaroxaban plasma concentrations Xarelto is to be used with caution

     

    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 sections 5.1 and 5.2).

     

    4.5     Interaction with other medicinal products and other forms of interaction

     

    CYP3A4 and P‑gp inhibitors

     

    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 2T(Hypericum perforatum))2T 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.

    4.7     Effects on ability to drive and use machines

     

    Xarelto has minor influence on the ability to drive and use machines. Adverse reactions like syncope (frequency: uncommon) and dizziness (frequency: common) have been reported to be common (see section 4.8).

     

     

    4.8         Undesirable effects

     

    Summary of the safety profile

    The safety of rivaroxaban has been evaluated in eight eleven phase III studies including 32,62516,041 patients exposed to rivaroxaban (see Table 1).

     

    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 recurrent DVT and PErecurrence

    4,5562,194

    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 events in patients after an ACS

    10,225

    5 mg or 10 mg respectively, co-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 %).

    In total about 7367% of patients exposed to at least one dose of rivaroxaban were reported with treatment emergent adverse events. About 2422 % of the patients experienced adverse events considered related to treatment as assessed by investigators. In patients treated with 10 mg Xarelto undergoing hip or knee replacement surgery and in hospitalised medically ill patients, bleeding events occurred in approximately 6.8 % and 12.6 % of patients, respectively, and anaemia occurred in approximately 5.9 % and 2.1 % of patients, respectively. In patients treated with either 15 mg twice daily Xarelto followed by 20 mg once daily for treatment of DVT or PE, or with 20 mg once daily for prevention of recurrent DVT and PE, bleeding events occurred in approximately 27.8 22.7% of patients and anaemia occurred in approximately 2.2 1.8% of patients. In patients treated for prevention of stroke and systemic embolism, bleeding of any type or severity was reported with an event rate of 28 per 100 patient years, and anaemia with an event rate of 2.5 per 100 patient years. In patients treated for prevention of atherothrombotic events after an acute coronary syndrome (ACS), bleeding of any type or severity was reported with an event rate of 22 per 100 patient years. Anaemia was reported with an event rate of 1.4 per 100 patient years.

     

     

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

     

    Common

    Uncommon

    Rare

    Not Knownknown

    Blood and lymphatic system disorders

    Anaemia (incl. respective laboratory parameters)

    Thrombocythemia (incl. platelet count increased)PA

     

     

    Immune system disorders

     

    Allergic reaction, dermatitis allergic

     

     

    Nervous system disorders

    Dizziness, headache, syncope

    Cerebral and intracranial haemorrhage, syncope

     

     

    Eye disorders

    Eye haemorrhage (incl. conjunctival haemorrhage)

     

     

     

    Cardiac disorders

    Tachycardia

    Tachycardia

     

     

    Vascular disorders

    Hypotension, haematoma

     

     

    Pseudoaneurysm formation following percutaneous intervention*

    Respiratory, thoracic and mediastinal disorders

    Epistaxis, haemoptysis

    Haemoptysis

     

     

    Gastrointestinal disorders

    Gingival bleeding, gGastrointestinal tract haemorrhage (incl. gingival bleeding and rectal haemorrhage), gastrointestinal and abdominal pains, dyspepsia, nausea, constipationPAP, diarrhoea, vomitingPA

    Dry mouth

     

     

    Hepatobiliary disorders

     

    Hepatic function abnormal

    Jaundice

     

    Skin and subcutaneous tissue disorders

    Pruritus (incl. uncommon cases of generalised pruritus), rash, ecchymosis, cutaneous and subcutaneous haemorrhage

    Urticaria, cutaneous and subcutaneous haemorrhage

     

     

    Musculoskeletal and connective tissue disorders

    Pain in extremityPA

    Haemarthrosis

    Muscle haemorrhage

    Compartment syndrome secondary to a bleeding

    Renal and urinary disorders

    Urogenital tract haemorrhage (incl. haematuria and menorrhagiaPBP), renal impairment (incl. blood creatinine increased, blood urea increased)PA

    Renal impairment (incl. blood creatinine increased, blood urea increased)PA

     

    Renal failure/acute renal failure secondary to a bleeding sufficient to cause hypoperfusion

    General disorders and administration site conditions

    FeverPAP, peripheral oedema, decreased general strength and energy (incl. fatigue and asthenia)

    Feeling unwell (incl. malaise), localised oedemaPA

    Localised oedemaPA

     

    Investigations

    Increase in transaminases

    Increased bilirubin, increased blood alkaline phosphatasePAP,P Pincreased LDHPAP, increased lipasePAP, increased amylasePAP, increased GGTPA

    Bilirubin conjugated increased (with or without concomitant increase of ALT)

     

    Injury, poisoning and procedural complications

    Postprocedural haemorrhage (incl. postoperative anaemia, and wound haemorrhage), contusion,
    wound secretion
    PA

     

    Vascular pseudoaneurysmPC

     

    A: observed in VTE-P after major orthopaedic surgery of the lower limbsprevention 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 DVT-T as very common in women < 55 years

    *) These reactions occurred in other clinical studies than the phase III studies in patients undergoing major orthopaedic surgery of the lower limbs, patients treated for DVT and prevention of recurrent DVT and PE, or patients treated for the prevention of stroke and systemic embolism

    C: observed as uncommon in prevention of atherothrombotic events 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.       PHARMACOLOGICAL PROPERTIES

     

    5.1     Pharmacodynamic properties

     

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

     

    Mechanism of action

    Rivaroxaban is a highly selective direct Factor 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

     

    Absorption

    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. Rivaroxaban 2.5 mg and 10 mg tablets can be taken with or without food…………………..

    Variability in rivaroxaban pharmacokinetics is moderate with inter-individual variability (CV %) ranging from 30 % to 40 %, apart from on the day of surgery and the following day when variability in exposure is high (70 %).

     

    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

    Cirrhotic patients with mild hepatic impairment (classified as Child Pugh A) exhibited only minor changes in rivaroxaban pharmacokinetics (1.2 fold increase in rivaroxaban AUC on average), nearly comparable to their matched healthy control group. In cirrhotic patients with moderate hepatic impairment (classified as Child Pugh B), rivaroxaban mean AUC was significantly increased by 2.3 fold compared to healthy volunteers. Unbound AUC was increased 2.6 fold. These patients also had reduced renal elimination of rivaroxaban, similar to patients with moderate renal impairment. There are no data in patients with severe hepatic impairment.

    The inhibition of Factor factor Xa activity was increased by a factor of 2.6 in patients with moderate hepatic impairment as compared to healthy volunteers; prolongation of PT was similarly increased by a factor of 2.1. Patients with moderate hepatic impairment were more sensitive to rivaroxaban resulting in a steeper PK/PD relationship between concentration and PT.

    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 section 4.3).

     

    Renal impairment

    There was an increase in rivaroxaban exposure correlated to decrease in renal function, as assessed via creatinine clearance measurements. In individuals with mild (creatinine clearance 50 ‑ 80 ml/min), moderate (creatinine clearance 30 ‑ 49 ml/min) and severe (creatinine clearance 15 ‑ 29 ml/min) renal impairment, rivaroxaban plasma concentrations (AUC) were increased 1.4, 1.5 and 1.6 fold respectively. Corresponding increases in pharmacodynamic effects were more pronounced. In individuals with mild, moderate and severe renal impairment the overall inhibition of Factor factor Xa activity was increased by a factor of 1.5, 1.9 and 2.0 respectively as compared to healthy volunteers; prolongation of PT was similarly increased by a factor of 1.3, 2.2 and 2.4 respectively. There are no data in patients with creatinine clearance < 15 ml/min.

    Due to the high plasma protein binding rivaroxaban is not expected to be dialysable.

    Use is not recommended in patients with creatinine clearance < 15 ml/min. Xarelto is to be used with caution in patients with creatinine clearance 15 ‑ 29 ml/min (see section 4.4).

     

    Pharmacokinetic data in patients

    In patients receiving rivaroxaban 2.5 mg twice daily for the prevention of atherothrombotic events in patients with ACS the geometric mean concentration (90 % prediction interval) 2 ‑ 4 h and about 12 h after dose (roughly representing maximum and minimum concentrations during the dose interval) was 47 (13 ‑ 123) and 9.2 (4.4 ‑ 18) µg/l, respectively.

     

    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. For PT, the linear intercept model generally described the data better. Depending on the different PT reagents used, the slope differed considerably. When Neoplastin PT was used, baseline PT was about 13 s and the slope was around 3 to 4 s/(100 µg/l). The results of the PK/PD analyses in Phase II and III were consistent with the data established in healthy subjects.

     

     

    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 10 December 2013 PIL

    Reasons for updating

    • Change to warnings or special precautions for use
    • Change to side-effects
    • Change to drug interactions
    • Change to information about driving or using machinery
    • Change to date of revision
    • Change to dosage and administration
    • Addition of information on reporting a side effect.
    • Addition of black triangle

    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

    Active clinically significant bleedingClinically significant active 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 the circumstances of switching therapy to or from rivaroxaban (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).

    Section 4.4 Special warnings and precautions for use

    ……………………………

    Rivaroxaban, like other antithrombotic agents, is to be used with caution in patients with an increased

    bleeding risk such as:

    · congenital or acquired bleeding disorders

    · uncontrolled severe arterial hypertension

    · active ulcerative gastrointestinal disease

    · recent gastrointestinal ulcerations

    · vascular retinopathy

    · recent intracranial or intracerebral haemorrhage

    · intraspinal or intracerebral vascular abnormalities

    · recent brain, spinal or ophthalmological surgery

    · bronchiectasis or history of pulmonary bleeding

    ……………………………

    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 administeredAn epidural catheter is not to be removed earlier than 18 hours after

    the last administration of rivaroxaban. The next rivaroxaban dose is to be administered not earlier than

    6 hours after the removal of the catheter.

    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 other than

    elective hip or knee replacement surgery

    If an invasive procedure or surgical intervention is required, Xarelto 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 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 latest renewal: 22 May 2013

    Section 10. DATE OF REVISION OF THE TEXT

    June 2013

    Updated on 30 July 2013 PIL

    Reasons for updating

    • Change to warnings or special precautions for use
    • Change of contraindications
    • Change to date of revision

    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 October 2012 to January 2013

    Updated on 18 January 2013 SmPC

    Reasons for updating

    • Introduction of new pack/pack size

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

    Free text change information supplied by the pharmaceutical company

    Notification to register a 10x10x1 tablet multipack

    Updated on 16 January 2013 PIL

    Reasons for updating

    • Introduction of new pack/pack size

    Updated on 25 June 2012 SmPC

    Reasons for updating

    • Change to section 2 - Qualitative and quantitative composition
    • Change to section 3 - Pharmaceutical form
    • 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 4.7 - Effects on ability to drive and use machines
    • 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
    • Change to section 5.3 - Preclinical safety data
    • Change to section 6.6 - Special precautions for disposal and other handling
    • 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

    • Section 2. Qualitative and Quantitative Composition
      • Updated in line with QRD version 8.
    • Section 3. Pharmaceutical Form
      • Updated to provide more detail regarding the appearance of the tablet.
    • Section 4.2 Posology and method of administration
      • Updated throughout in line with QRD version 8.
      • Posology updated with information on; 
        • Converting from Vitamin K Antagonists (KKA) to Xarelto
        • Converting from Xarelto to Vitamin K antagonists (VKA)
        • Converting from parenteral anticoagulants to Xarelto
        • Converting from Xarelto to parenteral anticoagulants.
      • The section on populations with Renal impairment has been modified slightly.
      • The section on Hepatic impairment has been updated; ‘Xarelto is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk (see sections 4.3 and 5.2). Xarelto may be used with caution in including cirrhotic patients with moderate hepatic impairment (Child Pugh B and C) if it is not associated with coagulopathy (see sections 4.43 and 5.2).’
      • The method of administration has been updated to detail that Xarelto can be taken with or without food.
    • Section 4.3
      • Updated in line with QRD.
      • Further detail added to the contraindication: ‘Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C (see section 5.2).’
    • Section 4.4 Special warnings and precautions for use
      • Subsection ‘Haemorrhagic risk’, has been amended as follows; ‘…These patients are to be carefully monitored for signs and symptoms of bleeding complications and anaemia after initiation of treatment….’
      • Subsection ‘Renal impairment’, has been amended as follows; ‘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. Use is not recommended in patients with creatinine clearance <15 ml/min. 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)…’
      • Subsection ‘Hepatic impairment’ has been deleted.
      • Subsection ‘Interaction with other medicinal products’, has been amended to remove the statement regarding Fluconazole. Further information on this medicinal product has been added to section 4.5.
      • Subsection ‘Other haemorrhagic risk factors’ has been updated with the additional bullet point ‘bronchiectasis or history of pulmonary bleeding’. And also to include the statement, ’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).’
      • Subsection ‘Interaction with CYP3A4 inducers has been deleted.
    • Section 4.5 Interaction with other medicinal products and other forms of interaction
      • The following text has been added to subsection ‘CYP3A4 and P-gp inhibitors’, ‘Fluconazole (400 mg once daily), considered as a moderate CYP3A4 inhibitor, led to a 1.4 fold increase in mean rivaroxaban AUC and a 1.3 fold increase in mean Cmax. This increase is not considered clinically relevant. Given the limited clinical data available with dronedarone, co-administration with rivaroxaban should be avoided.’ 
      • Subsection ‘NSAIDs/platelet aggregation inhibitors’ –reference to 15mg rivaroxaban has been added for clarity.
      • A subsection on the interaction with warfarin has been added.
      • Subsection ‘Other concomitant therapies’ – it has been added that no clinically significant pharmacokinetic or pharmcodynamic interactions were observed when rivaroxaban was co-administered with omeprazole (proton pump inhibitor)
    • Section 4.6 Fertility, pregnancy and breast feeding
      • Updated in line with QRD.
    • Section 4.7 Effects on ability to drive and use machines 
      • Updated in line with QRD.
    • Section 4.8 Undesirable effects
      • Information regarding phase III studies has been added.
      • The tabulation of adverse reactions has been updated based on new information.
      • There has been some changes to the subsection ‘Description of selected adverse reactions’, ‘Due to the pharmacological mode of action, the use of Xarelto may be associated with an increased risk of occult or overt bleeding from any tissue or organ which may result in posthaemorrhagic anaemia. The signs, symptoms, and severity (including possibly fatal outcome) will vary according to the location and degree or extent of the bleeding and/or anaemia (see section 4.9 Management of bleeding). In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary) and anemia 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, as judged to be appropriate. The risk of bleedings may be increased in certain patient groups e.g. those patients with uncontrolled severe arterial hypertension and/or on concomitant treatment with other medicinal products affecting haemostasis (see Haemorrhagic risk in section 4.4). Menstrual bleeding may be intensified and/or prolonged. Haemorrhagic complications may present as weakness, paleness, dizziness, headache or unexplained swelling, dyspnoea, and unexplained shock. In some cases as a consequence of anaemia, symptoms of cardiac ischaemia like chest pain or angina pectoris may occurhave been observed. Furthermore, Known complications secondary to severe bleeding, such as compartment syndrome orand renal failure due to hypoperfusion have been reported for Xarelto might occur. Therefore, the possibility of haemorrhage is to be considered in evaluating the condition in any anticoagulated patient.
    • Section 4.9 Overdose
      • Section 4.9 has been fully updated.
    • Section 5.1 Phamacodynamic properties
      • Subsection ‘Pharmacodynamic effects’ has been amended; …’The activated partial thomboplastin time (aPTT) and HepTest are also prolonged dose-dependently; however, they are not recommended to assess the pharmacodynamic effect of rivaroxaban. Anti-Factor Xa activity is also influenced by rivaroxaban; however, no standard for calibration is available. There is no need for monitoring of coagulation parameters during treatment with rivaroxaban in clinical routine. However, if clinically indicated rivaroxaban levels can be measured by calibrated quantitative anti-Factor Xa tests (see section 5.2).’ - Subsection Paediatric population has been amended to the following; ‘The European Medicines Agency has deferred the obligation to submit the results of studies with Xarelto in one or more subsets of the paediatric population in the treatment of thromboembolic events. The European Medicines Agency has waived the obligation to submit the results of studies with Xarelto in all subsets of the paediatric population in the prevention of thromboembolic events. See section 4.2 for information on paediatric use.’
    • Section 5.2 Pharmacokinetic properties 
      • Subsection 'Absorption' has been updated in respect to the statement on the absolute bioavailabilty of rivaroxaban 10mg dose.
      • Subsection 'Metabolism and Elimination' has become subsection 'Biotransformation and elimination'. Also, at the end of this subsection, the following changes have been made: '...After oral adminstration of a 10 mg dose the elimination becomes absorption rate limited. Elimination of rivaroxaban from plasma occurs with mean terminal half-lives of 75 to 119 hours in young individuals, and with terminal half-lives of 11 to 13 hours in the elderly.'   
      • In subsection 'Hepatic impairment' the following changes have occurred; '...Xarelto is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk. Xarelto may be used with caution in,including cirrhotic patients with moderate hepatic impairment (Child Pugh B and C) if it is not associated with coagulopathy (see section 4.3 and 4.4).  
      • A subsection on Pharmacokinetic data in patients has been added.
      • A subsection on Paediatric population has been added.
    • Section 5.3 Preclinical safety data
      • Updated in line with QRD.
    • Section 6.6 Special precautions for disposal
      • Updated in line with QRD.
    • Section 9. Date of first authorisation/renewal of the authorisation
      • Updated in line with QRD.
    • Section 10. Date of revision of the text 
      •  Update with the latest approval date.

    Updated on 6 June 2012 PIL

    Reasons for updating

    • Change to warnings or special precautions for use
    • Change of contraindications
    • Change to side-effects
    • Change to drug interactions
    • Change to information about driving or using machinery
    • Change to date of revision
    • Change to appearance of the medicine
    • Change to dosage and administration
    • Change of special precautions for disposal

    Updated on 4 January 2012 SmPC

    Reasons for updating

    • Change to section 4.7 - Effects on ability to drive and use machines
    • 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

    4.7     Effects on ability to drive and use machines

    Syncope and dizziness have been reported in the post-operative setting and may affect the ability to drive and use machines, these adverse reactions have been reported to be uncommon (see section 4.8). Patients experiencing these adverse reactions should not drive or use machines.

    has been amended to

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

     

    The following subsection of  5.1 Pharmacodynamic properties has been revised from 

     

     

    Paediatric population

    The European Medicines Agency has deferred the obligation to submit the results of studies with Xarelto in one or more subsets of the paediatric population in venous thromboembolism. The European Medicines Agency has waived the obligation to submit the results of studies with Xarelto in all subsets of the paediatric population in the prevention of venous thromboembolism (in hospitalised medically ill patients and patients undergoing elective hip and knee replacement surgery) and thromboembolism (in subjects with non-valvular atrial fibrillation and patients with a recent acute coronary syndrome). See section 4.2 for information on paediatric use.

    to

    Paediatric population

    The European Medicines Agency has deferred the obligation to submit the results of studies with Xarelto in one or more subsets of the paediatric population in the treatment of thromboembolic events. The European Medicines Agency has waived the obligation to submit the results of studies with Xarelto in all subsets of the paediatric population in the prevention of thromboembolic events. See section 4.2 for information on paediatric use.

     

     

     

     

    Updated on 21 September 2011 SmPC

    Reasons for updating

    • Change to section 10 - Date of revision of the text
    • Change to MA holder contact details

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

    Free text change information supplied by the pharmaceutical company

    • In section 7 (MARKETING AUTHORISATION HOLDER); Scherning has been deleted from the MA holder name, the corrected MA holder is Bayer Pharma AG.
    • In section 10 (DATE OF REVISION OF THE TEXT); the date had been updated to 07/2011.

    Updated on 15 September 2011 PIL

    Reasons for updating

    • Change to further information section
    • Change to date of revision
    • Change to MA holder contact details
    • Change to name of manufacturer

    Updated on 4 March 2011 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 4.6 - Pregnancy and lactation
    • Change to section 4.7 - Effects on ability to drive and use machines
    • Change to section 4.8 - Undesirable effects
    • Change to section 5.1 - Pharmacodynamic properties
    • Change to section 5.2 - Pharmacokinetic 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

    4.2     Posology and method of administration

    Insertion of subheading “Posology

     

    Change of subheading “Patients above 65 years” to “Elderly population

     

    Superceded text

    Newly approved

    Children and adolescents

    Xarelto is not recommended for use in children or adolescents below 18 years of age due to a lack of data on safety and efficacy.

     

    Paediatric population

    The safety and efficacy of Xarelto in children 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.

     

     

    Insertion of subparagraph:

    Method of administration

    For oral use.”

     

    4.4         Special warnings and precautions for use

     

    Under subheading “Interaction with other medicinal products”insertion of the sentence:

    For patients at risk of ulcerative gastrointestinal disease an appropriate prophylactic treatment may be considered”

     

    4.6     Fertility, pregnancy and breast feeding

     

    Superceded text

    Newly approved

    Pregnancy

    There are no adequate data from the use of rivaroxaban in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Due to the potential reproductive toxicity, the intrinsic risk of bleeding and the evidence that rivaroxaban passes the placenta, Xarelto is contraindicated during pregnancy (see section 4.3).

    Women of child-bearing potential should avoid becoming pregnant during treatment with rivaroxaban.

     

    Lactation

    No data on the use of rivaroxaban in breast-feeding women are available. Data from animals indicate that rivaroxaban is secreted into milk. Therefore Xarelto is contraindicated during breast-feeding (see section 4.3). A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from therapy.

     

    Fertility

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

     

    Pregnancy

    There are no adequate data from the use of rivaroxaban in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Due to the potential reproductive toxicity, the intrinsic risk of bleeding and the evidence that rivaroxaban passes the placenta, Xarelto is contraindicated during pregnancy (see section 4.3).

    Women of child-bearing potential should avoid becoming pregnant during treatment with rivaroxaban.

     

    Breast feeding

    No data on the use of rivaroxaban in breast feeding women are available. Data from animals indicate that rivaroxaban is secreted into milk. Therefore Xarelto is contraindicated during breast feeding (see section 4.3). A decision must be made whether to discontinue breast feeding or to discontinue/abstain from therapy.

     

     

     

    4.7         Effects on ability to drive and use machines

     

    Superceded text

    Newly approved

    No studies of the effects on the ability to drive and use machines have been performed.

    Syncope and dizziness have been reported in the post-operative setting and may affect the ability to drive and use machines, these adverse reactions have been reported to be uncommon (see section 4.8). Patients experiencing these adverse reactions should not drive or use machines.

     

     

     

    Syncope and dizziness have been reported in the post-operative setting and may affect the ability to drive and use machines, these adverse reactions have been reported to be uncommon (see section 4.8). Patients experiencing these adverse reactions should not drive or use machines.

     

     

     

    4.8     Undesirable effects

     

     

    Superceded text

    Newly approved

    The safety of rivaroxaban 10 mg has been evaluated in three phase III studies including 4,571 patients exposed to rivaroxaban undergoing major orthopaedic surgery of the lower limbs (total hip replacement or total knee replacement) treated for up to 39 days.

    In total, about 14 % of the treated patients experienced adverse reactions. Bleedings or anaemia occurred in approximately 3.3 % and 1 % of patients, respectively. Other common adverse reactions were nausea, increased GGT and an increase in transaminases. The adverse reactions should be interpreted within the surgical setting.

    Due to the pharmacological mode of action, the use of Xarelto may be associated with an increased risk of occult or overt bleeding from any tissue or organ which may result in posthaemorrhagic anaemia. The signs, symptoms, and severity (including possibly fatal outcome) will vary according to the location and degree or extent of the bleeding. The risk of bleedings may be increased in certain patient groups e.g. those patients with uncontrolled severe arterial hypertension and/or on concomitant treatment with other medicinal products affecting haemostasis (see Haemorrhagic risk in section 4.4).

    Haemorrhagic complications may present as weakness, asthenia, paleness, dizziness, headache or unexplained swelling. Therefore, the possibility of haemorrhage is to be considered in evaluating the condition in any anticoagulated patient.

     

    Adverse reactions in the three phase III studies are listed in table 1 below by system organ class (in MedDRA) and by frequency.

     

    Frequencies are defined as:

    Common:          ≥ 1/100 to < 1/10

    Uncommon:      ≥ 1/1,000 to < 1/100

    Rare:    ≥ 1/10,000 to < 1/1,000

    Very rare:         < 1/10,000

    Not known:       cannot be estimated from the available data.

     

    Summary of the safety profile

    The safety of rivaroxaban 10 mg has been evaluated in four phase III studies (RECORD 1-4) including 6,097 patients exposed to rivaroxaban undergoing major orthopaedic surgery of the lower limbs (total hip replacement or total knee replacement) treated for up to 39 days.

    In total, about 14 % of the treated patients experienced adverse reactions. Bleedings or anaemia occurred in approximately 3.3 % and 1 % of patients, respectively. Other common adverse reactions were nausea, increased GGT and an increase in transaminases. The adverse reactions should be interpreted within the surgical setting.

     

    Tabulated summary of adverse reactions

    The frequencies of adverse reactions reported with Xarelto in the phase III studies in patients undergoing elective hip or knee replacement surgery are summarized in table 1 below by system organ class (in MedDRA) and by frequency.

     

    Frequencies are defined as:

    Common:          ≥ 1/100 to < 1/10

    Uncommon:      ≥ 1/1,000 to < 1/100

    Rare:    ≥ 1/10,000 to < 1/1,000

    Not known:       cannot be estimated from the available data.

     

    Newly approved Table

    Common

    Uncommon

    Rare

    Not known*

    Blood and lymphatic system disorders

     

    Anaemia (incl. respective laboratory parameter), thrombocythaemia (incl. platelet count increased)

     

     

    Immune system disorders

     

     

    Dermatitis allergic

    Hypersensitivity

    Nervous system disorders

     

    Dizziness, headache

    Syncope (incl. loss of consciousness)

     

    Cardiac disorders

     

    Tachycardia

     

     

    Vascular disorders

    Post-procedural haemorrhage (incl. post-operative anaemia, and wound haemorrhage)

    Haematoma (incl. rare cases of muscle haemorrhage), gastrointestinal tract haemorrhage (incl. gingival bleeding, rectal haemorrhage, haememesis), urogenital tract haemorrhage, hypotension (incl. blood pressure decreased, procedural hypotension), nose bleed

     

    Bleeding into a critical organ (e.g. brain), adrenal haemorrhage, conjunctival haemorrhage, haemoptysis, pseudoaneurysm formation following percutaneous intervention**

    Gastrointestinal disorders

    Nausea

    Constipation, diarrhoea, abdominal and gastrointestinal pain (incl. upper abdominal pain, stomach discomfort), dyspepsia (incl. epigastric discomfort), dry mouth, vomiting

     

     

    Hepatobiliary disorders

     

     

    Hepatic function abnormal

    Jaundice

    Skin and subcutaneous tissue disorders

     

    Pruritus (incl. rare cases of generalised pruritus), rash, contusion

    Urticaria (incl. rare cases of generalised urticaria)

     

    Musculoskeletal and connective tissue disorders

     

    Pain in extremity

     

    Compartment syndrome secondary to a bleeding

    Renal and urinary disorders

     

    Renal impairment (incl. blood creatinine increased, blood urea increased)

     

    Renal failure/acute renal failure secondary to a bleeding sufficient to cause hypoperfusion

    General disorders and administration site conditions

    Fever,

    peripheral oedema

    Localised oedema, decreased general strength and energy (incl. fatigue, asthenia)

    Feeling unwell (incl. malaise)

     

    Investigations

    Increased GGT, increase in transaminases (incl. ALT increase, AST increase)

    Increased lipase, increased amylase, blood bilirubin increased, increased LDH, increased alkaline phosphatase

    Bilirubin conjugated increased (with or without concomitant increase of ALT)

     

    Injury, poisoning and procedural complications

     

    Wound secretion

     

     

     

    *) Adverse events have been reported in other clinical studies than the three phase III studies in patients undergoing major orthopaedic surgery of the lower limbs

     

    *) Adverse events have been reported in other clinical studies than the four phase III studies in patients undergoing major orthopaedic surgery of the lower limbs or during postmarketing surveillance, for which a frequency could not be estimated

    **) These events ocured in clinical studies in other indications than prevention of VTE in patients undergoing major orthopaedic surgery

     

     

    Description of selected adverse reactions

    Due to the pharmacological mode of action, the use of Xarelto may be associated with an increased risk of occult or overt bleeding from any tissue or organ which may result in posthaemorrhagic anaemia. The signs, symptoms, and severity (including possibly fatal outcome) will vary according to the location and degree or extent of the bleeding and/or anaemia. The risk of bleedings may be increased in certain patient groups e.g. those patients with uncontrolled severe arterial hypertension and/or on concomitant treatment with other medicinal products affecting haemostasis (see Haemorrhagic risk in section 4.4).

    Haemorrhagic complications may present as weakness, paleness, dizziness, headache or unexplained swelling, dyspnoea, and unexplained shock. In some cases as a consequence of anaemia symptoms of cardiac ischaemia like chest pain or angina pectoris may occur. Furthermore, known complications secondary to bleeding, such as compartment syndrome or renal failure might occur. Therefore, the possibility of haemorrhage is to be considered in evaluating the condition in any anticoagulated patient.

     

     

     

    5.       PHARMACOLOGICAL PROPERTIES

     

    5.1     Pharmacodynamic properties

    Addition of the text:

    Paediatric population

    The European Medicines Agency has deferred the obligation to submit the results of studies with Xarelto in one or more subsets of the paediatric population in venous thromboembolism. The European Medicines Agency has waived the obligation to submit the results of studies with Xarelto in all subsets of the paediatric population in the prevention of venous thromboembolism (in hospitalised medically ill patients and patients undergoing elective hip and knee replacement surgery) and thromboembolism (in subjects with non-valvular atrial fibrillation and patients with a recent acute coronary syndrome). See section 4.2 for information on paediatric use.

     

     

    5.2     Pharmacokinetic properties

    Under subheading “Special populations”

     

    Superceded text

    Newly approved

    Gender/Elderly (above 65 years)

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

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

     

    Special populations

    Gender

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

     

    Elderly population

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

     

     

     

    5.3     Preclinical safety data

    Insertion of:

    In rats, no effects on male and female fertility were seen.

     

    10.     DATE OF REVISION OF THE TEXT

     Changed to “01/2011

    Updated on 2 February 2011 PIL

    Reasons for updating

    • Change to side-effects
    • Change to drug interactions
    • Change to information about driving or using machinery
    • Change to MA holder contact details
    • Correction of spelling/typing errors

    Updated on 6 July 2010 SmPC

    Reasons for updating

    • Change to section 6.5 - Nature and contents of container
    • Change to section 10 - Date of revision of the text
    • Introduction of new pack/pack size

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

    Free text change information supplied by the pharmaceutical company

     

    6.5     Nature and contents of container

     

    Change from “PP/Aluminium foil blisters or PVC/PVDC/Aluminium foil blisters in cartons of 5, 10, 30 and 100 tablets.

    Not all pack sizes may be marketed.”

    To

    PP/Aluminium foil blisters or PVC/PVDC/Aluminium foil blisters in cartons of 5, 10 or 30 tablets or perforated unit dose blisters in cartons of 10 x 1 or 100 x 1 tablets.

    Not all pack sizes may be marketed.”

     

     

    8.       MARKETING AUTHORISATION NUMBER(S)

     

    Change from “EU/1/08/472/001-8” to “EU/1/08/472/001-010”

     

     

    10.     DATE OF REVISION OF THE TEXT

     

    Change to “April 2010”

    Updated on 2 July 2010 PIL

    Reasons for updating

    • Change to date of revision
    • Change to MA holder contact details
    • Introduction of new pack/pack size

    Updated on 4 August 2009 PIL

    Reasons for updating

    • Change to name of manufacturer
    • Change to date of revision

    Updated on 13 May 2009 SmPC

    Reasons for updating

    • Change to section 7 - Marketing authorisation holder
    • 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 7. Marketing Authorisation Holder

    changed to the following:
                        
                        Bayer Schering Pharma AG
                        13342 Berlin
                        Germany

    Section 10. Date of Revision of Text

            May 2009

    Updated on 9 October 2008 PIL

    Reasons for updating

    • New PIL for new product

    Updated on 9 October 2008 SmPC

    Reasons for updating

    • New SPC for new product

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