Xarelto 10 mg film-coated tablets

Section 4 bullet-point list with heading `Not known´ (frequency cannot be estimated from the available data)

- kidney failure after a severe bleeding

- Bleeding in the kidney sometimes with presence of blood in urine leading to inability of the kidneys to work properly (anticoagulant-related nephropathy). 

SmPC

Section 4.8

Table in section 4.8 undesirable effects:

Anticoagulant-related nephropathy inserted under `Renal and urinary disorders´ with a frequency as `not known´.

Description of selected adverse reactions” under the table of adverse events

(…)

“Known complications secondary to severe bleeding such as compartment syndrome and renal failure due to hypoperfusion, or anticoagulant-related nephropathy have been reported for Xarelto. Therefore, the possibility of haemorrhage is to be considered in evaluating the condition in any anticoagulated patient.”

For the attention of Healthcare Professionals (HCPs):

Please be aware that the black inverted triangle “▼”has been removed and that this product no longer requires additional monitoring.

*All other safety information remains the same.*

Removal of Black Triangle for Additional Monitoring

Section 4 Addition of “Eosinophilic Pneumonia” as very rare respiratory side effect; NL phone number changed.

Removal of Black Triangle for Additional Monitoring

Section 4.8 Addition of “Eosinophilic Pneumonia” as very rare respiratory side effect;

Section 5.1, Table 9, new paragraph [In a post-authorisation, non-interventional study, in more than 40,000 patients] … [for urogenital bleeding and 0.41 (95% CI 0.31 - 0.54) for other bleeding].

The following sections of the SmPC were updated:  

• Section 4.8: Summary of safety profile – increase in number of paediatric patients and increase in number of phase III studies
• Table 5: increase in number of phase II studies
• Section 4.9: Management of Bleeding  – “If bleeding cannot be controlled by the above measures, administration of a specific procoagulant reversal agent should be considered, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (r FVIIa).”
• Section 5.1 Clinical efficacy and safety: “Index VTE was classified as either central venous catheter related VTE (CVC-VTE; 90/335 patients in the rivaroxaban group, 37/165 patients in the comparator group), cerebral vein and sinus thrombosis (CVST; 74/335 patients in the rivaroxaban group, 43/165 patients in the comparator group), and all others including DVT and PE (non CVC VTE; 171/335 patients in the rivaroxaban group, 8485/165 patients in the comparator group).”
• Section 5.2 Table 5: “Time Intervals (7-8h post): N 35.

The main changes are as follows:

1. Additional information regarding patients with cancer - all Xarelto strengths
2. Xarelto 2.5mg film-coated tablet - addition of information in respect of Coronary Artery Disease (CAD)/ Peripheral Artery Disease (PAD) patients who have had a successful revascularisation procedure on a lower limb and patients with Acute Coronary Syndrome (ACS).

Introduction of Northern Ireland reporting details

Introduction of Northern Ireland reporting details

Introduction of Northern Ireland reporting details

4.8     Undesirable effects

Summary of the safety profile

The safety of rivaroxaban has been evaluated in thirteen pivotal phase III studies (see Table 1).

Overall, 69,608 adult  patients in nineteen phase III studies and 412 paediatric patients in two phase II and one phase III studies were exposed to rivaroxaban.

Table 1:

Table 2:

Table 3:

A pre-specified selective approach to adverse event collection was applied in selected phase III studies. The incidence of adverse reactions did not increase and no new adverse drug reaction was identified after analysis of these studies

or tumours located in the stomach or bowels or genital tract or urinary tract

Patients with cancer

Patients with malignant disease may simultaneously be at higher risk of bleeding and thrombosis. The individual benefit of antithrombotic treatment should be weighed against risk for bleeding in patients with active cancer dependent on tumour location, antineoplastic therapy and stage of disease. Tumours located in the gastrointestinal or genitourinary tract have been associated with an increased risk of bleeding during rivaroxaban therapy.

In patients with malignant neoplasms at high risk of bleeding, the use of rivaroxaban is contraindicated (see section 4.3).

4.9     Overdose

 In adults, rare cases of overdose up to 600 1,960 mg have been reported. In case of overdose, the patient should be observed carefully for without bleeding complications or other adverse reactions (see section “Management of bleeding”).

2.         What you need to know before you take Xarelto

Children and adolescents

Xarelto 10 mg tablets are not recommended for people under 18 years of age. There is not enough information on their use in children and adolescents.

Driving and using machines

Xarelto may cause dizziness (common side effect) or fainting (uncommon side effect) (see section 4 ”Possible side effects”). You should not drive, ride a bicycle or use any tools or machines if you are affected by these symptoms.

4.         Possible side effects

Like all medicines, Xarelto can cause side effects, although not everybody gets them.

Like other similar medicines to reduce the formation of blood clots, Xarelto may cause bleeding which may potentially be life threatening. Excessive bleeding may lead to a sudden drop in blood pressure (shock). In some cases the bleeding may not be obvious.

Tell your doctor immediately if you experience any of the following side effects:

• Signs of bleeding

-           bleeding into the brain or inside the skull (symptoms can include headache, one-sided weakness, vomiting, seizures, decreased level of consciousness, and neck stiffness.

A serious medical emergency. Seek medical attention immediately!)

-           long or excessive bleeding

-           exceptional weakness, tiredness, paleness, dizziness, headache, unexplained swelling, breathlessness, chest pain or angina pectoris.

Your doctor may decide to keep you under closer observation or change the treatment.

• Signs of severe skin reactions

• spreading intense skin rash, blisters or mucosal lesions, e.g. in the mouth or eyes (Stevens-Johnson syndrome/toxic epidermal necrolysis).
• a drug reaction that causes rash, fever, inflammation of internal organs, blood abnormalities and systemic illness (DRESS syndrome). The frequency of these side effects is very rare (up to 1 in 10,000 people).

• Signs of severe allergic reactions

-        swelling of the face, lips, mouth, tongue or throat; difficulty swallowing; hives and breathing difficulties; sudden drop in blood pressure.

The frequencies of severe allergic reactions are very rare (anaphylactic reactions, including anaphylactic shock; may affect up to 1 in 10,000 people) and uncommon (angioedema and allergic oedema; may affect up to 1 in 100 people).

Uncommon (may affect up to 1 in 100 people)

- bleeding into the brain or inside the skull (see above, signs of bleeding)

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly (see details below). By reporting side effects, you can help provide more information on the safety of this medicine

Ireland

HPRA Pharmacovigilance

Website: www.hpra.ie

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

5.         How to store Xarelto

Crushed tablets

Crushed tablets are stable in water or apple puree for up to 4 hours.

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder.

This leaflet was last revised in January 2021

4.2     Posology and method of administration

Paediatric population

The safety and efficacy of Xarelto 10 mg tablets in children aged 0 to 18 years have not been established. No data are available. Therefore, Xarelto 10 mg tablets are not recommended for use in children below 18 years of age.

Method of administration

Xarelto is for oral use.

The tablets can be taken with or without food (see sections 4.5 and 5.2).

Crushing of tablets

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 tablet may also be given through gastric tubes (see sections 5.2 and 6.6).

4.4     Special warnings and precautions for use

Information about excipients

Xarelto contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say essentially “sodium-free”.

4.8     Undesirable effects

Summary of the safety profile

The safety of rivaroxaban has been evaluated in thirteen phase III studies in adults including 53,103 patients exposed to rivaroxaban and in two phase II and one phase III paediatric studies including 412 patients . See phase III studies as listed in table 1. (Added to table)

Table 2: Bleeding* and anaemia events rates in patients exposed to rivaroxaban across the completed adult and paediatric phase III studies (Added to table)

Tabulated list of adverse reactions

The frequencies of adverse reactions reported with Xarelto in adult and paediatric patients are summarised in Table 3 below by system organ class (in MedDRA) and by frequency.

Table 3: All adverse reactions reported in adult patients in phase III clinical studies or through post-marketing use* and in two phase II and one phase III studies in paediatric patients (Table Title Change)

5.1     Pharmacodynamic properties

"Xarelto" replaced with "Rivaroxaban" throught section.

In the Einstein Choice study (Table 9) rivaroxaban 20 mg and 10 mg were both superior to 100 mg acetylsalicylic acid for the primary efficacy outcome. The principal safety outcome (major bleeding events) was similar for patients treated with rivaroxaban 20 mg and 10 mg once daily compared to 100 mg acetylsalicylic acid.

Paediatric population

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).

5.2     Pharmacokinetic properties

"Xarelto" replaced with "Rivaroxaban" throught section.

Paediatric population

Safety and efficacy have not been established in the indication primary prevention of VTE for children and adolescents up to 18 years.

6.3     Shelf life 

Crushed tablets

Crushed rivaroxaban tablets are stable in water and in apple puree for up to 4 hours.

6.5     Nature and contents of container

Cartons containing 5, 10, 14, 28, 30 or 98 film-coated tablets in PP/Alu foil blisters.

Cartons containing 10 x 1 or 100 x 1 film-coated tablets in PP/Alu foil perforated unit dose blisters.

Multipacks containing 10 packs of 10 x 1 (100 film-coated tablets) in PP/Alu foil perforated unit dose blisters.

Cartons containing 5, 10 or 30 film-coated tablets in PVC/PVDC/Alu foil blisters .

6.6     Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Crushing of tablets

Rivaroxaban tablets may be crushed and suspended in 50 mL of water and administered via a nasogastric tube or gastric feeding tube after confirming gastric placement of the tube. Afterwards, the tube should be flushed with water. Since rivaroxaban absorption is dependent on the site of active substance release, administration of rivaroxaban distal to the stomach should be avoided, as this can result in reduced absorption and thereby, reduced active substance exposure. Enteral feeding is not required immediately after administration of the 10 mg tablets.

10.     DATE OF REVISION OF THE TEXT

January 2021

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).

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

APS PRAC Update

APS PRAC update

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

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

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

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

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).

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 CR_max 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 CR_max 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 CR_maxR. 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

*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

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 CR_maxR 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 C_max 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 C_max) 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 ER_maxR 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

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

• 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.

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.

• 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.

4.2     Posology and method of administration

Insertion of subheading “Posology”

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

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

4.7         Effects on ability to drive and use machines

4.8     Undesirable effects

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”

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”

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”