Xarelto 2.5 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.

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

1. What Xarelto is and what it is used for

• • In some cases, if you get Xarelto after a procedure to open a narrowed or closed artery of your leg to restore blood flow, your doctor may also prescribe clopidogrel for you to take in addition to acetylsalicylic acid for a short while.3.

3. How to take Xarelto

If you get Xarelto after a procedure to open a narrowed or closed artery of your leg to restore blood flow, your doctor may also prescribe clopidogrel for you to take in addition to acetylsalicylic acid for a short while.

1. 4.2 Posology and method of administration

• CAD/PAD

Patients taking Xarelto 2.5 mg twice daily should also take a daily dose of 75 - 100 mg ASA.

 In patients after a successful revascularisation procedure of the lower limb (surgical or endovascular including hybrid procedures) due to symptomatic PAD, treatment should not be started until haemostasis is achieved (see section 5.1).

 Duration of treatment should be determined for each individual patient based on regular evaluations and should consider the risk for thrombotic events versus the bleeding risks.

• ACS, CAD/PAD

Co-administration with antiplatelet therapy

In patients with an acute thrombotic event or vascular procedure and a need for dual antiplatelet therapy, the continuation of Xarelto 2.5 mg twice daily should be evaluated depending on the type of event or procedure and antiplatelet regimen.

 Safety and efficacy of Xarelto 2.5 mg twice daily in combination with dual antiplatelet therapy  have been studied in patients .

• with recent ACS in combination with ASA plus clopidogrel/ticlopidine (see section 4.1), and
• after recent revascularisation procedure of the lower limb due to symptomatic PAD in combination with ASA and, if applicable, short-term clopidogrel use (see sections 4.4 and 5.1)

4.4     Special warnings and precautions for use

In ACS patients, efficacy and safety of Xarelto 2.5 mg twice daily have been investigated in combination with the antiplatelet agents ASA alone or ASA plus clopidogrel/ticlopidine.

In patients at high risk of ischaemic events with CAD/PAD, efficacy and safety of Xarelto 2.5 mg twice daily have been investigated in combination with ASA.

In patients after recent revascularisation procedure of the lower limb due to symptomatic PAD, efficacy and safety of Xarelto 2.5 mg twice daily have been investigated in combination with the antiplatelet agent ASA alone or ASA plus short-term clopidogrel. If required, dual antiplatelet therapy with clopidogrel should be short-term; long-term dual antiplatelet therapy should be avoided (see section 5.1).

 Treatment in combination with other antiplatelet agents, e.g. prasugrel or ticagrelor, has not been studied and is not recommended.

Patients with CAD/PAD

CAD/PAD patients with previous haemorrhagic or lacunar stroke, or an ischaemic, non-lacunar stroke with in the previous month were not studied (see section 4.3).

Patients after recent revascularisation procedures of the lower limb due to symptomatic PAD with a previous stroke or TIA were not studied. Treatment with Xarelto 2.5 mg should be avoided in these patients receiving dual antiplatelet therapy.

Spinal/epidural anaesthesia or puncture

There is no clinical experience with the use of Xarelto 2.5 mg  and antiplatelet agents in these situations. Platelet aggregation inhibitors should be discontinued as suggested by the manufacturer’s prescribing information.

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:

Footnote: 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.

5.1     Pharmacodynamic properties

Figure 2:

Patients after recent revascularisation procedure of the lower limb due to symptomatic PAD

In the pivotal phase III double-blind VOYAGER PAD trial, 6,564 patients after recent successful revascularisation procedure of the lower limb (surgical or endovascular including hybrid procedures) due to symptomatic PAD were randomly assigned to one of two antithrombotic treatment groups: rivaroxaban 2.5 mg twice daily in combination with ASA 100 mg once daily, or to ASA 100 mg once daily, in a 1:1 fashion. Patients were allowed to additionally receive standard dose of clopidogrel once daily for up to 6 months. The objective of the study was to demonstrate the efficacy and safety of rivaroxaban plus ASA for the prevention of myocardial infarction, ischaemic stroke, CV death, acute limb ischaemia, or major amputation of a vascular etiology in patients after recent successful lower limb revascularisation procedures due to symptomatic PAD. Patients aged ≥ 50 years with documented moderate to severe symptomatic lower extremity atherosclerotic PAD evidenced by all of the following: clinically (i.e. functional limitations), anatomically (i.e. imaging evidence of PAD distal to external iliac artery) and haemodynamically (ankle-brachial-index [ABI]  ≤ 0.80 or toe-brachial-index [TBI]  ≤ 0.60 for patients without a prior history of limb revascularisation or ABI ≤ 0.85 or TBI ≤ 0.65 for patients with a prior history of limb revascularisation) were included. Patients in need of dual antiplatelet therapy for > 6 months, or any additional antiplatelet therapy other than ASA and clopidogrel, or oral anticoagulant therapy, as well as patients with a history of intracranial haemorrhage, stroke, or TIA, or patients with eGFR < 15 mL/min were excluded.

The mean duration of follow-up was 24 months and the maximum follow-up was 4.1 years. The mean age of the enrolled patients was 67 years and 17% of the patient population were > 75 years. The median time from index revascularisation procedure to start of study treatment was 5 days in the overall population (6 days after surgical and 4 days after endovascular revascularisation including hybrid procedures). Overall, 53.0% of patients received short term background clopidogrel therapy with a median duration of 31 days. According to study protocol study treatment could be commenced as soon as possible but no later than 10 days after a successful qualifying revascularisation procedure and once hemostasis had been assured.

Rivaroxaban 2.5 mg twice daily in combination with ASA 100 mg once daily was superior in the reduction of the primary composite outcome of myocardial infarction, ischaemic stroke, CV death, acute limb ischaemia and major amputation of vascular etiology compared to ASA alone (see Table 9). The primary safety outcome of TIMI major bleeding events was increased in patients treated with rivaroxaban and ASA, with no increase in fatal or intracranial bleeding (see Table 10).

The secondary efficacy outcomes were tested in a prespecified, hierarchical order (see Table 9).

 Table 9:

Table 9: Efficacy results from phase III VOYAGER PAD

^a) intention to treat analysis set, primary analyses; ICAC adjudicated

^b) composite of MI, ischaemic stroke, CV death (CV death and unknown cause of death), ALI, and major amputation of vascular etiology

^c) only the first occurrence of the outcome event under analysis within the data scope from a subject is considered

^d) HR (95% CI) is based on the Cox proportional hazards model stratified by type of procedure and clopidogrel use with treatment as the only covariate.

^e) One sided p-value is based on the log-rank test stratified by type of procedure and clopidogrel use with treatment as factor.

^f) acute limb ischaemia is defined as sudden significant worsening of limb perfusion, either with new pulse deficit or requiring therapeutic intervention (i.e. thrombolysis or thrombectomy, or urgent revascularisation), and leading to hospitalisation

* The reduction in the efficacy outcome was statistically superior.

ALI: acute limb ischaemia; bid: twice daily; od: once daily; CI: confidence interval; MI: myocardial infarction; CV: cardiovascular; ICAC: Independent Clinical Adjudication Committee

Table 10:

Table 10: Safety results from phase III VOYAGER PAD

^a) Safety analysis set (all randomised subjects with at least one dose of study drug), ICAC: Independent Clinical Adjudication Committee

^b) n = number of subjects with events, N = number of subjects at risk, % = 100 * n/N, n/100p-yrs = ratio of number of subjects with incident events / cumulative at-risk time

^c) HR (95% CI) is based on the Cox proportional hazards model stratified by type of procedure and clopidogrel use with treatment as the only covariate

^d) Two sided p-value is based on the log rank-test stratified by type of procedure and clopidogrel use with treatment as a factor

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”).

Typo

2. What you need to know before you take Xarelto

Children and adolescents

Xarelto 2.5 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 tp 4 hours.

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

Ireland

Bayer Limited

Tel: +353 1 216 3300

This leaflet was last revised in January 2021

4.2 Posology and method of administration

Paediatric population

The safety and efficacy of Xarelto 2.5 mg tablets in children aged 0 to 18 years have not been established. No data are available. Therefore, Xarelto 2.5 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.

Table 1: Number of patients studied, total daily dose and maximum treatment duration in adult and paediatric phase III studies (section added to table)

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

5.1     Pharmacodynamic properties

Term "Xarelto" replaced by "Rivaroxaban" throughout Section 5.1.

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

Term "Xarelto" replaced by "Rivaroxaban" throughout Section 5.2.

Paediatric population

Safety and efficacy have not been established in the indications ACS and CAD/PAD for children and adolescents up to 18 years.

6.3     Shelf life

3 years

Crushed tablets

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

1. 6.5 Nature and contents of container

Cartons containing 14, 20, 28, 30, 56, 60, 98, 168 or 196 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 14 film-coated tablets in PVC/PVDC/Alu foil blisters .
HDPE bottles with a PP screw cap containing 100 film-coated tablets.

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 2.5 mg tablets.

SmPC for Xarelto 2.5mg only has been revised in respect of COMPASS CDB2 (pantoprazole part of the COMPASS study).  

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

Update as per APS PRAC reccommendation

New SmPC for medicines. 

Addition of therapeutic indication: Xarelto, co-administered with acetylsalicylic acid (ASA) alone or with ASA plus clopidogrel or ticlopidine, is indicated for the prevention of atherothrombotic events in adult patients after an acute coronary syndrome (ACS) with elevated cardiac biomarkers (see sections 4.3, 4.4 and 5.1).