Xarelto 1 mg/mL granules for oral suspension

• Addition Safety Symbols added. Section 5. Disposal: “Any unused medicine or waste material, syringes, and adapter should be disposed of in accordance with local requirements.”
• Section 6. Damage/Malfunction: “Any serious incidents that occur in connection with the product should be reported to the manufacturer and the relevant authority in your country.”

• Addition Safety Symbols added. Section 5. Disposal: “Any unused medicine or waste material, syringes, and adapter should be disposed of in accordance with local requirements.”
• Section 6. Damage/Malfunction: “Any serious incidents that occur in connection with the product should be reported to the manufacturer and the relevant authority in your country.”

• 6. Contents of the pack and other information - What Xarelto contains: The active substance is rivaroxaban. One glass bottle contains either, 51.7 mg of rivaroxaban, for 50 mL of water to be added, or 103.4 mg of rivaroxaban, for 100 mL water to be added.

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

Paediatric population

In vitro data does not indicate relevant differences in rivaroxaban plasma protein binding in children across different age groups and compared to adults.

6.5 Nature and contents of container - For children weighing less than 4 kg: 2.625 g granules, corresponding to 51.7 mg rivaroxaban, in 1 brown glass bottle, for reconstitution in 50 mL water, closed with a child resistant screw cap; Or, For children weighing 4 kg and more: 5.25 g granules, corresponding to 103.4 mg rivaroxaban, in 1 brown glass bottle, for reconstitution in 100 mL water, closed with a child resistant screw cap.

6.6 Special precautions for disposal and other handling - The amount of water to be used is: 50 mL for the bottle containing 2.625 g granules (51.7 mg of rivaroxaban), resulting in 51.7 mL total volume after reconstitution; 100 mL for the bottle containing 5.25 g granules (103.4 mg of rivaroxaban), resulting in 103.4 mL total volume after reconstitution.

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). 

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.*

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.*

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.

Removal of Black Triangle for Additional Monitoring

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

Section 5.1, Table 5, new paragraph [In a post-authorisation, non-interventional study, in more than 162,000 patients] … [for urogenital bleeding and 0.40 (95% CI 0.25 - 0.65) for other bleeding] & Update to Xantus patient figures.

Section 5.1, Table 10, 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
• Inclusion of title “Treatment of VTE and prevention of VTE recurrence”
• 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).”
• Inclusion of Paragraph on “Thromboprophylaxis in Paediatric Patients with Congenital Heart Disease after the Fontan Procedure”.
• 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

Including CF (Content Factory) code

PP-XAR-IE-0771-1

Including Local File Version Number (Content Factory)

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

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”).

Artwork

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Version 1 - New Marketing Authorisation

Version 1 - New Marketing Authorisation