Xarelto 15mg 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 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).”
• 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:

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”).

1.    What Xarelto is and what it is used forXarelto contains the active substance rivaroxaban. Xarelto is used in adults to:

-    prevent blood clots in brain (stroke) and other blood vessels in your body if you have a form of irregular heart rhythm called non-valvular atrial fibrillation.

-    treat blood clots in the veins of your legs (deep vein thrombosis) and in the blood vessels of your lungs (pulmonary embolism), and to prevent blood clots from re-occurring in the blood vessels of your legs and/or lungs.Xarelto is used in children and adolescents below 18 years and with a body weight of 30 kg or more to:-    treat blood clots and prevent re occurrence of blood clots in the veins or in the blood vessels of the lungs, following initial treatment of at least 5 days with injectable medicines used to treat blood clots.

Warnings and precautions

Talk to your doctor or pharmacist before taking Xarelto.

Take special care with Xarelto

-        if you have an increased risk of bleeding, as could be the case in situations such as:

▪        severe kidney disease for adults, and moderate or severe kidney disease for children and adolescents, since your kidney function may affect the amount of medicine that works in your body

Children and adolescents

Xarelto tablets are not recommended for children with a body weight below 30 kg.

There is not enough information on the use of Xarelto in children and adolescents in the adult indications.

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.

3.         How to take Xarelto

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

You must take Xarelto together with a meal.

Swallow the tablet(s) preferably with water.

If you have difficulty swallowing the tablet whole, talk to your doctor about other ways to take Xarelto. The tablet may be crushed and mixed with water or apple puree immediately before you take it. This mixture should be immediately followed by food.

If necessary, your doctor may also give you the crushed Xarelto tablet through a stomach tube.

How much to take

• Adults

• To prevent blood clots in brain (stroke) and other blood vessels in your body

The recommended dose is one tablet Xarelto 20 mg once a day.

If you have kidney problems, the dose may be reduced to one tablet Xarelto 15 mg once a day.

If you need a procedure to treat blocked blood vessels in your heart (called a percutaneous coronary intervention - PCI with an insertion of a stent), there is limited evidence to reduce the dose to one tablet Xarelto 15 mg once a day (or to one tablet Xarelto 10 mg once a day in case your kidneys are not working properly) in addition to an antiplatelet medicine such as clopidogrel.

• To treat blood clots in the veins of your legs and blood clots in the blood vessels of your lungs, and for preventing blood clots from re-occurring

The recommended dose is one tablet Xarelto 15 mg twice a day for the first 3 weeks. For treatment after 3 weeks, the recommended dose is one tablet Xarelto 20 mg once a day.

After at least 6 months blood clot treatment your doctor may decide to continue treatment with either one 10 mg tablet once a day or one 20 mg tablet once a day.

If you have kidney problems and take one tablet Xarelto 20 mg once a day, your doctor may decide to reduce the dose for the treatment after 3 weeks to one tablet Xarelto 15 mg once a day if the risk for bleeding is greater than the risk for having another blood clot.

• Children and adolescents

The dose of Xarelto depends on the body weight, and will be calculated by the doctor.

• • The recommended dose for children and adolescents with a body weight between 30 kg and less than 50 kg is one Xarelto 15 mg tablet once a day.
  • The recommended dose for children and adolescents with a body weight of 50 kg or more is one Xarelto 20 mg tablet once a day.

Take each Xarelto dose with a drink (e.g. water or juice) during a meal. Take the tablets every day at approximately the same time. Consider setting an alarm to remind you.

For parents or caregivers: please observe the child to ensure the full dose is taken.

As the Xarelto dose is based on body weight it is important to keep scheduled doctor’s visits because the dose may need to be adjusted as the weight changes.

Never adjust the dose of Xarelto by yourself. The doctor will adjust the dose if necessary.

Do not split the tablet in an attempt to provide a fraction of a tablet dose. If a lower dose is required please use the alternative presentation of Xarelto granules for oral suspension.

For children and adolescents who are unable to swallow tablets whole, please use Xarelto granules for oral suspension.

If the oral suspension is not available, you may crush the Xarelto tablet and mix with water or apple puree immediately before taking. Take some food after taking this mixture. If necessary, your doctor may also give the crushed Xarelto tablet through a stomach tube.

If you spit up the dose or vomit

• less than 30 minutes after you have taken Xarelto, take a new dose.
• more than 30 minutes after you have taken Xarelto, do not take a new dose. In this case, take the next Xarelto dose at the usual time.

Contact the doctor if you repeatedly spit up the dose or vomit after taking Xarelto.

If you forget to take Xarelto

• Adults, children and adolescents:

If you are taking one 20 mg tablet or one 15 mg tablet once a day and have missed a dose, take it as soon as you remember. Do not take more than one tablet in a single day to make up for a forgotten dose. Take the next tablet on the following day and then carry on taking one tablet once a day.

• Adults:

If you are taking one 15 mg tablet twice a day and have missed a dose, take it as soon as you remember. Do not take more than two 15 mg tablets in a single day. If you forget to take a dose you can take two 15 mg tablets at the same time to get a total of two tablets (30 mg) on one day. On the following day you should carry on taking one 15 mg tablet twice a day.

If you take more Xarelto than you should

Contact your doctor immediately if you have taken too many Xarelto tablets. Taking too much Xarelto increases the risk of bleeding.

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 or the child experience any of the following side effects:

• Signs of bleeding

• bleeding into the brain or inside the skull (symptoms can include headache, onesided 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).

Overall list of possible side effects found in adults, children and adolescents

Uncommon (may affect up to 1 in 100 people)

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

Side effects in children and adolescents

In general, the side effects observed in children and adolescents treated with Xarelto were similar in type to those observed in adults and were primarily mild to moderate in severity.

Side effects that were observed more often in children and adolescents:

Very common (may affect more than 1 in 10 people)

• headache
• fever
• nose bleeding
• vomiting

Common (may affect up to 1 in 10 people)

• raised heartbeat
• blood tests may show an increase in bilirubin (bile pigment)
• thrombocytopenia (low number of platelets which are cells that help blood to clot)
• heavy menstrual bleeding

Uncommon (may affect up to 1 in 100 people)

• blood tests may show an increase in a subcategory of bilirubin (direct bilirubin, bile pigment)

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

4.1     Therapeutic indications

Adults

Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors, such as congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke or transient ischaemic attack.

Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults. (See section 4.4 for haemodynamically unstable PE patients.)

Paediatric population

Treatment of venous thromboembolism (VTE) and prevention of VTE recurrence in children and adolescents aged less than 18 years and weighing from 30 kg to 50 kg after at least 5 days of initial parenteral anticoagulation treatment.

1. 4.2 Posology and method of administration

2. Posology

   Prevention of stroke and systemic embolism in adults

   The recommended dose is 20 mg once daily, which is also the recommended maximum dose.

   Therapy with Xarelto should be continued long term provided the benefit of prevention of stroke and systemic embolism outweighs the risk of bleeding (see section 4.4).

    

   If a dose is missed the patient should take Xarelto immediately and continue on the following day with the once daily intake as recommended. The dose should not be doubled within the same day to make up for a missed dose.

    

   Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE in adults

   The recommended dose for the initial treatment of acute DVT or PE is 15 mg twice daily for the first three weeks followed by 20 mg once daily for the continued treatment and prevention of recurrent DVT and PE.

Treatment of VTE and prevention of VTE recurrence in children and adolescents

Xarelto treatment in children and adolescents aged less than 18 years should be initiated following at least 5 days of initial parenteral anticoagulation treatment (see section 5.1).

The dose for children and adolescent is calculated based on body weight.

• Body weight from 30 to 50 kg:
  a once daily dose of 15 mg rivaroxaban is recommended. This is the maximum daily dose.
• Body weight of 50 kg or more:
  a once daily dose of 20 mg rivaroxaban is recommended. This is the maximum daily dose.
• For patients with body weight less 30 kg refer to the Summary of Product Characteristics of Xarelto granules for oral suspension.
   
  The weight of a child should be monitored and the dose reviewed regularly. This is to ensure a therapeutic dose is maintained. Dose adjustments should be made based on changes in body weight only.
   

Treatment should be continued for at least 3 months in children and adolescents. Treatment can be extended up to 12 months when clinically necessary. There is no data available in children to support a dose reduction after 6 months treatment. The benefit‑risk of continued therapy after 3 months should be assessed on an individual basis taking into account the risk for recurrent thrombosis versus the potential bleeding risk.

If a dose is missed, the missed dose should be taken as soon as possible after it is noticed, but only on the same day. If this is not possible, the patient should skip the dose and continue with the next dose as prescribed. The patient should not take two doses to make up for a missed dose.

Converting from Vitamin K Antagonists (VKA) to Xarelto

Prevention of stroke and systemic embolism:
VKA treatment should be stopped and Xarelto therapy should be initiated when the International Normalised Ratio (INR) is ≤ 3.0.

Treatment of DVT, PE and prevention of recurrence in adults and treatment of VTE and prevention of recurrence in paediatric patients:
VKA treatment should be stopped and Xarelto therapy should be initiated once the INR is ≤ 2.5.

When converting patients from VKAs to Xarelto, INR values will be falsely elevated after the intake of Xarelto. The INR is not valid to measure the anticoagulant activity of Xarelto, and therefore should not be used (see section 4.5).

Paediatric patients:

Children who convert from Xarelto to VKA need to continue Xarelto for 48 hours after the first dose of VKA. After 2 days of co‑administration an INR should be obtained prior to the next scheduled dose of Xarelto. Co‑administration of Xarelto and VKA is advised to continue until the INR is ≥ 2.0. Once Xarelto is discontinued INR testing may be done reliably 24 hours after the last dose (see above and section 4.5).

Converting from parenteral anticoagulants to Xarelto

For adult and paediatric patients currently receiving a parenteral anticoagulant, discontinue the parenteral anticoagulant and start Xarelto 0 to 2 hours before the time 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).

Converting from Xarelto to parenteral anticoagulants

Discontinue Xarelto and give the first dose of parenteral anticoagulant at the time the next Xarelto dose would be taken.

Special populations

Renal impairment

Adults:

Limited clinical data for patients with severe renal impairment (creatinine clearance 15 - 29 ml/min) indicate that rivaroxaban plasma concentrations are significantly increased. Therefore, Xarelto is to be used with caution in these patients. Use is not recommended in patients with creatinine clearance < 15 ml/min (see sections 4.4 and 5.2).

Paediatric population:

• Children and adolescents with mild renal impairment (glomerular filtration rate 50 ‑ 80 mL/min/1.73 m²): no dose adjustment is required, based on data in adults and limited data in paediatric patients (see section 5.2).
• Children and adolescents with moderate or severe renal impairment (glomerular filtration rate < 50 mL/min/1.73 m²): Xarelto is not recommended as no clinical data is available (see section 4.4).
   
  Hepatic impairment
  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 sections 4.3 and 5.2).
  No clinical data is available in children with hepatic impairment.
   
  Elderly population
  No dose adjustment (see section 5.2)
   
  Body weight
  No dose adjustment for adults (see section 5.2)
  For paediatric patients the dose is determined based on body weight.
   
  Gender
  No dose adjustment (see section 5.2)
   
   

  Paediatric population

  The safety and efficacy of Xarelto in children aged 0 to < 18 years have not been established in the indication prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. No data are available. Therefore, it is not recommended for use in children below 18 years of age in indications other than the treatment of VTE and prevention of VTE recurrence.

   

  Method of administration

  Adults

  Xarelto is for oral use.

  The tablets are to be taken with food (see section 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. After the administration of crushed Xarelto 15 mg or 20 mg film-coated tablets, the dose should be immediately followed by food.

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

   

  Children and adolescents weighing 30 kg to 50 kg

  Xarelto is for oral use.

  The patient should be advised to swallow the tablet with liquid. It should also be taken with food (see section 5.2). The tablets should be taken approximately 24 hours apart.

   

  In case the patient immediately spits up the dose or vomits within 30 minutes after receiving the dose, a new dose should be given. However, if the patient vomits more than 30 minutes after the dose, the dose should not be re-administered and the next dose should be taken as scheduled.

   

  The tablet must not be split in an attempt to provide a fraction of a tablet dose.

   

  Crushing of tablets

  For patients who are unable to swallow whole tablets, Xarelto granules for oral suspension should be used.

  If the oral suspension is not immediately available, when doses of 15 mg or 20 mg rivaroxaban are prescribed, these could be provided by crushing the 15 mg or 20 mg tablet and mixing it with water or apple puree immediately prior to use and administering orally.

  The crushed tablet may be given through a nasogastric or gastric feeding tube (see sections 5.2 and 6.6).

4.4     Special warnings and precautions for use

Haemorrhagic risk

Paediatric population

There is limited data in children with cerebral vein and sinus thrombosis who have a CNS infection (see section 5.1). The risk of bleeding should be carefully evaluated before and during therapy with rivaroxaban.

Renal impairment

In adult patients with severe renal impairment (creatinine clearance < 30 ml/min) rivaroxaban plasma levels may be significantly increased (1.6 fold on average) which may lead to an increased bleeding risk. Xarelto is to be used with caution in patients with creatinine clearance 15 - 29 ml/min. Use is not recommended in patients with creatinine clearance < 15 ml/min (see sections 4.2 and 5.2).

Xarelto should be used with caution in patients with renal impairment concomitantly receiving other medicinal products which increase rivaroxaban plasma concentrations (see section 4.5).

Xarelto is not recommended in children and adolescents with moderate or severe renal impairment (glomerular filtration rate < 50 mL/min/1.73 m²), as no clinical data is available.

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. No clinical data is available in children receiving concomitant systemic treatment with strong inhibitors of both CYP 3A4 and P‑gp (see section 4.5).

Spinal/epidural anaesthesia or puncture

Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of rivaroxaban is estimated to be low. However, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known and should be weighed against the urgency of a diagnostic procedure.

For the removal of an epidural catheter and based on the general PK characteristics at least 2x half-life, i.e. at least 18 hours in young adult patients and 26 hours in elderly patients should elapse after the last administration of rivaroxaban (see section 5.2). 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. No data is available on the timing of the placement or removal of neuraxial catheter in children while on Xarelto. In such cases, discontinue rivaroxaban and consider a short acting parenteral anticoagulant.

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”.

4.5     Interaction with other medicinal products and other forms of interaction

The extent of interactions in the paediatric population is not known. The below mentioned interaction data was obtained in adults and the warnings in section 4.4 should be taken into account for the paediatric population.

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

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 changed)

Paediatric population

The safety assessment in children and adolescents is based on the safety data from two phase II and one phase III open‑label active controlled studies in paediatric patients aged birth to less than 18 years. The safety findings were generally similar between rivaroxaban and comparator in the various paediatric age groups. Overall, the safety profile in the 412 children and adolescents treated with rivaroxaban was similar to that observed in the adult population and consistent across age subgroups, although assessment is limited by the small number of patients.

In paediatric patients, headache (very common, 16.7%), fever (very common, 11.7%), epistaxis (very common, 11.2%), vomiting (very common, 10.7%), tachycardia (common, 1.5%), increase in bilirubin (common, 1.5%) and bilirubin conjugated increased (uncommon, 0.7%) were reported more frequently as compared to adults. Consistent with adult population, menorrhagia was observed in 6.6% (common) of female adolescents after menarche. Thrombocytopenia as observed in the post-marketing experience in adult population was common (4.6%) in paediatric clinical studies. The adverse drug reactions in paediatric patients were primarily mild to moderate in severity.

4.9     Overdose

 In adults, rare cases of overdose up to 600 mg have been reported without bleeding complications or other adverse reactions. There is limited data available in children. Due to limited absorption a ceiling effect with no further increase in average plasma exposure is expected at supratherapeutic doses of 50 mg rivaroxaban or above in adults, however, no data is available at supratherapeutic doses in children.

A specific reversal agent (andexanet alfa) antagonising the pharmacodynamic effect of rivaroxaban is available for adults, but not established in children (refer to the Summary of Product Characteristics of andexanet alfa).

The use of activated charcoal to reduce absorption in case of rivaroxaban overdose may be considered.

Management of bleeding

Should a bleeding complication arise in a patient receiving rivaroxaban, the next rivaroxaban administration should be delayed or treatment should be discontinued as appropriate. Rivaroxaban has a half-life of approximately 5 to 13 hours in adults. The half life in children estimated using population pharmacokinetic (popPK) modelling approaches is shorter (see section 5.2). Management should be individualised according to the severity and location of the haemorrhage. Appropriate symptomatic treatment could be used as needed, such as mechanical compression (e.g. for severe epistaxis), surgical haemostasis with bleeding control procedures, fluid replacement and haemodynamic support, blood products (packed red cells or fresh frozen plasma, depending on associated anaemia or coagulopathy) or platelets.

If bleeding cannot be controlled by the above measures, either the administration of a specific factor Xa inhibitor reversal agent (andexanet alfa), which antagonises the pharmacodynamic effect of rivaroxaban, or a specific procoagulant reversal agent, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (r-FVIIa), should be considered. However, there is currently very limited clinical experience with the use of these medicinal products in adults and in children receiving rivaroxaban. The recommendation is also based on limited non-clinical data. Re-dosing of recombinant factor VIIa shall be considered and titrated depending on improvement of bleeding. Depending on local availability, a consultation with a coagulation expert should be considered in case of major bleedings (see section 5.1).

Protamine sulphate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is limited experience with tranexamic acid and no experience with aminocaproic acid and aprotinin in adults receiving rivaroxaban. There is no experience on the use of these agents in children receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with the use of the systemic haemostatic desmopressin in individuals receiving rivaroxaban. Due to the high plasma protein binding rivaroxaban is not expected to be dialysable.

5.1     Pharmacodynamic properties

"Xarelto" replaced by "Rivaroxaban" throught section

Paediatric population

PT (neoplastin reagent), aPTT, and anti‑Xa assay (with a calibrated quantitative test) display a close correlation to plasma concentrations in children. The correlation between anti‑Xa to plasma concentrations is linear with a slope close to 1. Individual discrepancies with higher or lower anti‑Xa values as compared to the corresponding plasma concentrations may occur. There is no need for routine monitoring of coagulation parameters during clinical treatment with rivaroxaban. However, if clinically indicated, rivaroxaban concentrations can be measured by calibrated quantitative anti-Factor Xa tests in mcg/L (see table 13 in section 5.2 for ranges of observed rivaroxaban plasma concentrations in children). The lower limit of quantifications must be considered when the anti‑Xa test is used to quantify plasma concentrations of rivaroxaban in children. No threshold for efficacy or safety events has been established.

Paediatric population

Treatment of VTE and prevention of VTE recurrence in paediatric patients

A total of 727 children with confirmed acute VTE, of whom 528 received rivaroxaban, were studied in 6 open-label, multicentre paediatric studies. Body weight-adjusted dosing in patients from birth to less than 18 years resulted in rivaroxaban exposure similar to that observed in adult DVT patients treated with rivaroxaban 20 mg once daily as confirmed in the phase III study (see section 5.2).

The EINSTEIN Junior phase III study was a randomised, active‑controlled, open‑label multicentre clinical study in 500 paediatric patients (aged from birth to < 18 years) with confirmed acute VTE. There were 276 children aged 12 to < 18 years, 101 children aged 6 to < 12 years, 69 children aged 2 to < 6 years, and 54 children aged < 2 years.

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, 84/165 patients in the comparator group). The most common presentation of index thrombosis in children aged 12 to < 18 years was non‑CVC‑VTE in 211 (76.4%); in children aged 6 to < 12 years and aged 2 to < 6 years was CVST in 48 (47.5%) and 35 (50.7%), respectively; and in children aged < 2 years was CVC-VTE in 37 (68.5%). There were no children < 6 months with CVST in the rivaroxaban group. 22 of the patients with CVST had a CNS infection (13 patients in the rivaroxaban group and 9 patients in comparator group).

VTE was provoked by persistent, transient, or both persistent and transient risk factors in 438 (87.6%) children.

Patients received initial treatment with therapeutic doses of UFH, LMWH, or fondaparinux for at least 5 days, and were randomised 2:1 to receive either body weight-adjusted doses of rivaroxaban or comparator group (heparins, VKA) for a main study treatment period of 3 months (1 month for children < 2 years with CVC-VTE). At the end of the main study treatment period, the diagnostic imaging test, which was obtained at baseline, was repeated, if clinically feasible. The study treatment could be stopped at this point, or at the discretion of the Investigator continued for up to 12 months (for children < 2 years with CVC‑VTE up to 3 months) in total.

The primary efficacy outcome was symptomatic recurrent VTE. The primary safety outcome was the composite of major bleeding and clinically relevant non‑major bleeding (CRNMB). All efficacy and safety outcomes were centrally adjudicated by an independent committee blinded for treatment allocation. The efficacy and safety results are shown in Tables 11 and 12 below.

Recurrent VTEs occurred in the rivaroxaban group in 4 of 335 patients and in the comparator group in 5 of 165 patients. The composite of major bleeding and CRNMB was reported in 10 of 329 patients (3%) treated with rivaroxaban and in 3 of 162 patients (1.9%) treated with comparator. Net clinical benefit (symptomatic recurrent VTE plus major bleeding events) was reported in the rivaroxaban group in 4 of 335 patients and in the comparator group in 7 of 165 patients. Normalisation of the thrombus burden on repeat imaging occurred in 128 of 335 patients with rivaroxaban treatment and in 43 of 165 patients in the comparator group. These findings were generally similar among age groups. There were 119 (36.2%) children with any treatment-emergent bleeding in the rivaroxaban group and 45 (27.8%) children in the comparator group.

Table 11: Efficacy results at the end of the main treatment period

Table 12: Safety results at the end of the main treatment period

The efficacy and safety profile of rivaroxaban was largely similar between the paediatric VTE population and the DVT/PE adult population, however, the proportion of subjects with any bleeding was higher in the paediatric VTE population as compared to the DVT/PE adult population.

5.2     Pharmacokinetic properties

Absorption

The following information is based on the data obtained in adults.

Rivaroxaban is rapidly absorbed with maximum concentrations (C_max) appearing 2 - 4 hours after tablet intake. 

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 C_max at the 2.5 mg and 10 mg dose.

Paediatric population

Children received rivaroxaban tablet or oral suspension during or closely after feeding or food intake and with a typical serving of liquid to ensure reliable dosing in children. As in adults, rivaroxaban is readily absorbed after oral administration as tablet or granules for oral suspension formulation in children. No difference in the absorption rate nor in the extent of absorption between the tablet and granules for oral suspension formulation was observed. No PK data following intravenous administration to children are available so that the absolute bioavailability of rivaroxaban in children is unknown. A decrease in the relative bioavailability for increasing doses (in mg/kg bodyweight) was found, suggesting absorption limitations for higher doses, even when taken together with food.

Rivaroxaban 15 mg tablets should be taken with feeding or with food (see section 4.2).

Distribution

Plasma protein binding in adults is high at approximately 92% to 95%, with serum albumin being the main binding component. The volume of distribution is moderate with V_ss being approximately 50 litres.

Paediatric population

No data on rivaroxaban plasma protein binding specific to children is available. No PK data following intravenous administration of rivaroxaban to children is available. V_ss estimated via population PK modelling in children (age range 0 to < 18 years) following oral administration of rivaroxaban is dependent on body weight and can be described with an allometric function, with an average of 113 L for a subject with a body weight of 82.8 kg.

Paediatric population

No metabolism data specific to children is available. No PK data following intravenous administration of rivaroxaban to children is available. CL estimated via population PK modelling in children (age range 0 to < 18 years) following oral administration of rivaroxaban is dependent on body weight and can be described with an allometric function, with an average of 8 L/h for a subject with body weight of 82.8 kg. The geometric mean values for disposition half-lives (t_1/2) estimated via population PK modelling decrease with decreasing age and ranged from 4.2 h in adolescents to approximately 3 h in children aged 2-12 years down to 1.9 and 1.6 h in children aged 0.5-< 2 years and less than 0.5 years, respectively.

Special populations

Gender

InAdults, there were no clinically relevant differences in pharmacokinetics and pharmacodynamics between male and female patients. An exploratory analysis did not reveal relevant differences in rivaroxaban exposure between male and female children.

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.

Different weight categories

In adults, extremes in body weight (< 50 kg or > 120 kg) had only a small influence on rivaroxaban plasma concentrations (less than 25%). No dose adjustment is necessary.

In children, rivaroxaban is dosed based on body weight. An exploratory analysis did not reveal a relevant impact of underweight or obesity on rivaroxaban exposure in children.

Inter-ethnic differences

In adults, no clinically relevant inter-ethnic differences among Caucasian, African-American, Hispanic, Japanese or Chinese patients were observed regarding rivaroxaban pharmacokinetics and pharmacodynamics.

An exploratory analysis did not reveal relevant inter‑ethnic differences in rivaroxaban exposure among Japanese, Chinese or Asian children outside Japan and China compared to the respective overall paediatric population.

Hepatic impairment

Cirrhotic adult 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 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.

Rivaroxaban 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).

No clinical data is available in children with hepatic impairment.`

Renal impairment

In adults, 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 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. Rivaroxaban is to be used with caution in patients with creatinine clearance 15 - 29 ml/min (see section 4.4).

No clinical data is available in children 1 year or older with moderate or severe renal impairment (glomerular filtration rate <50 mL/min/1.73 m²).

In paediatric patients with acute VTE receiving body weight-adjusted rivaroxaban leading to an exposure similar to that in adult DVT patients receiving a 20 mg once daily dose, the geometric mean concentrations (90% interval) at sampling time intervals roughly representing maximum and minimum concentrations during the dose interval are summarised in Table 13.

Table 13: Summary statistics (geometric mean (90% interval)) of rivaroxaban steady state plasma concentrations (mcg/L) by dosing regimen and age

Paediatric population

Safety and efficacy have not been established in the indication prevention of stroke and systemic embolism in patients with non‑valvular atrial fibrillation for children and adolescents up to 18 years.

5.3     Preclinical safety data

Rivaroxaban was tested in juvenile rats up to 3‑month treatment duration starting at postnatal day 4 showing a non dose-related increase in periinsular haemorrhage. No evidence of target organ‑specific toxicity was seen.

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 10, 14, 28, 42 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 14 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. After the administration of a crushed rivaroxaban 15 mg or 20 mg tablet, the dose should then be immediately followed by enteral feeding.

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: Addition of updated data of bleeding and anaemia events across completed phase 3 studies.

Section 10: Update to date of revision of the text

Section 4.2 - Minor typographical updates

Section 4.3 - Minor typographical updates

Section 4.4 - Minor typographical updates

Section 4.5 - Minor typographical updates

Section 4.8 - Minor typographical updates

Section 4.9 - minor typographical updates

Section 5.1 - Minor typographical updates

Section 5.2 - Minor typeographical udpates

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

Xarelto 15mg – EU/1/08/472/012
EMEA/H/C/944/IB/40/G
www.medicines.ie

(Inserted Text; Deleted Text)

6.5       Nature and contents of container

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

Not all pack sizes may be marketed

8          Marketing authorization number(s)

EU/1/08/472/011-016, EU/1/08/472/023, EU/1/08/472/036.

10           Date of revision of the text

05/2015 07/2015

Xarelto 15mg – EU/1/08/472/012
EMEA/H/C/944/IB/40/G
www.medicines.ie

(Inserted Text; Deleted Text)

6.5       Nature and contents of container

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

Not all pack sizes may be marketed

8          Marketing authorization number(s)

EU/1/08/472/011-016, EU/1/08/472/023, EU/1/08/472/036.

10           Date of revision of the text

05/2015 07/2015

Xarelto 15mg – EU/1/08/472/012
EMEA/H/C/944/11/37
www.medicines.ie

(Inserted Text; Deleted Text)

4.4          Special warnings and precautions for use

…

Spinal/epidural anaesthesia or puncture

When neuraxial anaesthesia (spinal/epidural anaesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal haematoma which can result in long-term or permanent paralysis. The risk of these events may be increased by the post-operative use of indwelling epidural catheters or the concomitant use of medicinal products affecting haemostasis. The risk may also be increased by traumatic or repeated epidural or spinal puncture. Patients are to be frequently monitored for signs and symptoms of neurological impairment (e.g. numbness or weakness of the legs, bowel or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. There is no clinical experience with the use of 15 mg rivaroxaban in these situations.
To reduce the potential risk of bleeding associated with the concurrent use of rivaroxaban and neuraxial (epidural/spinal) anaesthesia or spinal puncture, consider the pharmacokinetic profile of rivaroxaban. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of rivaroxaban is estimated to be low. However, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known.
For the removal of an epidural catheter and based on the general PK characteristics at least 2x half-life, i.e. at least 18 hours in young patients and 26 hours in elderly patients should elapse after the last administration of rivaroxaban (see section 5.2).At least 18 hours should elapse after the last administration of rivaroxaban before removal of an epidural catheter. Following removal of the catheter, at least 6 hours should elapse before the next rivaroxaban dose is administered.
If traumatic puncture occurs the administration of rivaroxaban is to be delayed for 24 hours.

4.8       Undesirable effects

…

Post-marketing observations

The following adverse reactions have been reported post-marketing in temporal association with the use of Xarelto. The frequency of these adverse reactions reported from post-marketing experience cannot be estimated.
Immune system disorders: Angioedema and allergic oedema have been reported post-marketing in temporal association with the use of Xarelto. The frequency of these adverse reactions reported from post-marketing experience cannot be estimated. (In the pooled phase III trials, these events were uncommon (≥ 1/1,000 to < 1/100)).
Hepatobiliary disorders: Cholestasis, Hepatitis (incl. hepatocellular injury) (In the pooled phase III trials, these events were rare (≥ 1/10,000 to < 1/1,000)).
Blood and lymphatic system disorders: Thrombocytopenia (In the pooled phase III trials, these events were uncommon (≥ 1/1,000 to < 1/100)).

10           Date of revision of the text

Xarelto 15mg – EU/1/08/472/012
EMEA/H/C/944/11/37
www.medicines.ie

(Inserted Text; Deleted Text)

4.4          Special warnings and precautions for use

…

Spinal/epidural anaesthesia or puncture

When neuraxial anaesthesia (spinal/epidural anaesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal haematoma which can result in long-term or permanent paralysis. The risk of these events may be increased by the post-operative use of indwelling epidural catheters or the concomitant use of medicinal products affecting haemostasis. The risk may also be increased by traumatic or repeated epidural or spinal puncture. Patients are to be frequently monitored for signs and symptoms of neurological impairment (e.g. numbness or weakness of the legs, bowel or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. There is no clinical experience with the use of 15 mg rivaroxaban in these situations.
To reduce the potential risk of bleeding associated with the concurrent use of rivaroxaban and neuraxial (epidural/spinal) anaesthesia or spinal puncture, consider the pharmacokinetic profile of rivaroxaban. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of rivaroxaban is estimated to be low. However, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known.
For the removal of an epidural catheter and based on the general PK characteristics at least 2x half-life, i.e. at least 18 hours in young patients and 26 hours in elderly patients should elapse after the last administration of rivaroxaban (see section 5.2).At least 18 hours should elapse after the last administration of rivaroxaban before removal of an epidural catheter. Following removal of the catheter, at least 6 hours should elapse before the next rivaroxaban dose is administered.
If traumatic puncture occurs the administration of rivaroxaban is to be delayed for 24 hours.

4.8       Undesirable effects

…

Post-marketing observations

The following adverse reactions have been reported post-marketing in temporal association with the use of Xarelto. The frequency of these adverse reactions reported from post-marketing experience cannot be estimated.
Immune system disorders: Angioedema and allergic oedema have been reported post-marketing in temporal association with the use of Xarelto. The frequency of these adverse reactions reported from post-marketing experience cannot be estimated. (In the pooled phase III trials, these events were uncommon (≥ 1/1,000 to < 1/100)).
Hepatobiliary disorders: Cholestasis, Hepatitis (incl. hepatocellular injury) (In the pooled phase III trials, these events were rare (≥ 1/10,000 to < 1/1,000)).
Blood and lymphatic system disorders: Thrombocytopenia (In the pooled phase III trials, these events were uncommon (≥ 1/1,000 to < 1/100)).

10           Date of revision of the text

In section 4.2 Posology and method of administration

Patients undergoing cardioversion

Xarelto can be initiated or continued in patients who may require cardioversion.
For transesophageal echocardiogram (TEE) guided cardioversion in patients not previously treated with anticoagulants, Xarelto treatment should be started at least 4 hours before cardioversion to ensure adequate anticoagulation (see sections 5.1 and 5.2). For all patients, confirmation should be sought prior to cardioversion that the patient has taken Xarelto as prescribed. Decisions on initiation and duration of treatment should take established guideline recommendations for anticoagulant treatment in patients undergoing cardioversion into account.

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

Spinal/epidural anaesthesia or puncture

When neuraxial anaesthesia (spinal/epidural anaesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal haematoma which can result in long-term or permanent paralysis. The risk of these events may be increased by the post-operative use of indwelling epidural catheters or the concomitant use of medicinal products affecting haemostasis. The risk may also be increased by traumatic or repeated epidural or spinal puncture. Patients are to be frequently monitored for signs and symptoms of neurological impairment (e.g. numbness or weakness of the legs, bowel or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. At least 18 hours should elapse after the last administration of rivaroxaban before removal of an epidural catheter. Following removal of the catheter, at least 6 hours should elapse before the next rivaroxaban dose is administered. If traumatic puncture occurs the administration of rivaroxaban is to be delayed for 24 hours.

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

In section 4.9 Overdose under “Management of bleeding”

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

·         Aprotinin has been deleted as a haemostatic

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

In a clinical pharmacology study on the reversal of rivaroxaban pharmacodynamics in healthy adult subjects (n=22), the effects of single doses (50 IU/kg) of two different types of PCCs, a 3-factor PCC (Factors II, IX and X) and a 4-factor PCC (Factors II, VII, IX and X) were assessed. The 3-factor PCC reduced mean Neoplastin PT values by approximately 1.0 second within 30 minutes, compared to reductions of approximately 3.5 seconds observed with the 4-factor PCC. In contrast, the 3-factor PCC had a greater and more rapid overall effect on reversing changes in endogenous thrombin generation than the 4-factor PCC (see section 4.9).

Patients undergoing cardioversion

A prospective, randomized, open-label, multicenter, exploratory study with blinded endpoint evaluation (X-VERT) was conducted in 1504 patients (oral anticoagulant naive and pre-treated) with non-valvular atrial fibrillation scheduled for cardioversion to compare rivaroxaban with dose-adjusted VKA (randomized 2:1), for the prevention of cardiovascular events. TEE- guided (1 - 5 days of pre-treatment) or conventional cardioversion (at least three weeks of pre-treatment) strategies were employed. The primary efficacy outcome (all stroke, transient ischemic attack, non-CNS systemic embolism, MI and cardiovascular death) occurred in 5 (0.5 %) patients in the rivaroxaban group (n = 978) and 5 (1.0 %) patients in the VKA group (n = 492; RR 0.50; 95 % CI 0.15-1.73; modified ITT population). The principal safety outcome (major bleeding) occurred in 6 (0.6 %) and 4 (0.8 %) patients in the rivaroxaban (n = 988) and VKA (n = 499) groups, respectively (RR 0.76; 95 % CI 0.21-2.67; safety population). This exploratory study showed comparable efficacy and safety between rivaroxaban and VKA treatment groups in the setting of cardioversion.

In section 4.2 Posology and method of administration

Patients undergoing cardioversion

Xarelto can be initiated or continued in patients who may require cardioversion.
For transesophageal echocardiogram (TEE) guided cardioversion in patients not previously treated with anticoagulants, Xarelto treatment should be started at least 4 hours before cardioversion to ensure adequate anticoagulation (see sections 5.1 and 5.2). For all patients, confirmation should be sought prior to cardioversion that the patient has taken Xarelto as prescribed. Decisions on initiation and duration of treatment should take established guideline recommendations for anticoagulant treatment in patients undergoing cardioversion into account.

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

Spinal/epidural anaesthesia or puncture

When neuraxial anaesthesia (spinal/epidural anaesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal haematoma which can result in long-term or permanent paralysis. The risk of these events may be increased by the post-operative use of indwelling epidural catheters or the concomitant use of medicinal products affecting haemostasis. The risk may also be increased by traumatic or repeated epidural or spinal puncture. Patients are to be frequently monitored for signs and symptoms of neurological impairment (e.g. numbness or weakness of the legs, bowel or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. At least 18 hours should elapse after the last administration of rivaroxaban before removal of an epidural catheter. Following removal of the catheter, at least 6 hours should elapse before the next rivaroxaban dose is administered. If traumatic puncture occurs the administration of rivaroxaban is to be delayed for 24 hours.

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

In section 4.9 Overdose under “Management of bleeding”

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

·         Aprotinin has been deleted as a haemostatic

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

In a clinical pharmacology study on the reversal of rivaroxaban pharmacodynamics in healthy adult subjects (n=22), the effects of single doses (50 IU/kg) of two different types of PCCs, a 3-factor PCC (Factors II, IX and X) and a 4-factor PCC (Factors II, VII, IX and X) were assessed. The 3-factor PCC reduced mean Neoplastin PT values by approximately 1.0 second within 30 minutes, compared to reductions of approximately 3.5 seconds observed with the 4-factor PCC. In contrast, the 3-factor PCC had a greater and more rapid overall effect on reversing changes in endogenous thrombin generation than the 4-factor PCC (see section 4.9).

Patients undergoing cardioversion

A prospective, randomized, open-label, multicenter, exploratory study with blinded endpoint evaluation (X-VERT) was conducted in 1504 patients (oral anticoagulant naive and pre-treated) with non-valvular atrial fibrillation scheduled for cardioversion to compare rivaroxaban with dose-adjusted VKA (randomized 2:1), for the prevention of cardiovascular events. TEE- guided (1 - 5 days of pre-treatment) or conventional cardioversion (at least three weeks of pre-treatment) strategies were employed. The primary efficacy outcome (all stroke, transient ischemic attack, non-CNS systemic embolism, MI and cardiovascular death) occurred in 5 (0.5 %) patients in the rivaroxaban group (n = 978) and 5 (1.0 %) patients in the VKA group (n = 492; RR 0.50; 95 % CI 0.15-1.73; modified ITT population). The principal safety outcome (major bleeding) occurred in 6 (0.6 %) and 4 (0.8 %) patients in the rivaroxaban (n = 988) and VKA (n = 499) groups, respectively (RR 0.76; 95 % CI 0.21-2.67; safety population). This exploratory study showed comparable efficacy and safety between rivaroxaban and VKA treatment groups in the setting of cardioversion.

·  In section 4.2, the following change was made:

Converting from parenteral anticoagulants to XareltoFor patients currently receiving a parenteral anticoagulant, discontinue the parenteral anticoagulant and start Xarelto should be started 0 to 2 hours before the time of that the next scheduled administration of the parenteral medicinal product (e.g. low molecular weight heparins) would be due or at the time of discontinuation of a continuously administered parenteral medicinal product (e.g.intravenous unfractionated heparin).

·  In section 4.3, the following change was made: Concomitant treatment with any other anticoagulants e.g. unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, dabigatran etexilate, apixaban, etc.) except under the specific circumstances of switching anticoagulant therapy to or from rivaroxaban (see section 4.2) or when UFH is given atdoses necessary to maintain an open central venous or arterial catheter (see section 4.5).

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

·  In section 4.2, the following change was made:

Converting from parenteral anticoagulants to XareltoFor patients currently receiving a parenteral anticoagulant, discontinue the parenteral anticoagulant and start Xarelto should be started 0 to 2 hours before the time of that the next scheduled administration of the parenteral medicinal product (e.g. low molecular weight heparins) would be due or at the time of discontinuation of a continuously administered parenteral medicinal product (e.g.intravenous unfractionated heparin).

·  In section 4.3, the following change was made: Concomitant treatment with any other anticoagulants e.g. unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, dabigatran etexilate, apixaban, etc.) except under the specific circumstances of switching anticoagulant therapy to or from rivaroxaban (see section 4.2) or when UFH is given atdoses necessary to maintain an open central venous or arterial catheter (see section 4.5).

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

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

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 15 mg rivaroxaban.

Excipients with known effect:

Each 15 mg film-coated tablet contains 24.13 mg lactose (as monohydrate), see section 4.4.

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. After the administration of crushed Xarelto 15 mg or 20 mg film-coated tablets, the dose should be immediately followed by food.

The crushed Xarelto tablet may also be given through gastric tubes after confirmation of the correct gastric placement of the tube. The crushed tablet should be administered in a small amount of water via a gastric tube after which it should be flushed with water. After the administration of crushed Xarelto15 mg or 20 mg film-coated tablets, the dose should then be immediately followed by enteral feeding (see section 5.2).

4.4     Special warnings and precautions for use

Renal impairment

In patients with severe renal impairment (creatinine clearance < 30 ml/min) rivaroxaban plasma levels may be significantly increased (1.6 fold on average) which may lead to an increased bleeding risk. Xarelto is to be used with caution in patients with creatinine clearance 15 ‑ 29 ml/min. Use is not recommended in patients with creatinine clearance < 15 ml/min (see sections 4.2 and 5.2).

Xarelto should be used with caution in patients with renal impairment concomitantly receiving other medicinal products that are potent inhibitors of CYP3A4 (e.g. clarithromycin, telithromycin) as PK modelling shows increased rivaroxaban concentrations in these patientswhich increase rivaroxaban plasma concentrations (see section 4.5).

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.

4.8         Undesirable effects

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 %).

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

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

Post-marketing observations

Angioedema and allergic oedema have been reported post-marketing in temporal association with the use of Xarelto. The frequency of these adverse reactions reported from post-marketing experience cannot be estimated. In the pooled phase III trials, these events were uncommon (≥ 1/1,000 to < 1/100).

Reporting of suspected adverse reactions

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

FREEPOST

Pharmacovigilance Section

Irish Medicines Board

Kevin O’Malley House

Earlsfort Centre

Earlsfort Terrace

Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

5.       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.

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).

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

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

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 15 mg rivaroxaban.

Excipients with known effect:

Each 15 mg film-coated tablet contains 24.13 mg lactose (as monohydrate), see section 4.4.

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. After the administration of crushed Xarelto 15 mg or 20 mg film-coated tablets, the dose should be immediately followed by food.

The crushed Xarelto tablet may also be given through gastric tubes after confirmation of the correct gastric placement of the tube. The crushed tablet should be administered in a small amount of water via a gastric tube after which it should be flushed with water. After the administration of crushed Xarelto15 mg or 20 mg film-coated tablets, the dose should then be immediately followed by enteral feeding (see section 5.2).

4.4     Special warnings and precautions for use

Renal impairment

In patients with severe renal impairment (creatinine clearance < 30 ml/min) rivaroxaban plasma levels may be significantly increased (1.6 fold on average) which may lead to an increased bleeding risk. Xarelto is to be used with caution in patients with creatinine clearance 15 ‑ 29 ml/min. Use is not recommended in patients with creatinine clearance < 15 ml/min (see sections 4.2 and 5.2).

Xarelto should be used with caution in patients with renal impairment concomitantly receiving other medicinal products that are potent inhibitors of CYP3A4 (e.g. clarithromycin, telithromycin) as PK modelling shows increased rivaroxaban concentrations in these patientswhich increase rivaroxaban plasma concentrations (see section 4.5).

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.

4.8         Undesirable effects

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 %).

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

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

Post-marketing observations

Angioedema and allergic oedema have been reported post-marketing in temporal association with the use of Xarelto. The frequency of these adverse reactions reported from post-marketing experience cannot be estimated. In the pooled phase III trials, these events were uncommon (≥ 1/1,000 to < 1/100).

Reporting of suspected adverse reactions

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

FREEPOST

Pharmacovigilance Section

Irish Medicines Board

Kevin O’Malley House

Earlsfort Centre

Earlsfort Terrace

Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

5.       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.

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).

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 at significant risk of for major bleeding. This may include

such as current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of

bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial

haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular

aneurysms or major intraspinal or intracerebral vascular abnormalities.

Concomitant treatment with any other anticoagulant agent s e.g. unfractionated heparin (UFH), low

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

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

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

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

Section 4.4 Special warnings and precautions for use

………………………..

a

Dosing recommendations before and after invasive procedures and surgical intervention

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 first authorisation: 30 September 2008

Date of latest renewal: 22 May 2013

Section 10. DATE OF REVISION OF THE TEXT

{MM/YYYY}June 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 at significant risk of for major bleeding. This may include

such as current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of

bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial

haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular

aneurysms or major intraspinal or intracerebral vascular abnormalities.

Concomitant treatment with any other anticoagulant agent s e.g. unfractionated heparin (UFH), low

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

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

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

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

Section 4.4 Special warnings and precautions for use

………………………..

a

Dosing recommendations before and after invasive procedures and surgical intervention

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 first authorisation: 30 September 2008

Date of latest renewal: 22 May 2013

Section 10. DATE OF REVISION OF THE TEXT

{MM/YYYY}June 2013

Section 5.1

From:

Pharmacotherapeutic group: Other antithrombotic agents, ATC code: B01AX06

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

Section 5.1

From:

Pharmacotherapeutic group: Other antithrombotic agents, ATC code: B01AX06

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