Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Bayer AG, 51368 Leverkusen, Germany
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.)
Treatment of venous thromboembolism (VTE) and prevention of VTE recurrence in children and adolescents aged less than 18 years and weighing more than 50 kg after at least 5 days of initial parenteral anticoagulation treatment.
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.
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.
Short duration of therapy (at least 3 months) should be considered in patients with DVT or PE provoked by major transient risk factors (i.e. recent major surgery or trauma). Longer duration of therapy should be considered in patients with provoked DVT or PE not related to major transient risk factors, unprovoked DVT or PE, or a history of recurrent DVT or PE.
When extended prevention of recurrent DVT and PE is indicated (following completion of at least 6 months therapy for DVT or PE), the recommended dose is 10 mg once daily. In patients in whom the risk of recurrent DVT or PE is considered high, such as those with complicated comorbidities, or who have developed recurrent DVT or PE on extended prevention with Xarelto 10 mg once daily, a dose of Xarelto 20 mg once daily should be considered.
The duration of therapy and dose selection should be individualised after careful assessment of the treatment benefit against the risk for bleeding (see section 4.4).
| Time period | Dosing schedule | Total daily dose | |
|---|---|---|---|
| Treatment and prevention of recurrent DVT and PE | Day 1 – 21 | 15 mg twice daily | 30 mg |
| Day 22 onwards | 20 mg once daily | 20 mg | |
| Prevention of recurrent DVT and PE | Following completion of at least 6 months therapy for DVT or PE | 10 mg once daily or 20 mg once daily | 10 mg or 20 mg |
To support the dose switch from 15 mg to 20 mg after Day 21 a first 4 weeks treatment initiation pack of Xarelto for treatment of DVT/PE is available.
If a dose is missed during the 15 mg twice daily treatment phase (day 1 – 21), the patient should take Xarelto immediately to ensure intake of 30 mg Xarelto per day. In this case two 15 mg tablets may be taken at once. The patient should continue with the regular 15 mg twice daily intake as recommended on the following day.
If a dose is missed during the once daily treatment phase, 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.
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.
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.
VKA treatment should be stopped and Xarelto therapy should be initiated when the International Normalised Ratio (INR) is ≤3.0.
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).
There is a potential for inadequate anticoagulation during the transition from Xarelto to VKA. Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant. It should be noted that Xarelto can contribute to an elevated INR.
In patients converting from Xarelto to VKA, VKA should be given concurrently until the INR is ≥ 2.0. For the first two days of the conversion period, standard initial dosing of VKA should be used followed by VKA dosing, as guided by INR testing. While patients are on both Xarelto and VKA the INR should not be tested earlier than 24 hours after the previous dose but prior to the next dose of Xarelto. Once Xarelto is discontinued INR testing may be done reliably at least 24 hours after the last dose (see sections 4.5 and 5.2).
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).
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).
Discontinue Xarelto and give the first dose of parenteral anticoagulant at the time the next Xarelto dose would be taken.
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).
In patients with moderate (creatinine clearance 30 – 49 ml/min) or severe (creatinine clearance 15 – 29 ml/min) renal impairment the following dose recommendations apply:
No dose adjustment is necessary in patients with mild renal impairment (creatinine clearance 50 – 80 ml/min) (see section 5.2).
Paediatric population:
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.
No dose adjustment (see section 5.2).
No dose adjustment for adults (see section 5.2)
For paediatric patients the dose is determined based on body weight.
For paediatric patients the dose is determined based on body weight.
No dose adjustment (see section 5.2)
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.
There is limited experience of a reduced dose of 15 mg Xarelto once daily (or 10 mg Xarelto once daily for patients with moderate renal impairment [creatinine clearance 30 – 49 ml/min]) in addition to a P2Y12 inhibitor for a maximum of 12 months in patients with non-valvular atrial fibrillation who require oral anticoagulation and undergo PCI with stent placement (see sections 4.4 and 5.1).
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.
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).
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).
In adults, rare cases of overdose up to 1,960 mg have been reported. In case of overdose, the patient should be observed carefully for bleeding complications or other adverse reactions (see section “Management of bleeding”). 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.
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 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.
3 years.
Crushed tablets:
Crushed rivaroxaban tablets are stable in water and in apple puree for up to 4 hours.
This medicinal product does not require any special storage conditions.
Cartons containing 10, 14, 28 or 98 film-coated tablets in PP/Alu foil blisters.
Cartons containing 10 × 1 or 100 × 1 film-coated tablets in PP/Alu foil perforated unit dose blisters.
Multipacks containing 10 packs of 10 × 1 (100 film-coated tablets) in PP/Alu foil perforated unit dose blisters.
Cartons containing 14 film-coated tablets in PVC/PVDC/Alu foil blisters.
HDPE bottles with a PP screw cap containing 100 film-coated tablets.
Not all pack sizes may be marketed.
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.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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