Posology : מינונים

4.2   Posology and method of administration

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,


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).
and longer durations should be based on permanent risk factors or idiopathic 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.
The safety and efficacy of treatment duration beyond 12 months has not been established. It should be considered whether to continue treatment beyond 12 months.

The duration of therapy 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             Day 1 - 21              15 mg twice daily        30 mg prevention of recurrent
DVT and PE                Day 22 onwards          20 mg once daily         20 mg 
Prevention of recurrent   Following completion    10 mg once daily         10 mg DVT and PE                of at least 6 months therapy for DVT or PE


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.

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 physician prescribing information 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).


Converting from Xarelto to Vitamin K antagonists (VKA)
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).

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).

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: 
-     For the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation, the recommended dose is 15 mg once daily (see section 5.2).

-     For the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE: patients should be treated with 15 mg twice daily for the first 3 weeks.
Thereafter, when the recommended dose is 20 mg once daily, a reduction of the dose from 20 mg once daily to 15 mg once daily should be considered if the patient’s assessed risk for bleeding outweighs the risk for recurrent DVT and PE. The recommendation for the use of 
15 mg is based on PK modelling and has not been studied in this clinical setting (see sections 4.4, 5.1 and 5.2).

No dose adjustment is necessary in patients with mild renal impairment (creatinine clearance 50 - 80 ml/min) (see section 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).
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.

Patients with non-valvular atrial fibrillation who undergo PCI (percutaneous coronary intervention) with stent placement
There is limited experience of a reduced dose of 15 mg Xarelto once daily 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).

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 section 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).

There is no data regarding chewing or halving the tablets.