XARELTO Granules for oral suspension Ref.[114627] Active ingredients: Rivaroxaban

Posology

The dose and frequency of administration are determined based on body weight (see Table 1).

Table 1. Recommended dose for Xarelto in paediatric patients from full-term neonates (following at least 10 days of oral feeding and weighing at least 2.6 kg) to children less than 18 years of age:

The weight of the child should be monitored and the dose reviewed regularly, especially for children below 12 kg. This is to ensure that a therapeutic dose is maintained. Dose adjustments should be made based on changes in body weight only.

Frequency of dosing

For a once a day regimen: The doses should be taken approximately 24 hours apart.

For a two times a day regimen: The doses should be taken approximately 12 hours apart.

For a three times a day regimen: The doses should be taken approximately 8 hours apart.

For patients with body weight of at least 2.6 kg to less than 30 kg only the oral suspension should be used. Do not split Xarelto tablets or use Xarelto tablets of lower strength in an attempt to provide doses for children with body weight below 30 kg.

For patients with body weight of at least 30 kg, Xarelto oral suspension or tablets of 15 mg or 20 mg strength can be administered once a day.

Xarelto oral suspension is provided with either 1 mL or 5 mL and 10 mL blue syringes (oral dosing syringe) with their adapter. To ensure accurate dosing it is recommended to use the blue syringes as follows (see Table 1):

• 1 mL blue syringe (with 0.1 mL graduations) for patients weighing less than 4 kg
• 5 mL blue syringe (with 0.2 mL graduations) for patients weighing 4 kg up to less than 30 kg
• 10 mL blue syringe (with 0.5 mL graduations) for patients weighing 12 kg or more

For patients weighing 12 kg up to less than 30 kg, either 5 mL or 10 mL blue syringes can be used.

It is recommended that the healthcare professional advises the patient or caregiver which blue syringe to use to ensure that the correct volume is administered.

Instructions for Use booklet is provided with the medicinal product.

Initiation of treatment

Paediatric patients from term neonates to less than 6 months

Treatment for paediatric patients from term neonates to less than 6 months of age, who at birth had at least 37 weeks of gestation, weigh at least 2.6 kg, and have had at least 10 days of oral feeding should be initiated following at least 5 days of initial parenteral anticoagulation treatment (see sections 4.4 and 5.1). Xarelto is dosed based on body weight using the oral suspension formulation (see Table 1).

Paediatric patients from 6 months of age to less than 18 years

Treatment for paediatric patients from 6 months to less than 18 years of age should be initiated following at least 5 days of initial parenteral anticoagulation treatment (see section 5.1). Xarelto is dosed based on body weight (see Table 1).

Duration of treatment

All children, except those aged less than 2 years with catheter-related thrombosis

Therapy should be continued for at least 3 months. 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.

Children aged less than 2 years with catheter-related thrombosis

Therapy should be continued for at least 1 month. Treatment can be extended up to 3 months when clinically necessary. The benefit-risk of continued therapy after 1 month should be assessed on an individual basis taking into account the risk for recurrent thrombosis versus the potential bleeding risk.

Missed doses

Once a day regimen

If taken once a day, a 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.

Two times a day regimen

If taken twice a day, a missed morning dose should be taken immediately when it is noticed, and it may be taken together with the evening dose. A missed evening dose can only be taken during the same evening, the patient should not take two doses the next morning.

Three times a day regimen

If taken three times a day, the three times daily administration schedule with approximately 8-hour intervals should simply be resumed at the next scheduled dose without compensating for the missed dose.

On the following day, the child should continue with the regular once, twice or three times daily regimen.

Converting from parenteral anticoagulants to Xarelto

For patients currently receiving a parenteral anticoagulant, start Xarelto 0 to 2 hours before the time of the next scheduled administration of the parenteral medicinal product (e.g. LMWH) 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 that the next Xarelto dose would be taken.

Converting from Vitamin K antagonists (VKA) to Xarelto

VKA treatment should be stopped and Xarelto therapy should be initiated once the International Normalised Ratio (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.

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).

Special populations

Renal impairment

• Children 1 year or older 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 1 year or older 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).
• Children below 1 year: the renal function should only be determined using serum creatinine. Xarelto is not recommended in children younger than 1 year with serum creatinine results above 97.5^th percentile (see Table 2), as no data are available (see section 4.4).

Table 2. Reference values of serum creatinine in children younger than 1 year of age (Boer et al, 2010):

Hepatic impairment

No clinical data is available in children with 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 section 4.3 and 5.2).

Body weight

For children the dose is determined based on body weight (see Posology above).

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 indications other than treatment of venous thromboembolism (VTE) and prevention of VTE recurrence. No or insufficient data are available for other indications (see also section 5.1). Therefore, Xarelto 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

Xarelto is for oral use.

The oral suspension should be taken with feeding or with food (see section 5.2).

For details on preparation and administration of the oral suspension see section 6.6.

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

Each dose should be immediately followed by the intake of one typical serving of liquid. This typical serving may include liquid volume used for feeding.

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.

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 it orally (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 antagonising the pharmacodynamic effect of rivaroxaban is not established in children.

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

Due to the high plasma protein binding rivaroxaban is not expected to be dialysable.

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, administration of a specific procoagulant agent should be considered, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (r-FVIIa). However, there is currently very limited clinical experience with the use of these medicinal products in adults and in children receiving rivaroxaban (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.

3 years.

After reconstitution the suspension is stable for 14 days.

Do not store above 30°C.

Do not freeze.

Store the prepared suspension upright.

Xarelto 1 mg/mL granules for oral suspension is packed in a folding box containing:

For children weighing less than 4 kg:

• 2.625 g granules, corresponding to 51.7 mg rivaroxaban, in 1 brown glass bottle, for reconstitution in 50 mL water, closed with a child resistant screw cap
• 2 blue syringes 1 mL with 0.1 mL marked graduations
• 1 adapter for bottles and blue syringes
• 1 water syringe 50 mL with 1 mL marked graduations

or

For children weighing 4 kg and more:

• 5.25 g granules, corresponding to 103.4 mg rivaroxaban, in 1 brown glass bottle, for reconstitution in 100 mL water, closed with a child resistant screw cap
• 2 blue syringes 5 mL with 0.2 mL marked graduations
• 2 blue syringes 10 mL with 0.5 mL marked graduations
• 1 adapter for bottles and blue syringes
• 1 water syringe 100 mL with 2 mL marked graduations

Not all pack sizes may be marketed.

Suspension

Before administration the granules must be suspended into a homogenous suspension with non-carbonated water giving a final concentration of 1 mg per mL.

The amount of water to be used is:

• 50 mL for the bottle containing 2.625 g granules (51.7 mg of rivaroxaban), resulting in 51.7 mL total volume after reconstitution
• 100 mL for the bottle containing 5.25 g granules (103.4 mg of rivaroxaban), resulting in 103.4 mL total volume after reconstitution.

The bottle has to be shaken after reconstitution for 60 seconds and before each dose for 10 seconds. After reconstitution the medicinal product is a white to off-white suspension.

For dose administration after reconstitution, the blue syringes (1 mL, 5 mL or 10 mL) are provided (see section 4.2, Table 1).

Complete details on preparation and administration of the oral suspension can be found in the Instructions for Use that is provided with the medicinal product or in an educational video which can be accessed via QR code displayed on the Patient Alert Card that is also provided with the medicinal product.

The suspension may be given through a nasogastric or gastric feeding tube. Gastric placement of the tube should be confirmed before administering Xarelto. 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, the feeding tube should be flushed with water. This should then be immediately followed by nasogastric or gastric feeding.

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