Xarelto 1 mg/mL granules for oral suspension

/ Bayer

The dose and frequency of administration are determined based on body weight.
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.
For patients with body weight of at least 2.6 kg to less than 30 kg only the oral suspension should be used.
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:
* 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.
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.
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.
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.
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.
Converting from parenteral anticoagulants to rivaroxaban
For patients currently receiving a parenteral anticoagulant, start this medical product 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 rivaroxaban to parenteral anticoagulants
Discontinue this medical product and give the first dose of parenteral anticoagulant at the time that the next rivaroxaban dose would be taken.
Converting from Vitamin K antagonists (VKA) to rivaroxaban
VKA treatment should be stopped and rivaroxaban should be initiated once the International Normalised Ratio (INR) is ≤ 2.5.
When converting patients from VKAs to rivaroxaban, INR values will be falsely elevated after the intake of rivaroxaban. The INR is not valid to measure the anticoagulant activity of rivaroxaban, and therefore should not be used.
Converting from rivaroxaban to Vitamin K antagonists (VKA)
There is a potential for inadequate anticoagulation during the transition from rivaroxaban to VKA. Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant. It should be noted that rivaroxaban can contribute to an elevated INR.
Children who convert from rivaroxaban to VKA need to continue rivaroxaban 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 rivaroxaban. Co-administration of rivaroxaban and VKA is advised to continue until the INR is ≥ 2.0. Once rivaroxaban is discontinued INR testing may be done reliably 24 hours after the last dose.

Treatment of venous thromboembolism (VTE) and prevention of VTE recurrence in term neonates, infants and toddlers, children, and adolescents aged less than 18 years after at least 5 days of initial parenteral anticoagulation treatment.

* Hypersensitivity to the active substance or to any of the excipients
* Active clinically significant bleeding
* Lesion or condition, if considered to be a significant risk for major bleeding. This may include 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 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 specific circumstances of switching anticoagulant therapy or when UFH is given at doses necessary to maintain an open central venous or arterial catheter.
* Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C.
* Pregnancy and breast-feeding

Dosing of rivaroxaban cannot be reliably determined in the following patient populations and was not studied. It is therefore not recommended in children less than 6 months of age who:
• at birth had less than 37 weeks of gestation, or
• have a body weight of less than 2.6 kg, or
• had less than 10 days of oral feeding.
Haemorrhagic risk
Carefully observed for signs of bleeding. It is recommended to be used with caution in conditions with increased risk of haemorrhage. This medical product administration should be discontinued if severe haemorrhage occurs.
Renal impairment
Rivaroxaban is not recommended in children 1 year or older with moderate or severe renal impairment (glomerular filtration rate < 50 mL/min/1.73 m2), as no clinical data is available.
Rivaroxaban is not recommended in children younger than 1 year with serum creatinine results above 97.5th percentile, as no clinical data are available.
Interaction with other medicinal products
No clinical data is available in children receiving concomitant systemic treatment with strong inhibitors of both CYP3A4 and P-gp.
Rivaroxaban 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.
Care is to be taken if patients are treated concomitantly with medicinal products affecting haemostasis such as non-steroidal anti-inflammatory medicinal products (NSAIDs), acetylsalicylic acid and platelet aggregation inhibitors or selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs). For patients at risk of ulcerative gastrointestinal disease an appropriate prophylactic treatment may be considered.
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 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)
• vascular retinopathy
• bronchiectasis or history of pulmonary bleeding
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.
Patients with prosthetic valves
Rivaroxaban should not be used for thromboprophylaxis in patients having recently undergone transcatheter aortic valve replacement (TAVR). Safety and efficacy of rivaroxaban have not been studied in patients with prosthetic heart valves; therefore, there are no data to support that this medicinal product provides adequate anticoagulation in this patient population.
Patients with antiphospholipid syndrome
Direct acting oral anticoagulants (DOACs) including rivaroxaban are not recommended for patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome. In particular for patients that are triple positive (for lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies), treatment with DOACs could be associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.
Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary embolectomy
Rivaroxaban is not recommended as an alternative to unfractionated heparin in patients with pulmonary embolism who are haemodynamically unstable or may receive thrombolysis or pulmonary embolectomy since the safety and efficacy of rivaroxaban have not been established in these clinical situations.
Spinal/epidural anaesthesia or lumbar 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).
Dosing recommendations before and after invasive procedures and surgical intervention
If an invasive procedure or surgical intervention is required, this medical product should be stopped at least 24 hours before the intervention, if possible.
If the procedure cannot be delayed the increased risk of bleeding should be assessed against the urgency of the intervention.
Rivaroxaban should be restarted as soon as possible after the invasive procedure or surgical intervention provided the clinical situation allows and adequate haemostasis has been established.
Dermatological reactions
Serious skin reactions, including Stevens-Johnson syndrome/toxic epidermal necrolysis and DRESS syndrome, have been reported during post-marketing surveillance in association with the use of rivaroxaban. Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first weeks of treatment. Rivaroxaban should be discontinued at the first appearance of a severe skin rash (e.g. spreading, intense and/or blistering), or any other sign of hypersensitivity in conjunction with mucosal lesions.
See prescribing information for full details.

Common: Anaemia (incl. respective laboratory parameters), dizziness, headache, eye haemorrhage (incl. conjunctival haemorrhage), hypotension, haematoma, epistaxis, haemoptysis, gingival bleeding, gastrointestinal tract haemorrhage (incl. rectal haemorrhage), gastrointestinal and abdominal pains, dyspepsia, nausea, constipation, diarrhoea, vomiting, increase in transaminases, pruritus (incl. uncommon cases of generalised pruritus), rash, ecchymosis, cutaneous and subcutaneous haemorrhage, pain in extremity, urogenital tract haemorrhage (incl. haematuria and menorrhagiaB), renal impairment (incl. blood creatinine increased, blood urea increased), fever, peripheral oedema, decreased general strength and energy (incl. fatigue and asthenia), postprocedural haemorrhage (incl. postoperative anaemia, and wound haemorrhage), contusion, wound secretion.
See prescribing information for full details.

The extent of interactions in the paediatric population is not known. The mentioned interaction data was obtained in adults.
See prescribing information for full details.

Pregnancy: Safety and efficacy of rivaroxaban have not been established in pregnant women. Due to the potential reproductive toxicity, the intrinsic risk of bleeding and the evidence that rivaroxaban passes the placenta, this medical product is contraindicated during pregnancy.
Female adolescents of child-bearing potential should avoid becoming pregnant during treatment with rivaroxaban.
Lactation: Safety and efficacy have not been established in breast-feeding women. Data from animals indicate that rivaroxaban is secreted into milk. Therefore is contraindicated during breast-feeding. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from therapy.

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. 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.
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.
Protamine sulphate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban.

* Store the prepared suspension in an upright position.
* After reconstitution, the suspension remains stable for 14 days at room temperature.
* For children weighing <4 kg: 2.625 g of granules (equivalent to 51.7 mg rivaroxaban) supplied in one brown glass bottle, to be reconstituted with 50 mL of water.
* For children weighing ≥4 kg: 5.25 g of granules (equivalent to 103.4 mg rivaroxaban) supplied in one brown glass bottle, to be reconstituted with 100 mL of water.