4.1. Therapeutic indications

Adults

Rivaroxaban 5 mg/ml Oral Suspension is intended for:

• Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery.

• 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 more than 30 kg after at least 5 days of initial parenteral anticoagulation treatment.

4.2. Posology and method of administration

Table 1: Summary of posology per indication

Indication

Posology

Method of administration

Prevention of venous thromboembolism (VTE) in adults undergoing elective hip or knee replacement surgery.

10 mg rivaroxaban (2 ml of suspension) once daily

with water (with or without food)

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

15 mg rivaroxaban (3 ml of suspension) once daily

with food

Treatment of 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.

20 mg rivaroxaban (4 ml of suspension) once daily

with food

Prevention of stroke and systemic embolism in adults 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.

20 mg rivaroxaban (4 ml of suspension) once daily

with food

Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults.

15 mg rivaroxaban (3 ml of suspension) twice daily (day 1-21)

with food

20 mg rivaroxaban (4 ml of suspension) once daily (day 22 onwards)

Prevention of recurrent DVT and PE in adults (following completion of at least 6 months therapy for DVT or PE).

10 mg rivaroxaban (2 ml of suspension) once daily

or

20 mg

rivaroxaban (4 ml of suspension) once daily

with water (with or without food)

with food

Prevention of stroke and systemic embolism in adults with moderate or severe renal impairment (creatinine clearance 15 – 49 ml/min).

15 mg rivaroxaban (3 ml of suspension) once daily

with food

Treatment of DVT and PE, and prevention of recurrent DVT and PE in adults with moderate or severe renal impairment (creatinine clearance 15 – 49 ml/min).

15 mg rivaroxaban (3 ml of suspension) twice daily (day 1-21)

with food

15 mg rivaroxaban (3 ml of suspension) once daily (day 22 onwards)

Posology

Prevention of VTE in adult patients undergoing elective hip or knee replacement surgery

The recommended dose is 10 mg of rivaroxaban (2 ml of suspension) taken orally once daily. The initial dose should be taken 6 to 10 hours after surgery, provided that haemostasis has been established.

The duration of treatment depends on the individual risk of the patient for venous thromboembolism which is determined by the type of orthopaedic surgery.

• For patients undergoing major hip surgery, a treatment duration of 5 weeks is recommended.

• For patients undergoing major knee surgery, a treatment duration of 2 weeks is recommended

If a dose is missed the patient should take Rivaroxaban 5 mg/ml Oral Suspension immediately and then continue the following day with once daily intake as before.

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

Rivaroxaban 5 mg/ml Oral Suspension 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.

1. Body weight from 30 to 50 kg:

a once daily dose of 15 mg rivaroxaban (3 ml of suspension) is recommended.

This is the maximum daily dose.

2. For patients with body weight of 50 kg or more:

a once daily dose of 20 mg rivaroxaban (4 ml of suspension) is recommended.

This is the maximum daily dose.

3. For patients with body weight less 30 kg refer to the Summary of Product Characteristics of rivaroxaban formulation intended for paediatric population.

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 are 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.

Prevention of stroke and systemic embolism in adults

The recommended dose is 20 mg of rivaroxaban (4 ml of suspension) once daily, which is also the recommended maximum dose.

Therapy with Rivaroxaban 5 mg/ml Oral Suspension 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 Rivaroxaban 5 mg/ml Oral Suspension 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 of rivaroxaban (3 ml of suspension) twice daily for the first three weeks followed by 20 mg of rivaroxaban (4 ml of suspension) 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 of rivaroxaban (2 ml of suspension) 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 10 mg of rivaroxaban (2 ml of suspension) once daily, a dose of 20 mg of rivaroxaban (4 ml of suspension) 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).

Table 2: Treatment and prevention of recurrent DVT and PE

Time period

Dosing schedule

Total daily dose

Treatment and prevention of recurrent DVT and PE

Day 1 - 21

15 mg of rivaroxaban (3 ml of suspension) twice daily

30 mg of rivaroxaban

(6 ml of suspension)

Day 22 onwards

20 mg of rivaroxaban (4 ml of suspension) once daily

20 mg of rivaroxaban

(4 ml of suspension)

Prevention of recurrent DVT and PE

Following completion of at least 6 months therapy for DVT or PE

10 mg of rivaroxaban (2 ml of suspension) once daily or 20 mg of rivaroxaban (4 ml of suspension) once daily

10 mg or 20 mg of rivaroxaban

(2 or 4 ml of suspension)

If a dose is missed during the 15 mg of rivaroxaban (3 ml of suspension) twice daily treatment phase (day 1 - 21), the patient should take Rivaroxaban 5 mg/ml Oral Suspension immediately to ensure intake of 30 mg of rivaroxaban (6 ml of suspension) per day. In this case 30 mg of rivaroxaban (6 ml of suspension) may be taken at once. The patient should continue with the regular 15 mg of rivaroxaban (3 ml of suspension) twice daily intake as recommended on the following day.

If a dose is missed during the once daily treatment phase, the patient should take Rivaroxaban 5 mg/ml Oral Suspension 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.

Converting from Vitamin K Antagonists (VKA) to Rivaroxaban 5 mg/ml Oral Suspension

• Prevention of stroke and systemic embolism:

• VKA treatment should be stopped and Rivaroxaban 5 mg/ml Oral Suspension therapy should be initiated when the International Normalized 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 Rivaroxaban 5 mg/ml Oral Suspension therapy should be initiated once the INR is ≤ 2.5.

When converting patients from VKAs to Rivaroxaban 5 mg/ml Oral Suspension, INR values will be falsely elevated after the intake of Rivaroxaban 5 mg/ml Oral Suspension. The INR is not valid to measure the anticoagulant activity of, and therefore should not be used (see section 4.5).

Converting from Rivaroxaban 5 mg/ml Oral Suspension to Vitamin K antagonists (VKA)

There is a potential for inadequate anticoagulation during the transition from Rivaroxaban 5 mg/ml Oral Suspension to VKA. Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant. It should be noted that Rivaroxaban 5 mg/ml Oral Suspension can contribute to an elevated INR.

In patients converting from Rivaroxaban 5 mg/ml Oral Suspension 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 Rivaroxaban 5 mg/ml Oral Suspension and VKA the INR should not be tested earlier than 24 hours after the previous dose but prior to the next dose of Rivaroxaban 5 mg/ml Oral Suspension. Once Rivaroxaban 5mg/ml Oral Suspension 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 Rivaroxaban 5 mg/ml Oral Suspension to VKA need to continue Rivaroxaban 5 mg/ml Oral Suspension 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 5 mg/ml Oral Suspension. Co-administration of Rivaroxaban 5 mg/ml Oral Suspension and VKA is advised to continue until the INR is ≥ 2.0. Once Rivaroxaban 5 mg/ml Oral Suspension 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 Rivaroxaban 5 mg/ml Oral Suspension

For adult and paediatric patients currently receiving a parenteral anticoagulant, discontinue the parenteral anticoagulant and start Rivaroxaban 5 mg/ml Oral Suspension 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 Rivaroxaban 5 mg/ml Oral Suspension to parenteral anticoagulants

Discontinue Rivaroxaban 5 mg/ml Oral Suspension and give the first dose of parenteral anticoagulant at the time the next Rivaroxaban 5 mg/ml Oral Suspension dose would be taken.

Special populations

Renal impairment in 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, Rivaroxaban 5 mg/ml Oral Suspension 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).

• For the prevention of VTE in adult patients undergoing elective hip or knee replacement surgery, no dose adjustment is necessary in patients with mild renal impairment (creatinine clearance 50 – 80 ml/min) or moderate renal impairment (creatinine clearance 30- 49 ml/min) (see section 5.2).

• For the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation,

- no dose adjustment from the recommended dose is necessary in patients with mild renal impairment (creatinine clearance 50 – 80 ml/min) (see section 5.2).

- in patients with moderate (creatinine clearance 30 – 49 ml/min) or severe (creatinine clearance 15 – 29 ml/min) renal impairment: the recommended dose is 15 mg of rivaroxaban (3 ml of suspension) once daily (see section 5.2).

• For the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE,

- no dose adjustment from the recommended dose is necessary in patients with mild renal impairment (creatinine clearance 50 – 80 ml/min) (see section 5.2).

- in patients with moderate (creatinine clearance 30 – 49 ml/min) or severe (creatinine clearance 15 – 29 ml/min) renal impairment: patients should be treated with 15 mg of rivaroxaban (3 ml of suspension) twice daily for the first 3 weeks. Thereafter, when the recommended dose is 20 mg of rivaroxaban (4 ml of suspension) once daily, a reduction of the dose from 20 mg of rivaroxaban (4 ml of suspension) once daily to 15 mg of rivaroxaban (3 ml of suspension) 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 of rivaroxaban (3 ml of suspension) is based on PK modelling and has not been studied in this clinical setting (see sections 4.4, 5.1 and 5.2).

When the recommended dose is 10 mg of rivaroxaban (2 ml of suspension) once daily, no dose adjustment from the recommended dose is necessary.

Renal impairment in 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): Rivaroxaban is not recommended as no clinical data are available (see section 4.4).

Hepatic impairment

Rivaroxaban 5 mg/ml Oral Suspension 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 are available in children with hepatic impairment.

Elderly

No dose adjustment (see section 5.2).

The risk of bleeding increases with increasing age (see section 4.4).

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

Rivaroxaban 5 mg/ml Oral Suspension can be initiated or continued in patients who may require cardioversion.

For transoesophageal echocardiogram (TEE) guided cardioversion in patients not previously treated with anticoagulants, Rivaroxaban 5 mg/ml Oral Suspension 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 Rivaroxaban 5 mg/ml Oral Suspension 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 of rivaroxaban (3 ml of suspension) once daily or 10 mg of rivaroxaban (2 ml of suspension) 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).

Paediatric population

The safety and efficacy of rivaroxaban in children aged 0 to < 18 years have not been established in other indications than the treatment of VTE and prevention of VTE recurrence. 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

Rivaroxaban 5 mg/ml Oral Suspension is for oral use.

The doses of 15 and 20 mg of rivaroxaban (3 and 4 ml of suspension) must be taken with food (see section 5.2).

The dose of 10 mg of rivaroxaban (2 ml of suspension) must be taken with water (with or without food ; see section 5.2).

This medicinal product is administered orally as a “ready for-use” oral suspension using a graduated oral syringe. It may be administered directly into the mouth and followed by liquid, preferably with water.

The suspension may also be given through gastric tubes after confirmation of the correct gastric placement of the tube. The suspension should be administered in a small amount of water via a gastric tube after which it should be flushed with water (see sections 5.2 and 6.6).

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.

Instruction for use of the oral syringe

Shake the bottle before each use for five seconds. Check the prescribed dose.

4.3. Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

• Active clinically significant bleeding.

• Lesions or conditions, 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 (see section 4.2) or when UFH is given at doses necessary to maintain an open central venous or arterial catheter (see section 4.5).

• Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C (see section 5.2).

• Pregnancy and breast-feeding (see section 4.6).

4.4. Special warnings and precautions for use

Clinical surveillance in line with anticoagulation practice is recommended throughout the treatment period.

Haemorrhagic risk

As with other anticoagulants, patients taking Rivaroxaban 5 mg/ml Oral Suspension are to be carefully observed for signs of bleeding. It is recommended to be used with caution in conditions with increased risk of haemorrhage. Rivaroxaban 5 mg/ml Oral Suspension administration should be discontinued if severe haemorrhage occurs (see section 4.9).

In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary including abnormal vaginal or increased menstrual bleeding) and anaemia were seen more frequently during long term rivaroxaban treatment compared with VKA treatment. Thus, in addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit could be of value to detect occult bleeding and quantify the clinical relevance of overt bleeding, as judged to be appropriate.

Several sub-groups of patients, as detailed below, are at increased risk of bleeding. These patients are to be carefully monitored for signs and symptoms of bleeding complications and anaemia after initiation of treatment (see section 4.8).

In patients receiving Rivaroxaban 5 mg/ml Oral Suspension for VTE prevention following elective hip or knee replacement surgery, this may be done by regular physical examination of the patients, close observation of the surgical wound drainage and periodic measurements of haemoglobin. Any unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site.

Although treatment with rivaroxaban does not require routine monitoring of exposure, rivaroxaban levels measured with a calibrated quantitative anti-factor Xa assay may be useful in exceptional situations where knowledge of rivaroxaban exposure may help to inform clinical decisions, e.g. overdose and emergency surgery (see sections 5.1 and 5.2).

Paediatric population

There are 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. Rivaroxaban 5 mg/ml Oral Suspension 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).

In patients with moderate renal impairment (creatinine clearance 30 - 49 ml/min) concomitantly receiving other medicinal products which increase rivaroxaban plasma concentrations Rivaroxaban 5 mg/ml Oral Suspension is to be used with caution (see section 4.5).

Rivaroxaban 5 mg/ml Oral Suspension 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 are available.

Interaction with other medicinal products

The use of Rivaroxaban 5 mg/ml Oral Suspension 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 are available in children receiving concomitant systemic treatment with strong inhibitors of both CYP 3A4 and P-gp (see section 4.5).

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 (ASA) 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 (see section 4.5 and 5.1).

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)

• 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 (see section 4.3).

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 rivaroxaban provides adequate anticoagulation in this patient population. Treatment with Rivaroxaban 5 mg/ml Oral Suspension is not recommended for these patients.

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.

Hip fracture surgery

Rivaroxaban has not been studied in interventional clinical studies in patients undergoing hip fracture surgery to evaluate efficacy and safety.

Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary embolectomy

Rivaroxaban 5 mg/ml Oral Suspension 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.

Patients with non-valvular atrial fibrillation who undergo PCI with stent placement

Clinical data are available from an interventional study with the primary objective to assess safety in patients with non-valvular atrial fibrillation who undergo PCI with stent placement. Data on efficacy in this population are limited (see sections 4.2 and 5.1). No data are available for such patients with a history of stroke/ transient ischaemic attack (TIA).

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 or 20 mg of 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 (see section 5.2). 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 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 are available on the timing of the placement or removal of neuraxial catheter in children while on rivaroxaban. In such cases, discontinue rivaroxaban and consider a short acting parenteral anticoagulant.

Dosing recommendations before and after invasive procedures and surgical intervention other than elective hip or knee replacement surgery

If an invasive procedure or surgical intervention is required, Rivaroxaban 5 mg/ml Oral Suspension 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.

Rivaroxaban 5 mg/ml Oral Suspension 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 as determined by the treating physician (see section 5.2).

Elderly population

Increasing age may increase haemorrhagic risk (see section 5.2).

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 (see section 4.8). 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.

Excipients

Propylene glycol

This medicinal product contains 37 mg propylene glycol per 1 ml of oral suspension.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per the highest individual dose (6ml), that is to say essentially “sodium-free”.

Sodium benzoate

This medicinal product contains 2.5 mg sodium benzoate per 1 ml.

Maltitol

Patients with rare hereditary problems of fructose intolerance should not take this medicinal product.

Sorbitol

This medicinal product contains 50 mg liquid sorbitol per 1 ml of oral suspension. Patients with hereditary fructose intolerance (HFI) should not take/be given this medicinal product.

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 were obtained in adults and the warnings in section 4.4 should be taken into account for the paediatric population.

CYP3A4 and P-gp inhibitors

Co-administration of rivaroxaban with ketoconazole (400 mg once a day) or ritonavir (600 mg twice a day) led to a 2.6 fold / 2.5 fold increase in mean rivaroxaban AUC and a 1.7 fold / 1.6 fold increase in mean rivaroxaban Cmax, with significant increases in pharmacodynamic effects which may lead to an increased bleeding risk. Therefore, the use of Rivaroxaban 5 mg/ml Oral Suspension is not recommended in patients receiving concomitant systemic treatment with azole-antimycotics such as ketoconazole, itraconazole, voriconazole and posaconazole or HIV protease inhibitors. These active substances are strong inhibitors of both CYP3A4 and P-gp (see section 4.4).

Active substances strongly inhibiting only one of the rivaroxaban elimination pathways, either CYP3A4 or P-gp, are expected to increase rivaroxaban plasma concentrations to a lesser extent. Clarithromycin (500 mg twice a day), for instance, considered as a strong CYP3A4 inhibitor and moderate P-gp inhibitor, led to a 1.5 fold increase in mean rivaroxaban AUC and a 1.4 fold increase in Cmax. The interaction with clarithromycin is likely not clinically relevant in most patients but can be potentially significant in high-risk patients. (For patients with renal impairment: see section 4.4).

Erythromycin (500 mg three times a day), which inhibits CYP3A4 and P-gp moderately, led to a 1.3 fold increase in mean rivaroxaban AUC and Cmax. The interaction with erythromycin is likely not clinically relevant in most patients but can be potentially significant in high-risk patients.

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 Cmax 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 Cmax 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 Cmax. The interaction with fluconazole is likely not clinically relevant in most patients but can be potentially significant in high-risk patients. (For patients with renal impairment: see section 4.4).

Given the limited clinical data available with dronedarone, co-administration with rivaroxaban should be avoided.

Anticoagulants

After combined administration of enoxaparin (40 mg single dose) with rivaroxaban (10 mg single dose) an additive effect on anti-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).

NSAIDs/platelet aggregation inhibitors

No clinically relevant prolongation of bleeding time was observed after concomitant administration of rivaroxaban (15 mg) and 500 mg naproxen. Nevertheless, there may be individuals with a more pronounced pharmacodynamic response.

No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when rivaroxaban was co-administered with 500 mg acetylsalicylic acid.

Clopidogrel (300 mg loading dose followed by 75 mg maintenance dose) did not show a pharmacokinetic interaction with rivaroxaban (15 mg) but a relevant increase in bleeding time was observed in a subset of patients which was not correlated to platelet aggregation, P-selectin or GPIIb/IIIa receptor levels.

Care is to be taken if patients are treated concomitantly with NSAIDs (including acetylsalicylic acid) and platelet aggregation inhibitors because these medicinal products typically increase the bleeding risk (see section 4.4).

SSRIs/SNRIs

As with other anticoagulants the possibility may exist that patients are at increased risk of bleeding in case of concomitant use with SSRIs or SNRIs due to their reported effect on platelets. When concomitantly used in the rivaroxaban clinical programme, numerically higher rates of major or non-major clinically relevant bleeding were observed in all treatment groups.

Warfarin

Converting patients from the vitamin K antagonist warfarin (INR 2.0 to 3.0) to rivaroxaban (20 mg) or from rivaroxaban (20 mg) to warfarin (INR 2.0 to 3.0) increased prothrombin time/INR (Neoplastin) more than additively (individual INR values up to 12 may be observed), whereas effects on aPTT, inhibition of factor Xa activity and endogenous thrombin potential were additive.

If it is desired to test the pharmacodynamic effects of rivaroxaban during the conversion period, anti-factor Xa activity, PiCT, and Heptest can be used as these tests were not affected by warfarin. On the fourth day after the last dose of warfarin, all tests (including PT, aPTT, inhibition of factor Xa activity and ETP) reflected only the effect of rivaroxaban.

If it is desired to test the pharmacodynamic effects of warfarin during the conversion period, INR measurement can be used at the Ctrough of rivaroxaban (24 hours after the previous intake of rivaroxaban) as this test is minimally affected by rivaroxaban at this time point.

No pharmacokinetic interaction was observed between warfarin and rivaroxaban.

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 (Hypericum perforatum)) may also lead to reduced rivaroxaban plasma concentrations. Therefore, concomitant administration of strong CYP3A4 inducers should be avoided unless the patient is closely observed for signs and symptoms of thrombosis.

Other concomitant therapies

No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when rivaroxaban was co-administered with midazolam (substrate of CYP3A4), digoxin (substrate of P-gp), atorvastatin (substrate of CYP3A4 and P-gp) or omeprazole (proton pump inhibitor). Rivaroxaban neither inhibits nor induces any major CYP isoforms like CYP3A4.

No clinically relevant interaction with food was observed for the dose of 10 mg of rivaroxaban (2 ml of suspension) (see section 4.2).

Laboratory parameters

Clotting parameters (e.g. PT, aPTT, HepTest) are affected as expected by the mode of action of rivaroxaban (see section 5.1).

4.6. Fertility, pregnancy and lactation

Pregnancy

Safety and efficacy of rivaroxaban have not been established in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Due to the potential reproductive toxicity, the intrinsic risk of bleeding and the evidence that rivaroxaban passes the placenta, this medicinal product is contraindicated during pregnancy (see section 4.3).

Women of child-bearing potential should avoid becoming pregnant during treatment with rivaroxaban.

Breast-feeding

Safety and efficacy of rivaroxaban have not been established in breast-feeding women. Data from animals indicate that rivaroxaban is secreted into milk. Therefore this medicinal product is contraindicated during breast-feeding (see section 4.3). A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from therapy.

Fertility

No specific studies with rivaroxaban in humans have been conducted to evaluate effects on fertility. In a study on male and female fertility in rats no effects were seen (see section 5.3).

4.7. Effects on ability to drive and use machines

Rivaroxaban has minor influence on the ability to drive and use machines. Adverse reactions like syncope (frequency: uncommon) and dizziness (frequency: common) have been reported (see section 4.8). Patients experiencing these adverse reactions should not drive or use machines.

4.8. Undesirable effects

Summary of the safety profile

The safety of rivaroxaban has been evaluated in thirteen pivotal phase III studies (see Table 3).

Overall, 69 608 adult patients in nineteen phase III studies and 488 paediatric patients in two phase II and two phase III studies were exposed to rivaroxaban.

Table 3: Number of patients studied, total daily dose and maximum treatment duration in adult and paediatric phase III studies

Indication

Number of patients*

Total daily dose

Maximum treatment duration

Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery

6 097

10 mg

39 days

Prevention of VTE in medically ill patients

3 997

10 mg

39 days

Treatment of deep vein thrombosis (DVT), pulmonary embolism (PE) and prevention of recurrence

6 790

Day 1 - 21: 30 mg Day 22 and onwards: 20 mg

After at least 6 months: 10 mg or 20 mg

21 months

Treatment of VTE and prevention of VTE recurrence in term neonates and children aged less than 18 years following initiation of standard anticoagulation treatment

329

Body weight-adjusted dose to achieve a similar exposure as that observed in adults treated for DVT with 20 mg rivaroxaban once daily

12 months

Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation

7 750

20 mg

41 months

Prevention of atherothrombotic events in patients after an ACS

10 225

5 mg or 10 mg respectively, co- administered with either ASA or ASA plus clopidogrel or ticlopidine

31 months

Prevention of atherothrombotic events in patients with CAD/PAD

18 244

5 mg co-administered with ASA or 10 mg alone

47 months

3 256**

5 mg co-administered with ASA

42 months

*Patients exposed to at least one dose of rivaroxaban

** From the VOYAGER PAD study

The most commonly reported adverse reactions in patients receiving rivaroxaban were bleedings (see section 4.4 and 'Description of selected adverse reactions' below) (Table 4). The most commonly reported bleedings were epistaxis (4.5%) and gastrointestinal tract haemorrhage (3.8%).

Table 4: Bleeding* and anaemia events rates in patients exposed to rivaroxaban across the completed adult and paediatric phase III studies

Indication

Any bleeding

Anaemia

Prevention of VTE in adult patients undergoing elective hip or knee replacement surgery

6.8% of patients

5.9% of patients

Prevention of VTE in medically ill patients

12.6% of patients

2.1% of patients

Treatment of DVT, PE and prevention of recurrence

23% of patients

1.6% of patients

Treatment of VTE and prevention of VTE recurrence in term neonates and children aged less than 18 years following initiation of standard anticoagulation treatment

39.5% of patients

4.6% of patients

Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation

28 per 100 patient years

2.5 per 100 patient years

Prevention of atherothrombotic events in patients after an ACS

22 per 100 patient years

1.4 per 100 patient years

Prevention of atherothrombotic events in patients with CAD/PAD

6.7 per 100 patient years

0.15 per 100 patient years**

8.38 per 100 patient years#

0.74 per 100 patient years***#

* For all rivaroxaban studies all bleeding events are collected, reported and adjudicated.

** In the COMPASS study, there is a low anaemia incidence as a selective approach to adverse event collection was applied.

*** A selective approach to adverse event collection was applied

# From the VOYAGER PAD study

Tabulated list of adverse reactions

The frequencies of adverse reactions reported with rivaroxaban in adult and paediatric patients are summarised in Table 5 below by system organ class (in MedDRA) and by frequency.

Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare ( < 1/10 000), not known (cannot be estimated from the available data).

Table 5: All adverse reactions reported in adult patients in phase III clinical studies or through post- marketing use* and in two phase II and two phase III studies in paediatric patients

Common

Uncommon

Rare

Very rare

Not known

Blood and lymphatic system disorders

Anaemia (incl. respective laboratory parameters)

Thrombocytosis (incl. platelet count increased)A, thrombocytopenia

Immune system disorders

Allergic reaction, dermatitis allergic, angioedema and allergic oedema

Anaphylactic reactions including anaphylactic shock

Nervous system disorders

Dizziness, headache

Cerebral and intracranial haemorrhage, syncope

Eye disorders

Eye haemorrhage (incl. conjunctival haemorrhage)

Cardiac disorders

Tachycardia

Vascular disorders

Hypotension, haematoma

Respiratory, thoracic and mediastinal disorders

Epistaxis, haemoptysis

Eosinophilic pneumonia

Gastrointestinal disorders

Gingival bleeding, gastrointestinal tract haemorrhage (incl. rectal haemorrhage), gastrointestinal and abdominal pains, dyspepsia, nausea, constipationA, diarrhoea, vomitingA

Dry mouth

Hepatobiliary disorders

Increase in transaminases

Hepatic impairment, increased bilirubin, increased blood alkaline phosphataseA, increased GGTA

Jaundice, bilirubin conjugated increased (with or without concomitant increase of ALT), cholestasis, hepatitis (incl. hepatocellular injury)

Skin and subcutaneous tissue disorders

Pruritus (incl. uncommon cases of generalised pruritus), rash, ecchymosis, cutaneous and subcutaneous haemorrhage

Urticaria

Stevens-Johnson syndrome/ Toxic Epidermal Necrolysis, DRESS syndrome

Musculoskeletal and connective tissue disorders

Pain in extremityA

Haemarthrosis

Muscle haemorrhage

Compartment syndrome secondary to a bleeding

Renal and urinary disorders

Urogenital tract haemorrhage (incl. haematuria and menorrhagiaB), renal impairment (incl. blood creatinine increased, blood urea increased)

Renal failure/acute renal failure secondary to a bleeding sufficient to cause hypoperfusion, Anticoagulant related nephropathy

General disorders and administration site conditions

FeverA, peripheral oedema, decreased general strength and energy (incl. fatigue and asthenia)

Feeling unwell (incl. malaise)

Localised oedemaA

Investigations

Increased LDHA, increased lipaseA, increased amylaseA

Injury, poisoning and procedural complications

Postprocedural haemorrhage (incl. postoperative anaemia, and wound haemorrhage), contusion, wound secretionA

Vascular pseudoaneurysmC

A: observed in prevention of VTE in adult patients undergoing elective hip or knee replacement surgery

B: observed in treatment of DVT, PE and prevention of recurrence as very common in women < 55 years

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

* 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 reaction was identified after analysis of these studies.

Description of selected adverse reactions

Due to the pharmacological mode of action, the use of rivaroxaban may be associated with an increased risk of occult or overt bleeding from any tissue or organ which may result in post haemorrhagic anaemia. The signs, symptoms, and severity (including fatal outcome) will vary according to the location and degree or extent of the bleeding and/or anaemia (see section 4.9 Management of bleeding). In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary including abnormal vaginal or increased menstrual bleeding) and anaemia were seen more frequently during long term rivaroxaban treatment compared with VKA treatment. Thus, in addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit could be of value to detect occult bleeding and quantify the clinical relevance of overt bleeding, as judged to be appropriate. The risk of bleedings may be increased in certain patient groups e.g. those patients with uncontrolled severe arterial hypertension and/or on concomitant treatment affecting haemostasis (see section 4.4 “Haemorrhagic risk”). Menstrual bleeding may be intensified and/or prolonged.

Haemorrhagic complications may present as weakness, paleness, dizziness, headache or unexplained swelling, dyspnoea and unexplained shock. In some cases as a consequence of anaemia, symptoms of cardiac ischaemia like chest pain or angina pectoris have been observed.

Known complications secondary to severe bleeding such as compartment syndrome and renal failure due to hypoperfusion, or anticoagulant-related nephropathy have been reported for rivaroxaban. Therefore, the possibility of haemorrhage is to be considered in evaluating the condition in any anticoagulated patient.

Paediatric population

Treatment of VTE and prevention of VTE recurrence

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.

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 the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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 are 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 are 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 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.