Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Berlin-Chemie AG, Glienicker Weg 125, 12489 Berlin, Germany
Roteas is indicated in prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation (NVAF) with one or more risk factors, such as congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke or transient ischaemic attack (TIA).
Roteas is indicated in treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and for the prevention of recurrent DVT and PE in adults (see section 4.4 for haemodynamically unstable PE patients).
The recommended dose is 60 mg edoxaban once daily.
Therapy with edoxaban in NVAF patients should be continued long term.
The recommended dose is 60 mg edoxaban once daily following initial use of parenteral anticoagulant for at least 5 days (see section 5.1). Edoxaban and initial parenteral anticoagulant should not be administered simultaneously.
The duration of therapy for treatment of DVT and PE (venous thromboembolism (VTE)), and prevention of recurrent VTE should be individualised after careful assessment of the treatment benefit against the risk for bleeding (see section 4.4). Short duration of therapy (at least 3 months) should be based on transient risk factors (e.g. recent surgery, trauma, immobilisation) and longer durations should be based on permanent risk factors or idiopathic DVT or PE.
For NVAF and VTE the recommended dose is 30 mg edoxaban once daily in patients with one or more of the following clinical factors:
Table 1. Summary of posology in NVAF and VTE (DVT and PE):
| Summary guide for dosing | ||
|---|---|---|
| Recommended dose | 60 mg edoxaban once daily | |
| Dose recommendation for patients with one or more of the following clinical factors: | ||
| Renal impairment | Moderate or severe (CrCl 15–50 mL/min) | 30 mg edoxaban once daily |
| Low body weight | ≤60 kg | |
| P-gp inhibitors | Ciclosporin, dronedarone, erythromycin, ketoconazole | |
If a dose of edoxaban is missed, the dose should be taken immediately and then be continued the following day with the once-daily intake as recommended. The patient should not take double the prescribed dose on the same day to make up for a missed dose.
Continued anticoagulant therapy is important in patients with NVAF and VTE. There may be situations that warrant a change in anticoagulation therapy (Table 2).
Table 2. Switching of anticoagulant treatment in NVAF and VTE (DVT and PE):
| Switching to edoxaban | ||
| From | To | Recommendation |
| Vitamin K antagonist (VKA) | Edoxaban | Discontinue the VKA and start edoxaban when the international normalised ratio (INR) is ≤2.5. |
| Oral anticoagulants other than VKA • dabigatran • rivaroxaban • apixaban | Edoxaban | Discontinue dabigatran, rivaroxaban or apixaban and start edoxaban at the time of the next dose of the oral anticoagulant (see section 5.1). |
| Parenteral anticoagulants | Edoxaban | These medicinal products should not be administered simultaneously. Subcutaneous anticoagulant (i.e. low molecular weight heparin (LMWH), fondaparinux): Discontinue subcutaneous anticoagulant and start edoxaban at the time of the next scheduled subcutaneous anticoagulant dose. |
| Intravenous unfractionated heparin (UFH): Discontinue the infusion and start edoxaban 4 hours later. | ||
| Switching from edoxaban | ||
| From | To | Recommendation |
| Edoxaban | VKA | There is a potential for inadequate anticoagulation during the transition from edoxaban to VKA. Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant. Oral option: For patients currently on a 60 mg dose, administer an edoxaban dose of 30 mg once daily together with an appropriate VKA dose. For patients currently on a 30 mg dose (for one or more of the following clinical factors: moderate to severe renal impairment (CrCl 15–50 mL/min), low body weight, or use with certain P-gp inhibitors), administer an edoxaban dose of 15 mg once daily together with an appropriate VKA dose. Patients should not take a loading dose of VKA in order to promptly achieve a stable INR between 2 and 3. It is recommended to take into account the maintenance dose of VKA and if the patient was previously taking a VKA or to use valid INR driven VKA treatment algorithm, in accordance with local practice. Once an INR ≥2.0 is achieved, edoxaban should be discontinued. Most patients (85%) should be able to achieve an INR ≥2.0 within 14 days of concomitant administration of edoxaban and VKA. After 14 days it is recommended that edoxaban is discontinued and the VKA continued to be titrated to achieve an INR between 2 and 3. It is recommended that during the first 14 days of concomitant therapy the INR is measured at least 3 times just prior to taking the daily dose of edoxaban to minimise the influence of edoxaban on INR measurements. Concomitant edoxaban and VKA can increase the INR post edoxaban dose by up to 46%. Parenteral option: Discontinue edoxaban and administer a parenteral anticoagulant and VKA at the time of the next scheduled edoxaban dose. Once a stable INR of ≥2.0 is achieved, the parenteral anticoagulant should be discontinued and the VKA continued. |
| Edoxaban | Oral anticoagulants other than VKA | Discontinue edoxaban and start the non-VKA anticoagulant at the time of the next scheduled dose of edoxaban. |
| Switching from edoxaban | ||
| From | To | Recommendation |
| Edoxaban | Parenteral anticoagulants | These medicinal products should not be administered simultaneously. Discontinue edoxaban and start the parenteral anticoagulant at the time of the next scheduled dose of edoxaban. |
No dose reduction is required (see section 5.2).
Renal function should be assessed in all patients by calculating the CrCl prior to initiation of treatment with edoxaban to exclude patients with end stage renal disease (i.e. CrCl <15 mL/min), to use the correct edoxaban dose in patients with CrCl 15–50 mL/min (30 mg once daily), in patients with CrCl >50 mL/min (60 mg once daily) and when deciding on the use of edoxaban in patients with increased CrCl (see section 4.4).
Renal function should also be assessed when a change in renal function is suspected during treatment (e.g. hypovolaemia, dehydration, and in case of concomitant use of certain medicinal products).
The method used to estimate renal function (CrCl in mL/min) during the clinical development of edoxaban was the Cockcroft-Gault method. The formula is as follows:
For creatinine in µmol/L:
1.23 × (140-age [years]) × weight [kg] (× 0.85 if female) / serum creatinine [µmol/L]
For creatinine in mg/dL:
(140-age [years]) × weight [kg] (× 0.85 if female) / 72 × serum creatinine [mg/dL]
This method is recommended when assessing patients' CrCl prior to and during edoxaban treatment.
In patients with mild renal impairment (CrCl >50–80 mL/min), the recommended dose is 60 mg edoxaban once daily.
In patients with moderate or severe renal impairment (CrCl 15–50 mL/min), the recommended dose is 30 mg edoxaban once daily (see section 5.2).
In patients with end stage renal disease (ESRD) (CrCl <15 mL/min) or on dialysis, the use of edoxaban is not recommended (see sections 4.4 and 5.2).
Edoxaban is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk (see section 4.3).
In patients with severe hepatic impairment edoxaban is not recommended (see sections 4.4 and 5.2).
In patients with mild to moderate hepatic impairment the recommended dose is 60 mg edoxaban once daily (see section 5.2). Edoxaban should be used with caution in patients with mild to moderate hepatic impairment (see section 4.4).
Patients with elevated liver enzymes (alanine aminotransferase (ALT) or aspartate transaminase (AST) >2 x upper limit of normal (ULN)) or total bilirubin ≥1.5 x ULN, were excluded in clinical studies. Therefore edoxaban should be used with caution in this population (see sections 4.4 and 5.2). Prior to initiating edoxaban, liver function testing should be performed.
For patients with body weight ≤ 60 kg, the recommended dose is 30 mg edoxaban once daily (see section 5.2).
No dose reduction is required (see section 5.2).
In patients concomitantly taking Roteas and the following P-gp inhibitors: ciclosporin, dronedarone, erythromycin, or ketoconazole, the recommended dose is 30 mg Roteas once daily (see section 4.5). No dose reduction is required for concomitant use of amiodarone, quinidine or verapamil (see section 4.5).
The use of Roteas with other P-gp inhibitors including HIV protease inhibitors has not been studied.
Roteas can be initiated or continued in patients who may require cardioversion. For transoesophageal echocardiogram (TEE) guided cardioversion in patients not previously treated with anticoagulants, Roteas treatment should be started at least 2 hours before cardioversion to ensure adequate anticoagulation (see sections 5.1 and 5.2). Cardioversion should be performed no later than 12 hours after the dose of Roteas on the day of the procedure.
For all patients undergoing cardioversion: Confirmation should be sought prior to cardioversion that the patient has taken Roteas as prescribed. Decisions on initiation and duration of treatment should follow established guidelines for anticoagulant treatment in patients undergoing cardioversion.
The safety and efficacy of edoxaban in children and adolescents less than 18 years of age have not been established. No data are available.
For oral use.
Edoxaban can be taken with or without food (see section 5.2).
For patients who are unable to swallow whole tablets, Roteas tablets may be crushed and mixed with water or apple puree and immediately administered orally (see section 5.2).
Alternatively, Roteas tablets may be crushed and suspended in a small amount of water and immediately delivered through a gastric tube after which it should be flushed with water (see section 5.2). Crushed Roteas tablets are stable in water and apple puree for up to 4 hours.
Overdose with edoxaban may lead to haemorrhage. Experience with overdose cases is very limited.
A specific antidote antagonising the pharmacodynamic effect of edoxaban is not available.
Early administration of activated charcoal may be considered in case of edoxaban overdose to reduce absorption. This recommendation is based on standard treatment of medicinal product overdose and data available with similar compounds, as the use of activated charcoal to reduce absorption of edoxaban has not been specifically studied in the edoxaban clinical programme.
Should a bleeding complication arise in a patient receiving edoxaban, the next edoxaban administration should be delayed or treatment should be discontinued as appropriate. Edoxaban has a half-life of approximately 10 to 14 hours (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.
For life-threatening bleeding that cannot be controlled with the measures such as transfusion or haemostasis, the administration of a 4-factor prothrombin complex concentrate (PCC) at 50 IU/kg has been shown to reverse the effects of edoxaban 30 minutes after completing the infusion.
Recombinant factor VIIa (r-FVIIa) can also be considered. However, there is limited clinical experience with the use of this product in individuals receiving edoxaban.
Depending on local availability, a consultation with a coagulation expert should be considered in case of major bleedings.
Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of edoxaban.
There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving edoxaban. There is neither scientific rationale for benefit nor experience with the use of systemic haemostatics (desmopressin, aprotinin) in individuals receiving edoxaban. Due to the high plasma protein binding edoxaban is not expected to be dialysable.
5 years.
This medicinal product does not require any special storage conditions.
Roteas 15 mg film-coated tablets:
PVC/Aluminium blisters in cartons of 10 film-coated tablets.
PVC/Aluminium perforated unit dose blisters in cartons of 10 × 1 film-coated tablets.
Roteas 30 mg film-coated tablets:
PVC/Aluminium blisters in cartons of 10, 14, 28, 30, 56, 60, 84, 90, 98, 100 film-coated tablets.
PVC/Aluminium perforated unit dose blisters in cartons of 10 × 1, 50 × 1 and 100 × 1 film-coated tablets.
HDPE bottles with a PP screw cap containing 90 film-coated tablets.
Roteas 60 mg film-coated tablets:
PVC/Aluminium blisters in cartons of 10, 14, 28, 30, 56, 60, 84, 90, 98, 100 film-coated tablets.
PVC/Aluminium perforated unit dose blisters in cartons of 10 × 1, 50 × 1 and 100 × 1 film-coated tablets.
HDPE bottles with a PP screw cap containing 90 film-coated tablets.
Not all pack sizes may be marketed.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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