Chemical formula: C₂₄H₃₀ClN₇O₄S Molecular mass: 548.06 g/mol PubChem compound: 10280735
Edoxaban interacts in the following cases:
Co-administration of naproxen and edoxaban increased bleeding time relative to either medicine alone. Naproxen had no effect on the Cmax and AUC of edoxaban. In clinical studies, co-administration of NSAIDs resulted in increased clinically relevant bleeding. Chronic use of NSAIDs with edoxaban is not recommended.
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.
Co-administration of edoxaban with the P-gp inducer rifampicin led to a decrease in mean edoxaban AUC and a shortened half-life, with possible decreases in its pharmacodynamic effects. The concomitant use of edoxaban with other P-gp inducers (e.g. phenytoin, carbamazepine, phenobarbital or St. John’s Wort) may lead to reduced edoxaban plasma concentrations. Edoxaban should be used with caution when co-administered with P-gp inducers.
Edoxaban is a substrate for the efflux transporter P-gp. In pharmacokinetic (PK) studies, concomitant administration of edoxaban with the P-gp inhibitors: ciclosporin, dronedarone, erythromycin, ketoconazole, quinidine, or verapamil resulted in increased plasma concentrations of edoxaban. Concomitant use of edoxaban with ciclosporin, dronedarone, erythromycin, or ketoconazole requires dose reduction to 30 mg once daily. Concomitant use of edoxaban with quinidine, verapamil, or amiodarone does not require dose reduction based on clinical data.
The use of edoxaban with other P-gp inhibitors including HIV protease inhibitors has not been studied.
In patients with mild to moderate hepatic impairment the recommended dose is 60 mg edoxaban once daily. Edoxaban should be used with caution in patients with mild to moderate hepatic impairment.
In patients with severe hepatic impairment edoxaban is not recommended.
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:
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.
In patients with end stage renal disease (ESRD) (CrCL <15 mL/min) or on dialysis, the use of edoxaban is not recommended.
Co-administration of ASA (100 mg or 325 mg) and edoxaban increased bleeding time relative to either medicine alone. Co-administration of high dose ASA (325 mg) increased the steady state Cmax and AUC of edoxaban by 35% and 32%, respectively. The concomitant chronic use of high dose ASA (325 mg) with edoxaban is not recommended. Concomitant administration of higher doses than 100 mg ASA should only be performed under medical supervision.
In clinical studies concomitant use of ASA (low dose ≤100 mg/day), other antiplatelet agents, and thienopyridines was permitted and resulted in approximately a 2-fold increase in major bleeding in comparison with no concomitant use, although to a similar extent in the edoxaban and warfarin groups. Co-administration of low dose ASA (≤100 mg) did not affect the peak or total exposure of edoxaban either after single dose or at steady-state. Edoxaban can be co-administered with low dose ASA (≤100 mg/day).
Co-administration of amiodarone 400 mg once daily with edoxaban 60 mg once daily increased AUC by 40% and Cmax by 66%. This was not considered clinically significant. In ENGAGE AF-TIMI 48 study in NVAF, efficacy and safety results were similar for subjects with and without concomitant amiodarone use.
Edoxaban 30 mg once daily must be administered during concomitant use with ciclosporin: Concurrent administration of a single dose of ciclosporin 500 mg with a single dose of edoxaban 60 mg increased edoxaban AUC and Cmax by 73% and 74%, respectively.
Edoxaban 60 mg once daily on days 1 to 14 with coadministration of multiple daily doses of digoxin 0.25 mg twice daily (days 8 and 9) and 0.25 mg once daily (days 10 to 14) increased the Cmax of edoxaban by 17%, with no significant effect on AUC or renal clearance at steady state. When the effects of edoxaban on digoxin PK were also examined, the Cmax of digoxin increased by approximately 28% and AUC by 7%. This was not considered clinically relevant. No dose modification is necessary when edoxaban is administered with digoxin.
Edoxaban 30 mg once daily must be administered during concomitant use with dronedarone: Dronedarone 400 mg twice daily for 7 days with a single concomitant dose of edoxaban 60 mg on Day 5 increased edoxaban AUC and Cmax by 85% and 46%, respectively.
Edoxaban 30 mg once daily must be administered during concomitant use with erythromycin: Erythromycin 500 mg four times daily for 8 days with a single concomitant dose of edoxaban 60 mg on Day 7 increased the edoxaban AUC and Cmax by 85% and 68%, respectively.
Edoxaban 30 mg once daily must be administered during concomitant use with ketoconazole: Ketoconazole 400 mg once daily for 7 days with a single concomitant dose of edoxaban 60 mg on Day 4, increased edoxaban AUC and Cmax by 87% and 89%, respectively.
Quinidine 300 mg once daily on Days 1 and 4 and three times daily on Days 2 and 3, with a single concomitant dose of edoxaban 60 mg on Day 3, increased edoxaban AUC over 24 hours by 77% and Cmax by 85%, respectively.
Verapamil 240 mg once daily for 11 days with a single concomitant dose of edoxaban 60 mg on Day 10 increased the edoxaban AUC and Cmax by approximately 53%.
Edoxaban decreased the Cmax and AUC of concomitantly administered verapamil by 14% and 16%, respectively.
Edoxaban can be initiated or continued in patients who may require cardioversion. For transoesophageal echocardiogram (TEE) guided cardioversion in patients not previously treated with anticoagulants, edoxaban treatment should be started at least 2 hours before cardioversion to ensure adequate anticoagulation. Cardioversion should be performed no later than 12 hours after the dose of edoxaban on the day of the procedure.
For all patients undergoing cardioversion: Confirmation should be sought prior to cardioversion that the patient has taken edoxaban as prescribed. Decisions on initiation and duration of treatment should follow established guidelines for anticoagulant treatment in patients undergoing cardioversion.
Haemodialysis does not significantly contribute to edoxaban clearance.
If anticoagulation must be discontinued to reduce the risk of bleeding with surgical or other procedures, edoxaban should be stopped as soon as possible and preferably at least 24 hours before the procedure.
In deciding whether a procedure should be delayed until 24 hours after the last dose of edoxaban, the increased risk of bleeding should be weighed against the urgency of the intervention. Edoxaban should be restarted after the surgical or other procedures as soon as adequate haemostasis has been established, noting that the time to onset of the edoxaban anticoagulant therapeutic effect is 1–2 hours. If oral medicinal products cannot be taken during or after surgical intervention, consider administering a parenteral anticoagulant and then switch to oral once daily edoxaban.
Edoxaban increases the risk of bleeding and can cause serious, potentially fatal bleeding. Edoxaban, like other anticoagulants, is recommended to be used with caution in patients with increased risk of bleeding. Edoxaban administration should be discontinued if severe haemorrhage occurs.
In the clinical studies mucosal bleedings (e.g. epistaxis, gastrointestinal, genitourinary) and anaemia were seen more frequently during long term edoxaban 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, 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. Any unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site.
The anticoagulant effect of edoxaban cannot be reliably monitored with standard laboratory testing. A specific anticoagulant reversal agent for edoxaban is not available.
Safety and efficacy of edoxaban have not been established in pregnant women. Studies in animals have shown reproductive toxicity. Due to the potential reproductive toxicity, the intrinsic risk of bleeding and the evidence that edoxaban passes the placenta, edoxaban is contraindicated during pregnancy.
Safety and efficacy of edoxaban have not been established in breast-feeding women. Data from animals indicate that edoxaban is secreted into breast milk. Therefore edoxaban is contraindicated during breast-feeding. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from therapy.
No specific studies with edoxaban in humans have been conducted to evaluate effects on fertility. In a study on male and female fertility in rats no effects were seen.
Women of childbearing potential should avoid becoming pregnant during treatment with edoxaban.
Edoxaban has no or negligible influence on the ability to drive and use machines.
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