Edoxadar

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Edoxadar (Edoxadar)

Composition:

Active substance: edoxaban;

One film-coated tablet contains edoxaban 30.000 mg, equivalent to 40.410 mg of edoxaban tosylate monohydrate, or 60.000 mg, equivalent to 80.820 mg of edoxaban tosylate monohydrate.

Excipients: mannitol (E 421), hydroxypropylcellulose, crospovidone, pregelatinized starch (corn), colloidal anhydrous silicon dioxide, magnesium stearate; coating:

30 mg tablets: sodium carmellose; maltodextrin; glucose monohydrate; lecithin (soy); calcium carbonate; iron oxide red (E 172);

60 mg tablets: sodium carmellose; maltodextrin; glucose monohydrate; lecithin (soy); calcium carbonate; iron oxide yellow (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

30 mg tablets: pink, round-shaped, film-coated tablets, embossed with "30" on one side and smooth on the other side;

60 mg tablets: yellow, round-shaped, film-coated tablets, embossed with "60" on one side and smooth on the other side.

Pharmacotherapeutic group. Antithrombotic agents. Direct factor Xa inhibitors. Edoxaban. ATC code B01AF03.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Edoxaban is a highly selective, direct, reversible inhibitor of factor Xa, a serine protease that is the final common pathway in the coagulation cascade. Edoxaban inhibits free factor Xa and prothrombinase activity. Inhibition of factor Xa in the coagulation cascade leads to reduced thrombin generation, prolongs blood clotting time, and reduces the risk of thrombus formation.

Pharmacodynamic Effects

Edoxaban produces a rapid onset of pharmacodynamic effect within 1–2 hours, corresponding to the time of maximum plasma concentration (Cmax) of edoxaban. Pharmacodynamic effects, measured by anti-factor Xa activity assays, are predictable and correlate with the dose and plasma concentration of edoxaban. As a result of factor Xa inhibition, edoxaban also prolongs clotting times in prothrombin time (PT) and activated partial thromboplastin time (aPTT) tests. Changes in clotting parameters observed with therapeutic doses are minor and variable; therefore, these parameters are not recommended for monitoring the anticoagulant effect of edoxaban.

Effect of coagulation markers when switching from rivaroxaban, dabigatran, or apixaban to edoxaban

In clinical pharmacological studies, healthy subjects received rivaroxaban 20 mg once daily, dabigatran 150 mg twice daily, or apixaban 5 mg twice daily, followed by a single dose of edoxaban 60 mg on Day 4. The effects on PT and other coagulation biomarkers (e.g., anti-factor Xa activity, aPTT) were assessed. On Day 4 after switching to edoxaban, PT values were equivalent to those observed on Day 3 of rivaroxaban and apixaban treatment. aPTT values were higher after edoxaban administration following prior dabigatran treatment compared to edoxaban alone. This is considered to be due to the residual effect of dabigatran; however, this did not result in prolonged bleeding time.

Based on these data, when switching from these anticoagulants to edoxaban, the first dose of edoxaban can be administered in place of the next scheduled dose of the previous anticoagulant.

Clinical Efficacy and Safety

Prevention of Stroke and Systemic Embolism

The clinical trial program evaluating edoxaban in atrial fibrillation was designed to demonstrate the efficacy and safety of two edoxaban dose regimens compared with warfarin for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and moderate to high risk of stroke and systemic embolic events. The primary efficacy endpoint was a composite of stroke and systemic embolism. Secondary efficacy endpoints included: composite of stroke, systemic embolism, and cardiovascular death; major adverse cardiovascular events (MACE), defined as a composite of non-fatal myocardial infarction (MI), non-fatal stroke, non-fatal systemic embolic event, and death from cardiovascular causes or bleeding; and composite of stroke, systemic embolic event, and death from any cause.

The primary efficacy analysis aimed to demonstrate that edoxaban was non-inferior to warfarin regarding the primary endpoint of stroke or systemic embolic events occurring during treatment or within three days after the last dose in the modified intent-to-treat population. Edoxaban 60 mg demonstrated non-inferior efficacy compared to warfarin for the primary efficacy endpoint—stroke or systemic embolic event.

The primary safety endpoint was major bleeding.

A significant reduction in the risk of major bleeding, intracranial hemorrhage, and other types of bleeding was observed in the edoxaban 60 mg group compared to the warfarin group.

The edoxaban 60 mg treatment group also showed a significant reduction in fatal bleeding compared to the warfarin group, primarily due to a reduction in fatal intracranial hemorrhages.

Treatment of Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE), and Prevention of Recurrent DVT and PE [VTE (Venous Thromboembolism)]

The clinical trial program for edoxaban in VTE was designed to demonstrate the efficacy and safety of edoxaban for the treatment of DVT and PE and for the prevention of recurrent DVT and PE.

The study demonstrated that edoxaban was non-inferior to warfarin for the primary efficacy endpoint—recurrent VTE.

Efficacy results in pre-specified major subgroups (with dose reduction as needed), including age, body weight, sex, and renal function, were consistent with the overall efficacy results in the entire trial population.

The primary safety endpoint was clinically relevant bleeding (major or non-major but clinically relevant).

In the edoxaban group, there was a significant reduction in the risk of clinically relevant bleeding, major bleeding, and clinically relevant non-major bleeding compared to warfarin.

Prevention of Stroke and Systemic Embolism in Patients with NVAF and Creatinine Clearance (CrCl) > 100 mL/min

Based on the collective data from patients with NVAF and high CrCl (> 100 mL/min) receiving edoxaban 60 mg, the expected annual rate of ischemic stroke/systemic embolism is ≤ 1%. Increasing the dose of edoxaban (above 60 mg) in patients with NVAF and high CrCl (> 100 mL/min) does not provide additional protection against stroke and may be associated with increased adverse effects. Therefore, a dosing regimen of edoxaban 60 mg once daily is recommended for these patients after careful assessment of individual thromboembolic and bleeding risk.

Patients Undergoing Cardioversion

During clinical trials, a low incidence of major and clinically relevant non-major bleeding and thromboembolic events was observed in patients undergoing cardioversion.

Pediatric Population

The European Medicines Agency has deferred the obligation to submit the results of edoxaban studies in one or more pediatric subgroups for the prevention of arterial thromboembolism, treatment of thromboembolism, and prevention of thromboembolism (see section "Posology and Method of Administration").

Pharmacokinetics

Absorption. Maximum plasma concentration of edoxaban is achieved within 1–2 hours after administration. Absolute bioavailability is approximately 62%. Food intake increases peak exposure variably but has minimal effect on overall exposure. Edoxaban was studied both with and without food. Edoxaban has poor solubility at pH levels of 6.0 or higher. Concomitant use of proton pump inhibitors does not have a significant effect on the exposure of edoxaban.

Distribution. Edoxaban exhibits biphasic distribution. The mean volume of distribution is 107 L (standard deviation 19.9 L).

Plasma protein binding in vitro is approximately 55%. There is no clinically significant accumulation of edoxaban (accumulation ratio 1.14) with once-daily dosing. Steady-state concentrations are achieved within 3 days.

Metabolism. Edoxaban is predominantly present unchanged in plasma. It is metabolized via hydrolysis (mediated by carboxylesterase 1), conjugation, or oxidation by CYP3A4/5 (< 10%). Edoxaban has three active metabolites, the main one (M-4) formed via hydrolysis, which is active and accounts for less than 10% of the parent drug concentration in healthy subjects. Concentrations of other metabolites are less than 5%. Edoxaban is a substrate of the efflux transporter P-glycoprotein (P-gp) but is not a substrate of uptake transporters such as organic anion transporting polypeptide OATP1B1, organic anion transporters OAT1 or OAT3, or organic cation transporter OCT2. Its active metabolite is a substrate of OATP1B1.

Elimination. In healthy subjects, the calculated total clearance is 22 (± 3) L/h; 50% of the drug is excreted renally (11 L/h). Renal clearance accounts for approximately 35% of the administered dose. The remainder is cleared via metabolism and biliary/intestinal excretion. The elimination half-life after oral administration is 10–14 hours.

Linearity. Edoxaban exhibits approximately dose-proportional pharmacokinetics over the dose range of 15 mg to 60 mg.

Special Populations

Elderly Patients

Population pharmacokinetic analysis, adjusted for renal function and body weight, showed that patient age has no additional clinically significant effect on the pharmacokinetics of edoxaban.

Renal Impairment

The AUC (area under the concentration-time curve) in patients with mild (CrCl > 50–80 mL/min), moderate (CrCl 30–50 mL/min), and severe (CrCl < 30 mL/min, not on dialysis) renal impairment was increased by 32%, 74%, and 72%, respectively, compared to patients with normal renal function. In patients with renal impairment, the metabolite profile is altered, with increased formation of active metabolites.

A linear correlation between plasma edoxaban concentration and anti-factor Xa activity was observed, independent of renal function.

Patients with end-stage renal disease undergoing peritoneal dialysis had 93% higher total exposure compared to healthy subjects.

Population pharmacokinetic modeling indicates that exposure is approximately doubled in patients with severe renal impairment compared to those with normal renal function.

Anti-Factor Xa Activity vs. CrCl

Edoxaban therapy does not require routine monitoring; however, the anticoagulant effect can be assessed using a calibrated quantitative anti-factor Xa assay, which may be useful in exceptional circumstances where information on edoxaban exposure may assist clinical decision-making, such as in overdose or emergency surgery.

After a 4-hour hemodialysis session, total edoxaban exposure was reduced by less than 9%.

Hepatic Impairment

Pharmacokinetic and pharmacodynamic parameters in patients with mild or moderate hepatic impairment were similar to those observed in healthy control subjects. The use of edoxaban in patients with severe hepatic impairment has not been studied.

Sex

Population pharmacokinetic analysis showed that patient sex has no additional clinically significant effect on the pharmacokinetics of edoxaban.

Ethnic Origin

Population pharmacokinetic analysis showed that maximum and total exposure in Asian patients and non-Asian patients were comparable.

Body Weight

Population pharmacokinetic analysis showed that in patients with low body weight (55 kg), Cmax and AUC were increased by 40% and 13%, respectively, compared to patients with average body weight (84 kg). In a clinical trial (for NVAF and VTE indications), patients with body weight ≤ 60 kg received a 50% reduced dose of edoxaban and demonstrated comparable efficacy and fewer bleeding events compared to warfarin.

Pharmacokinetic/Pharmacodynamic Relationship

PT, INR (International Normalized Ratio), aPTT, and anti-factor Xa activity showed linear correlation with edoxaban concentration.

Clinical Characteristics

Indications

• For the prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF) and one or more risk factors such as congestive heart failure, hypertension, diabetes mellitus, prior stroke or transient ischemic attack (TIA), or age ≥75 years.
• For the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as for the prevention of recurrent DVT and PE in adults (see section "Special Warnings and Precautions for Use" regarding patients with PE who have hemodynamically unstable conditions).

Contraindications

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
• Clinically significant active bleeding.
• Liver disease associated with coagulopathy and a clinically relevant bleeding risk.
• Lesions or conditions associated with a significant risk of bleeding, including current or recent peptic ulcer disease of the gastrointestinal tract, presence of malignant neoplasms with a high bleeding risk, recent head or spinal trauma, recent surgery on the brain, spinal cord or eyes, recent intracranial hemorrhage, diagnosed or suspected esophageal varices, arteriovenous malformations, vascular aneurysms, or severe intraspinal or intracranial vascular anomalies.
• Uncontrolled severe hypertension.
• Concomitant use of any other anticoagulants, such as unfractionated heparin (UFH), low molecular weight heparins (LMWH) (e.g., enoxaparin, dalteparin), heparin derivatives (e.g., fondaparinux), or oral anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, apixaban), except in specific situations of switching anticoagulant therapy (see section "Dosage and Administration") or administration of UFH at doses required to maintain patency of central venous or arterial catheters.
• Pregnancy or breastfeeding (see section "Use in Pregnancy and Breastfeeding").

Interaction with Other Medicinal Products and Other Forms of Interaction

Edoxaban is predominantly absorbed in the upper gastrointestinal tract. Therefore, medicinal products or diseases that increase gastric emptying and intestinal peristalsis may reduce the dissolution and absorption of edoxaban.

P-glycoprotein (P-gp) Inhibitors

Edoxaban is a substrate of the efflux transporter P-gp. In pharmacokinetic studies, concomitant administration of edoxaban with P-gp inhibitors such as cyclosporine, dronedarone, erythromycin, ketoconazole, quinidine, or verapamil resulted in increased plasma concentrations of edoxaban.

Concomitant use of edoxaban with cyclosporine, 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.

Concomitant use of edoxaban with other P-gp inhibitors, including HIV protease inhibitors, has not been studied.

Edoxaban 30 mg once daily may be used concomitantly with the following P-gp inhibitors:

• Cyclosporine: Concomitant administration of a single 500 mg dose of cyclosporine with a single 60 mg dose of edoxaban increased the AUC and Cmax of edoxaban.
• Dronedarone: Dronedarone 400 mg twice daily for 7 days with a single concomitant 60 mg dose of edoxaban on day 5 increased the AUC and Cmax of edoxaban.
• Erythromycin: Erythromycin 500 mg four times daily for 8 days with a single concomitant 60 mg dose of edoxaban on day 7 increased the AUC and Cmax of edoxaban.
• Ketoconazole: Ketoconazole 400 mg once daily for 7 days with a single concomitant 60 mg dose of edoxaban on day 4 increased the AUC and Cmax of edoxaban.

Edoxaban 60 mg once daily may be used concomitantly with the following P-gp inhibitors:

• Quinidine: Administration of quinidine 300 mg once daily on days 1 and 4, and three times daily on days 2 and 3, together with a single concomitant 60 mg dose of edoxaban on day 3, resulted in an increase in the AUC of edoxaban over 24 hours.
• Verapamil: Administration of verapamil 240 mg once daily for 11 days together with a single 60 mg dose of edoxaban on day 10 resulted in an approximately 53% increase in AUC and Cmax of edoxaban.
• Amiodarone: Concomitant administration of amiodarone 400 mg once daily with edoxaban 60 mg once daily resulted in increased AUC and Cmax. This increase was not considered clinically significant. In a clinical trial in patients with NVAF, efficacy and safety were similar in patients receiving amiodarone concomitantly and those not receiving amiodarone.
• Clarithromycin: Clarithromycin (500 mg twice daily) for 10 days with a single 60 mg dose of edoxaban on day 9 increased AUC and Cmax of edoxaban by approximately 53% and 27%, respectively.

P-gp Inducers

Concomitant administration of edoxaban with the P-gp inducer rifampicin resulted in reduced mean AUC of edoxaban and shortened elimination half-life, potentially reducing pharmacodynamic effects. Concomitant use of edoxaban with other P-gp inducers (e.g., phenytoin, carbamazepine, phenobarbital, or St. John’s wort) may lead to decreased plasma concentrations of edoxaban. Edoxaban should be used with caution when administered concomitantly with P-gp inducers.

P-gp Substrates

Digoxin: Administration of edoxaban 60 mg once daily for 1–14 days with multiple-dose digoxin 0.25 mg twice daily (on days 8 and 9) and 0.25 mg once daily (on days 10 and 11) resulted in a 17% increase in Cmax of edoxaban, without any significant effect on AUC or renal clearance at steady state. In a study evaluating the effect of edoxaban on digoxin pharmacokinetics, Cmax of digoxin increased by approximately 28% and AUC by 7%. This increase was not considered clinically significant. No dose adjustment is required when edoxaban is used concomitantly with digoxin.

Anticoagulants, Antiplatelet Agents, Nonsteroidal Anti-inflammatory Drugs (NSAIDs), and Selective Serotonin Reuptake Inhibitors / Serotonin-Norepinephrine Reuptake Inhibitors (SSRIs/SNRIs)

Anticoagulants: Concomitant use of edoxaban with other anticoagulants is contraindicated due to increased bleeding risk (see section "Contraindications").

Acetylsalicylic acid (ASA): Concomitant use of ASA (100 mg or 325 mg) with edoxaban increases bleeding time. Concomitant use of high-dose ASA (325 mg) resulted in increased Cmax and AUC of edoxaban at steady state. Long-term concomitant use of high-dose ASA and edoxaban is not recommended. Concomitant use of ASA doses above 100 mg should be undertaken only under medical supervision.

In clinical trials, concomitant use of low-dose ASA (≤100 mg/day), other antiplatelet agents, and thienopyridines was permitted, resulting in approximately a two-fold increase in major bleeding compared to monotherapy, with similar increases observed in both the edoxaban and warfarin treatment groups. Concomitant use of low-dose ASA did not affect the peak or overall anticoagulant effect of edoxaban after a single dose.

Edoxaban may be used concomitantly with low-dose ASA.

Antiplatelet agents: In a clinical trial, concomitant use of thienopyridines (e.g., clopidogrel) as monotherapy increased the frequency of clinically relevant bleeding, although the relative risk was lower with edoxaban than with warfarin.

Experience with edoxaban in combination with dual antiplatelet therapy or fibrinolytic agents is very limited.

NSAIDs: Concomitant use of naproxen and edoxaban prolongs bleeding time compared to monotherapy with either agent. Naproxen does not affect Cmax or AUC of edoxaban. Clinical trials have shown that concomitant use of NSAIDs increases the incidence of clinically relevant bleeding. Long-term use of NSAIDs with edoxaban is not recommended.

SSRIs/SNRIs: As with other anticoagulants, the risk of bleeding is increased in patients receiving SSRIs or SNRIs concomitantly with edoxaban, due to the effect of these agents on platelet function (see section "Special Warnings and Precautions for Use").

Special precautions for use

Edoxaban 15 mg should not be used as monotherapy, as this may lead to reduced efficacy. This dose is indicated only during transition from edoxaban 30 mg [with one or more clinical factors increasing exposure (see Table 1)] to vitamin K antagonists (VKA), together with an appropriate dose of VKA (see Table 2, section "Dosage and administration").

Bleeding risk

Edoxaban increases the risk of bleeding and may cause serious, potentially life-threatening hemorrhage. As with other anticoagulants, edoxaban should be used with caution in patients with conditions associated with increased bleeding risk. In case of serious bleeding, the drug should be discontinued.

Clinical trials have shown that mucosal bleeding (e.g., epistaxis, gastrointestinal bleeding, genitourinary bleeding) and anemia occur more frequently during long-term edoxaban therapy compared to treatment with VKAs. Therefore, in addition to appropriate clinical monitoring, laboratory testing for hemoglobin/hematocrit levels should be considered in relevant cases to detect occult bleeding.

Certain patient categories, as listed below, have an increased risk of bleeding. Such patients should be closely monitored after initiation of treatment for signs of hemorrhagic complications and anemia. Any unexplained decrease in hemoglobin levels or arterial blood pressure requires identification of the bleeding source.

The anticoagulant effect of edoxaban cannot be reliably monitored with standard laboratory tests. There is no specific reversal agent for edoxaban.

Hemodialysis has minimal effect on edoxaban clearance.

Elderly patients

Concomitant use of edoxaban and acetylsalicylic acid (ASA) in elderly patients requires caution due to increased bleeding risk.

Patients with renal impairment

Plasma AUC values in patients with mild (CrCl > 50–80 mL/min), moderate (CrCl 30–50 mL/min), and severe (CrCl < 30 mL/min, not on dialysis) renal impairment are increased compared to patients with normal renal function (see section "Dosage and administration").

Edoxaban is not recommended in patients with CrCl < 15 mL/min or in patients on dialysis.

Renal function in non-valvular atrial fibrillation (NVAF)

A trend toward reduced efficacy of edoxaban with increasing CrCl has been observed compared to appropriate warfarin use. Therefore, edoxaban should be used in patients with NVAF and high CrCl only after careful assessment of individual thromboembolic and bleeding risk.

Renal function assessment: CrCl should be monitored at the start of treatment in all patients and subsequently as clinically indicated.

Patients with hepatic impairment

Edoxaban is not recommended for patients with severe hepatic impairment.

Edoxaban should be used with caution in patients with mild to moderate hepatic impairment.

Patients with elevated liver enzymes (alanine aminotransferase/aspartate aminotransferase (ALT/AST) more than 2 times above the upper limit of normal) or total bilirubin levels exceeding the upper limit of normal by 1.5 times or more were excluded from clinical trials. Therefore, edoxaban should be used cautiously in such patients. Liver function tests should be performed before initiating edoxaban therapy. Periodic monitoring of liver function is recommended in patients treated with edoxaban for more than one year.

Discontinuation due to surgery and other procedures

If anticoagulant therapy needs to be discontinued to reduce bleeding risk during surgery or other procedures, edoxaban should be stopped as early as possible, at least 24 hours before the intervention.

If the procedure cannot be delayed, the risk of bleeding and urgency of the intervention should be assessed. Edoxaban therapy should be resumed after surgical or other procedures once adequate hemostasis is achieved, keeping in mind that the anticoagulant effect of edoxaban begins within 1–2 hours after administration.

If oral medication cannot be administered during or after surgery, parenteral anticoagulation should be considered, followed by transition to once-daily oral edoxaban.

Interactions with other drugs affecting blood coagulation

Concomitant use of drugs affecting blood coagulation increases bleeding risk. These include ASA, platelet aggregation inhibitors, other antiplatelet agents, fibrinolytics, SSRIs, and long-term use of NSAIDs (see section "Interaction with other medicinal products and other types of interactions").

Prosthetic heart valves and moderate or severe mitral stenosis

The efficacy of edoxaban has not been studied in patients with prosthetic heart valves, within the first 3 months after bioprosthetic valve implantation (with or without atrial fibrillation), or in patients with moderate to severe mitral stenosis. Therefore, edoxaban is not recommended for treatment of such patients.

Patients with pulmonary embolism (PE) and unstable hemodynamics, or patients requiring thrombolysis or pulmonary embolectomy

Edoxaban is not recommended as an alternative to unfractionated heparin (UFH) in patients with PE and unstable hemodynamics or those who may undergo thrombolysis or pulmonary embolectomy, as the safety and efficacy of edoxaban in these clinical situations have not been established.

Patients with active cancer

The efficacy and safety of edoxaban for treatment and/or prevention of VTE in patients with active cancer have not been established.

Patients with antiphospholipid syndrome

Direct oral anticoagulants, including edoxaban, are not recommended for patients with a history of thrombosis and diagnosed antiphospholipid syndrome. In particular, in patients with confirmed positive results for all three antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibodies, anti-beta-2-glycoprotein I antibodies), direct oral anticoagulant therapy increases the risk of recurrent thrombotic events compared to VKA therapy.

Laboratory parameters

Although edoxaban therapy does not require routine monitoring, the anticoagulant effect can be assessed using calibrated quantitative anti-factor Xa assays, which may assist in clinical decision-making in specific situations, such as overdose or emergency surgery.

Edoxaban prolongs standard coagulation tests such as PT, INR, and aPTT due to factor Xa inhibition. However, changes in these coagulation tests within the expected therapeutic range are minimal and subject to high variability, making them unsuitable for monitoring the anticoagulant effect of edoxaban.

Important information on excipients

The medicinal product contains glucose; therefore, patients with known sugar intolerance should consult their physician before taking this medicine.

Use during pregnancy or breastfeeding

Effect on fertility. Women of reproductive potential should avoid pregnancy during edoxaban treatment.

Pregnancy. The efficacy and safety of edoxaban in pregnant women have not been studied. Animal studies have shown reproductive toxicity. Due to potential reproductive toxicity, high bleeding risk, and placental transfer of edoxaban, the medicinal product Edoxadar is contraindicated during pregnancy (see section "Contraindications").

Breastfeeding. The efficacy and safety of edoxaban in breastfeeding women have not been studied. Animal studies have shown that edoxaban is excreted in breast milk. Therefore, Edoxadar is contraindicated during breastfeeding (see section "Contraindications"). A decision should be made whether to discontinue breastfeeding or to discontinue/withhold therapy.

Fertility. Specific studies evaluating the effect of edoxaban on human fertility have not been conducted. Fertility studies in male and female rats showed no effect.

Ability to influence reaction speed when driving or operating machinery

The medicinal product Edoxadar has no or negligible effect on the ability to drive or operate machinery.

Administration and Dosage

Prevention of stroke and systemic embolism

The recommended dose is 60 mg of edoxaban once daily.

Edoxaban therapy in patients with NVAF should be long-term.

Treatment of VTE and prevention of recurrent VTE (DVT and PE)

The recommended dose is 60 mg of edoxaban once daily, following initial parenteral anticoagulant therapy for at least 5 days. Edoxaban should not be used concomitantly with parenteral anticoagulants.

The duration of treatment for DVT and PE (VTE), as well as prevention of recurrent VTE, should be determined individually after careful assessment of the benefits of therapy relative to the risk of bleeding. Short-term treatment (at least 3 months) should be considered in the presence of transient risk factors (e.g., recent surgery, trauma, immobilization), whereas extended treatment is recommended in the presence of persistent risk factors or in cases of idiopathic DVT or PE.

The recommended dose of edoxaban in NVAF and VTE is 30 mg once daily in patients with one or more of the following clinical factors (see also Table 1):

• moderate or severe renal impairment (CrCl 15–50 mL/min);
• low body weight: ≤ 60 kg;
• concomitant use of the following P-glycoprotein (P-gp) inhibitors: cyclosporine, dronedarone, erythromycin, or ketoconazole.

Table 1

Summary of dosing recommendations in NVAF and VTE (DVT and PE)

Missed dose

If a dose of edoxaban is missed, this dose should be taken immediately, and the patient should continue with once-daily dosing the next day according to the recommendations. A double dose should not be taken within one day to compensate for the missed dose.

Switching to edoxaban and switching from edoxaban

Patients with NVAF and VTE should receive continuous anticoagulant therapy. In certain situations, a switch in anticoagulant therapy may be necessary (Table 2).

Table 2

Switching between anticoagulants in NVAF and VTE (DVT and PE)

Switching to edoxaban

Edoxaban translation

Special patient populations

Elderly patients

Dose adjustment is not required (see section "Pharmacokinetics").

Renal impairment

Renal function should be assessed in all patients prior to initiating edoxaban therapy by determining the creatinine clearance (CrCl) value, in order to avoid using edoxaban in patients with end-stage renal disease (CrCl < 15 mL/min), to establish the appropriate edoxaban dose for patients with CrCl 15–50 mL/min (30 mg once daily), for patients with CrCl > 50 mL/min (60 mg once daily), and to evaluate the appropriateness of edoxaban use in patients with elevated CrCl values.

Renal function assessment should also be performed whenever changes in renal function are expected during treatment (e.g., in cases of hypovolemia, dehydration, or concomitant use of certain medications).

Renal function (CrCl in mL/min) is calculated using the Cockcroft-Gault formula:

For creatinine levels expressed in µmol/L:

For creatinine levels expressed in mg/dL:

This method is recommended for estimating CrCl in patients before and during edoxaban treatment.

For patients with mild renal impairment (CrCl > 50–80 mL/min), the recommended dose is 60 mg of edoxaban once daily.

For patients with moderate or severe renal impairment (CrCl 15–50 mL/min),
the recommended dose is 30 mg of edoxaban once daily.

Edoxaban is not recommended for patients with end-stage renal disease (CrCl < 15 mL/min) or for patients undergoing dialysis.

Hepatic impairment

Edoxaban is contraindicated in patients with liver disease associated with coagulopathy and clinically relevant bleeding risk (see section "Contraindications").

Edoxaban is not recommended for use in patients with severe hepatic impairment.

Edoxaban should be used with caution in patients with mild or moderate hepatic impairment; the recommended dose of edoxaban in such patients is 60 mg once daily.

Patients with elevated liver enzymes (alanine aminotransferase [ALT] or aspartate aminotransferase [AST] > 2 times the upper limit of normal [ULN]) or elevated total bilirubin (≥1.5 times ULN) were excluded from clinical trials. Therefore, edoxaban should be used with caution in these patients. Liver function tests should be performed before initiating edoxaban therapy.

Body weight

For patients with body weight ≤ 60 kg, the recommended dose is 30 mg of edoxaban once daily.

Gender

Dose adjustment is not required (see section "Pharmacokinetics").

Concomitant use of edoxaban and P-glycoprotein (P-gp) inhibitors

For patients receiving concomitant edoxaban and P-gp inhibitors such as cyclosporine, dronedarone, erythromycin, or ketoconazole, the recommended dose of edoxaban is 30 mg once daily. Dose reduction is not required when amiodarone, quinidine, or verapamil are used concomitantly.

The use of edoxaban together with other P-gp inhibitors, including HIV protease inhibitors, has not been studied.

Patients undergoing cardioversion

Initiating or continuing edoxaban therapy is permitted in patients who may require cardioversion.

When performing cardioversion under transesophageal echocardiography (TEE) guidance in patients who have not previously received anticoagulants, edoxaban treatment should be initiated 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: prior to the procedure, it must be confirmed that patients have been taking edoxaban as prescribed. Decisions regarding the initiation and duration of therapy should follow current guidelines for anticoagulation in patients undergoing cardioversion.

Method of administration

For oral use.

Edoxaban can be taken with or without food.

Children

Safety and efficacy of this medicinal product in children and adolescents under 18 years of age have not been established. No data are available.

Overdose

Overdose of edoxaban may lead to bleeding. Experience with overdose cases is very limited.

There is no specific antidote available to reverse the pharmacodynamic effect of edoxaban.

In case of edoxaban overdose, early administration of activated charcoal may be considered to reduce absorption. This recommendation is based on standard overdose management practices and available data on similar compounds, as the use of activated charcoal to reduce edoxaban absorption has not been specifically studied.

Management of bleeding. In the event of bleeding complications, the next dose of edoxaban should be delayed or treatment discontinued. The elimination half-life of edoxaban is approximately 10–14 hours. Management should be individualized depending on the severity and site of bleeding. If necessary, appropriate symptomatic treatment should be provided, such as mechanical compression for severe epistaxis, surgical hemostasis with bleeding control procedures, restoration of fluid and electrolyte balance, hemodynamic support, blood transfusion (packed red blood cells or fresh frozen plasma, depending on the clinical condition—anaemia or coagulopathy), or platelet transfusion.

Since life-threatening bleeding cannot be controlled by measures such as transfusion or hemostasis alone, administration of a 4-factor prothrombin complex concentrate (4F-PCC) at a dose of 50 IU/kg has been shown to reverse the effect of edoxaban within 30 minutes after completion of infusion.

Recombinant factor VIIa (r-FVIIa) may also be considered. However, clinical experience with this agent in patients receiving edoxaban is limited.

In cases of major bleeding, consultation with a hematologist may be required.

Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of edoxaban.

There is no experience with the use of antifibrinolytic agents (tranexamic acid, aminocaproic acid) in patients receiving edoxaban. There is no scientific rationale supporting their use, and no experience exists with systemic hemostatic agents (desmopressin, aprotinin) in patients receiving edoxaban. Due to high plasma protein binding, edoxaban is not expected to be removed by dialysis.

Adverse Reactions

The most commonly reported adverse reactions with edoxaban were epistaxis, haematuria, and anaemia. Bleeding may occur at any site and can be severe, even fatal.

The adverse reactions listed below are classified by system organ classes (according to MedDRA) and frequency of occurrence: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated from the available data).

Blood and lymphatic system disorders: common — anaemia; uncommon — thrombocytopenia.

Immune system disorders: rare — anaphylactic reactions, angioedema; uncommon — hypersensitivity.

Nervous system disorders: common — dizziness, headache; uncommon — intracranial haemorrhage; rare — subarachnoid haemorrhage.

Eye disorders: uncommon — ocular haemorrhage, conjunctival/scleral haemorrhage.

Cardiac disorders: rare — pericardial haemorrhage.

Vascular disorders: uncommon — other haemorrhages.

Respiratory, thoracic and mediastinal disorders: common — epistaxis; uncommon — haemoptysis.

Gastrointestinal disorders: common — abdominal pain, gastrointestinal haemorrhage (upper and lower), oral/pharyngeal haemorrhage, nausea; rare — peritoneal haemorrhage.

Hepatobiliary disorders: common — increased blood bilirubin and gamma-glutamyl transferase levels; uncommon — increased blood alkaline phosphatase and transaminase levels.

Skin and subcutaneous tissue disorders: common — haemorrhage into soft tissues, skin; rash, pruritus; uncommon — urticaria.

Musculoskeletal and connective tissue disorders: rare — muscle haemorrhage (without compartment syndrome), intra-articular haemorrhage.

Renal and urinary disorders: common — macroscopic haematuria/urethral haemorrhage; frequency not known — anticoagulant nephropathy.

Reproductive system and breast disorders: common — vaginal bleeding¹.

General disorders and administration site conditions: common — bleeding at the site of administration.

Investigations: common — abnormal liver function tests.

Injury, poisoning and procedural complications: uncommon — surgical site haemorrhage; rare — subdural haemorrhage.

¹Vaginal bleeding was generally observed in women under 50 years of age and was uncommon in women over 50 years of age (based on clinical trial data).

Description of selected adverse reactions

Haemorrhagic anaemia

Edoxaban increases the risk of internal or overt bleeding in any tissues and organs, which may lead to post-haemorrhagic anaemia. Signs, symptoms, and severity (including potentially fatal outcomes) vary depending on the location and extent of bleeding and/or anaemia (see section "Overdose"). Clinical trials have shown that mucosal bleeding (e.g., epistaxis, gastrointestinal bleeding, genitourinary bleeding) and anaemia occurred more frequently with long-term edoxaban treatment than with vitamin K antagonists (VKAs). Therefore, in addition to appropriate clinical monitoring, laboratory testing for haemoglobin/haematocrit levels is recommended in appropriate cases to detect occult internal bleeding. The risk of bleeding may be higher in certain patient groups, such as patients with uncontrolled severe hypertension and/or those taking concomitant medications affecting blood coagulation. The intensity and/or duration of menstrual bleeding may be increased. Manifestations of haemorrhagic complications may include weakness, pallor, dizziness, headache, unexplained swelling, dyspnoea, or shock of unknown origin.

Complications known to result from severe bleeding, such as compartment syndrome and renal failure due to hypoperfusion, have been reported. Therefore, when assessing patients prescribed anticoagulants, the risk of bleeding should be carefully considered.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine registration is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and/or lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Packaging

10 tablets in a blister; 3 blisters in a carton.

Prescription status. Prescription only.

Manufacturer

Pharos MT Limited

Pharos Pharmaceutical Oriented Services Ltd.

Manufacturer's address and place of business

XF62EX, Casam Industries Hell Farr, Hell Farr, Birzebbuga, BBG 3000, Malta.

Lesvou Street End, Thessy Loggos Industrial Zone, Metamorfossi, 144 52, Greece.

Marketing Authorisation Holder

JSC "Pharmaceutical Company "Darnytsia".

Address of the Marketing Authorisation Holder

13 Boryspilska Street, Kyiv, 02093, Ukraine.