Date of approval.
Date of revision.
Edoxaban Methylphenidate Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Warnings
A. Early discontinuation of this product will increase the risk of ischemic events.
Early discontinuation of any oral anticoagulant in the absence of adequate alternative anticoagulant therapy will increase the risk of ischemic events. If this product is discontinued for reasons other than pathologic bleeding or completed therapy, another anticoagulant needs to be considered for administration.
B. Spinal/epidural hematoma.
Spinal/epidural hematomas may occur in patients treated with edoxaban while undergoing epidural anesthesia or spinal puncture. These hematomas may result in long-term or permanent paralysis. These risks need to be considered when scheduling patients for spinal surgery. Factors that may increase the risk of epidural or spinal hematomas in these patients include: use of indwelling catheters; concomitant use of other medications that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants; history of traumatic or repeated epidural or spinal punctures; and history of spinal deformity or spinal surgery. The optimal interval between edoxaban administration and intraspinal surgery is not known (see [PRECAUTIONS]).
Close observation of the patient is required to detect signs and symptoms of neurological impairment. If neurological impairment is detected, emergency treatment must be administered. For patients who have received or are about to receive anticoagulation to prevent thrombosis, an assessment of benefit and risk should be performed prior to epidural anesthesia or spinal puncture (see [Precautions]).
Drug Name]
Generic name: Edoxaban mesylate tablets
Trade name: LIXIANA® (LIXIANA®)
English name: Edoxaban Tosilate Tablets
Hanyu Pinyin: Jiabenhuangsuan Aiduoshaban Pian
Ingredients
The active ingredient of this product is Aiduoshaban Methylphenidate.
Chemical name: N-(5-chloropyridin-2-yl)-N’-[(1S, 2R, 4S)-4-(N, N-dimethylaminocarbonyl)-2-(5-methyl-4, 5, 6, 7-tetrahydro[1, 3]thiazolo[5, 4-c]pyridine-2-carboxamido)cyclohexyl]oxalamide, mono(4-methylbenzenesulfonate) monohydrate
Chemical structure formula.
Molecular formula: C24H30ClN7O4S-C7H8O3S-H2O
Molecular weight: 738.27
Properties
This product is orange round film-coated tablet with “DSC L15” engraved on one side (specification 15mg); or pink round film-coated tablet with “DSC L30” engraved on one side (specification 30mg); or yellow round film-coated tablet with “DSC L60” engraved on one side (specification 60mg).
Indications】1.
1. For the prevention of stroke and embolism in adult patients with non-valvular atrial fibrillation (NVAF) with one or more risk factors (e.g., congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, history of previous stroke or transient ischemic attack (TIA)).
2. for the treatment of adult deep vein thrombosis (DVT) and pulmonary embolism (PE), and for the prevention of recurrent DVT and pulmonary embolism in adults. (See [Precautions] for use in patients with hemodynamically unstable PE).
Specification
Press
C24H30ClN7O4S: (1) 15mg; (2) 30mg; (3) 60mg.
Dosage and Administration
Usage
It can be taken orally with food or alone. (See [Pharmacokinetics]).
Dosage
Prevention of stroke and embolism in the body circulation
The recommended dose of edoxaban is 60 mg once daily.
Edoxaban should be used long-term when treating patients with non-valvular atrial fibrillation (NVAF).
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of recurrent DVT and pulmonary embolism (venous thromboembolism, VTE)
The recommended dose of edoxaban is 60 mg once daily, initiated after at least 5 days of initial non-oral anticoagulant therapy (see [Clinical Trials]). Edoxaban and non-oral anticoagulants should not be given concurrently.
The duration of treatment for deep vein thrombosis, pulmonary embolism (venous thromboembolism, VTE), and prevention of recurrent VTE should be determined on an individual basis after careful assessment of treatment benefit and bleeding risk (see [Precautions]). Short-term treatment (at least 3 months) should be based on transient risk factors (e.g., recent surgery, trauma, braking) and longer-term treatment should be based on permanent risk factors or idiopathic DVT or PE.
For non-valvular atrial fibrillation (NVAF) and venous thromboembolism (VTE), the recommended dose of edoxaban is 30 mg once daily in patients with one or more of the following clinical factors.
Moderate or severe renal impairment (creatinine clearance (CrCL) 15 to 50 mL/min)
Low body weight (≤ 60 kg)
Coadministration with the following P-glycoprotein (Pgp) inhibitors: cyclosporine, dronedarone, erythromycin or ketoconazole.
Table 1 Dose summary in patients with NVAF and VTE (DVT and PE)
Dosing guidelines summarize the recommended dose of 60 mg once daily. Recommended dose for patients with one or more of the following clinical factors: moderate or severe renal impairment (CrCL 15 to 50 mL/min) 30 mg once daily. Low weight ≤ 60 kg Pgp inhibitors cyclosporine, dronedarone, erythromycin, ketoconazole missed dose
If a missed dose occurs, the patient should take the product immediately and continue to take it once daily the following day. Patients should not take twice the dose on the same day because of a missed dose.
Switching from other drugs to this product or from this product to other drugs
It is important to continue anticoagulation therapy in patients with NVAF and VTE. Adjustment of anticoagulation therapy is required in some cases (Table 2).
Table 2 Drug switch
Switching from other drugs to this drug Original drug switch to recommended method Vitamin K antagonist (VKA) Discontinue VKA and start this drug if the international normalized ratio (INR) of this drug is ≤ 2.5. Oral anticoagulants other than VKA
Dabigatran
Rivaroxaban
Apixaban discontinue dabigatran, rivaroxaban or apixaban and start treatment with this product when oral anticoagulant is next scheduled to be given (see [Clinical Trials]). Non-oral anticoagulants this product these drugs should not be used together.
Subcutaneous anticoagulants (i.e., LMWH, sulforaphane).
Discontinue subcutaneous anticoagulant injection and begin treatment with this product at the next scheduled subcutaneous anticoagulant injection. Intravenous administration of normal heparin (UFH).
Discontinue infusion and start treatment with this product 4 hours later.
Conversion from this product to other drugs Original drug conversion to the recommended method Vitamin K antagonist (VKA) of this product Inadequate anticoagulation may occur during conversion from this product to VKA. Continued adequate anticoagulation during conversion to other anticoagulants should be ensured.
Choice of oral formulation: For patients administered at a dose of 60 mg, take 30 mg of this product once daily with an appropriate dose of VKA.
For patients administered at a dose of 30 mg (in the presence of one or more of the following clinical factors: moderate to severe renal impairment (CrCL 15-50 mL/min), low body weight, or co-administration with some Pgp inhibitor), take 15 mg of this product once daily along with an appropriate dose of VKA.
Patients should not use loading doses of VKA in order to rapidly achieve a stable INR (2 to 3.) Depending on local treatment practice, it is recommended that maintenance doses of VKA be considered in patients with prior VKA use or that a VKA regimen based on an effective INR be recommended.
Once an INR ≥ 2.0 is achieved, administration of this product should be discontinued. The majority of patients (85%) are able to achieve an INR ≥ 2.0 within 14 days after initiation of combination therapy with VKA. After 14 days, it is recommended to discontinue treatment with VKA and continue to adjust the VKA dose until an INR of 2 to 3 is achieved.
It is recommended that the INR be measured at least three times during the first 14 days of combination therapy and that it be measured prior to daily dosing in order to minimize the effect of the drug on the INR measurement. Combination therapy with VKA resulted in a 46% increase in INR after administration of this product. Choice of non-oral formulation: discontinue this product and start non-oral anticoagulant and VKA therapy at the next scheduled dose. Upon reaching a stable INR ≥ 2.0, the non-oral anticoagulant must be discontinued but VKA therapy must be continued. At the next scheduled dose of oral anticoagulant other than VKA for this product, discontinue this product and begin non-VKA anticoagulant therapy. These drugs should not be used concurrently with this non-oral anticoagulant. At the time of the next scheduled dose, discontinue this product and start non-oral anticoagulant therapy. Special Populations
Renal function assessment.
Prior to initiating therapy with this product, creatinine clearance (CrCL) should be calculated to assess renal function in all patients to exclude patients with end-stage renal disease (i.e., CrCL < 15 mL/min) and to provide guidance for the proper use of this product in patients with CrCL 15-50 mL/min (30 mg once daily) and in patients with CrCL > 50 mL/min (60 mg once daily). Provide guidance on the dosing of this product and the decision to use it in patients with elevated creatinine clearance (see [Precautions]).
Renal function should be evaluated when changes in renal function are suspected during treatment (e.g., hypovolemia, dehydration, and when used in combination with certain drugs).
During clinical development of this product, renal function (CrCL units mL/min) was assessed using the Cockcroft-Gault method. The formula is as follows.
Creatinine (µmol/L).
1.23 × (140 – age [years]) × weight [kg] (× 0.85, female)
Serum creatinine [µmol/L]
Creatinine (mg/dL).
(140 – age [years]) × body weight [kg] ( × 0.85, female)
72 × serum creatinine [mg/dL]
This method is recommended for assessing patients’ CrCL before and during treatment with this product.
Renal impairment
In patients with mild renal impairment (CrCL > 50 to 80 mL/min), the recommended dose of this product is 60 mg once daily.
For patients with moderate to severe renal impairment (CrCL 15-50 mL/min), the recommended dose is 30 mg once daily (see [Pharmacokinetics]).
This product is not recommended for patients with end-stage renal disease (ESRD) (CrCL < 15 mL/min) or dialysis (see [Precautions] and [Pharmacokinetics]).
Liver damage
This product is contraindicated in patients with liver disease with coagulation disorders and clinically relevant bleeding risk (see [Contraindications]).
This product is not recommended for patients with severe hepatic impairment (see [Precautions] and [Pharmacokinetics]).
In patients with mild to moderate hepatic impairment, the recommended dose is 60 mg once daily (see [Pharmacokinetics]). This product should be used with caution in patients with mild to moderate hepatic impairment (see [Precautions]).
Clinical trials have not included patients with elevated liver enzymes (ALT/AST > 2 x ULN) or total bilirubin ≥ 1.5 x ULN. Therefore, this product should be used with caution in this population (see [Precautions] and [Pharmacokinetics]). Liver function should be checked prior to initiating treatment with this product.
Body weight
For patients weighing ≤ 60 kg, the recommended dose is 30 mg once daily (see [Pharmacokinetics]).
Geriatric patients
No dose reduction is required (see [Pharmacokinetics]).
Gender
No dose reduction is required (see [Pharmacokinetics]).
Combination of this product with P-glycoprotein (P-gp) inhibitors
The recommended dose of this product is 30 mg once daily in combination with P-gp inhibitors (cyclosporine, dronedarone, erythromycin, or ketoconazole) (see [Drug Interactions]).
No dose reduction is required for patients taking this product in combination with amiodarone, quinidine, or verapamil (see [Drug Interactions]).
The combination of this product with other P-gp inhibitors, including HIV protease inhibitors, has not been studied.
Pediatric Population
The safety and efficacy of this product in children and adolescent patients under 18 years of age have not been established and no data are available.
Patients Receiving Cardioversion
This product may be initiated or continued in patients requiring cardioversion. In patients who have not received prior anticoagulant therapy and have undergone cardioversion guided by transesophageal echocardiography (TEE), this product should be started at least 2 hours prior to cardioversion to ensure adequate anticoagulation (see [Clinical Trials]). Cardioversion should be performed within 12 hours of taking this product on the day of the procedure.
For all patients undergoing cardioversion: Verify that the patient is taking this product as prescribed prior to cardioversion. Patients undergoing cardioversion should follow established anticoagulation guidelines to determine the start and duration of therapy.
Adverse Reactions]
Summary of safety characteristics
The safety of edoxaban was evaluated in two phase 3 studies including 21,105 patients with NVAF (ENGAGE AF-TIMI 48 study) and 8,292 patients with VTE (DVT and PE) (Hokusai-VTE study).
In the edoxaban 60 mg group (including dose reduction to 30 mg), the mean duration of drug exposure was 2.5 years in 7,012 patients in the ENGAGE AF-TIMI 48 study and 251 days in 4,118 patients in the Hokusai-VTE study.
Adverse reactions occurred in 2,256 (32.2%) patients in the ENGAGE AFTIMI 48 study and 1,249 (30.3%) patients in the Hokusai-VTE study in the edoxaban 60 mg group (including dose reduction to 30 mg).
In both studies, the most common bleeding-related adverse reactions (based on selected terms) in the edoxaban 60 mg group included soft tissue bleeding from the skin (up to 5.9%) and epistaxis (up to 4.7%), while the most common bleeding-related adverse reaction in the Hokusai-VTE study was vaginal bleeding (9.0%).
Bleeding may occur at any site and may be severe or even fatal (see [Precautions]).
Other common adverse reactions to edoxaban were anemia, skin rash, and abnormal liver function tests.
In the ENGAGE AF-TIMI 48 study, one of the most common adverse reactions to the 60 mg dose of edoxaban was abnormal liver function, with an incidence of 4.8% and 4.6% for edoxaban compared to warfarin, respectively.
In the edoxaban 60 mg group, 15 (0.2%) patients in the ENGAGE AF TIMI 48 study had a serious adverse event-interstitial lung disease (ILD) compared with 7 (0.1%) in the warfarin group. Many patients in both groups had confounding factors of amiodarone use or co-infectious pneumonia, which was previously reported to be associated with ILD. Throughout the trial period, there were 5 and 0 deaths from ILD in the 60 mg dose group of this product and the warfarin group, respectively. A correlation between edoxaban and ILD has not been established.
List of Adverse Reactions
Table 3 lists the adverse reactions that occurred in patients with both indications in the two pivotal phase 3 studies VTE (DVT and PE) (Hokusai-VTE study) and AF (ENGAGE AF-TIMI 48 study). Adverse reactions were classified by system organ classification and frequency of occurrence as follows.
Very common (≥ 1/10); Common (≥ 1/100 to < 1/10); Occasional (≥ 1/1,000 to < 1/100); Rare (≥ 1/10,000 to < 1/1,000); Very rare (< 1/10,000), Unknown (not estimable based on available data).
Table 3 List of adverse reactions in patients with NVAF and VTE
System Organ Classification Frequency Blood and lymphatic system disorders Anemia common Thrombocytopenia occasional Immune system disorders Hypersensitivity reactions occasional Rapid allergic reactions rare Anaphylaxis rare Neurologic disorders Dizziness common Headache common Intracranial hemorrhage (ICH) occasional Subarachnoid hemorrhage rare Ocular disorders Conjunctival/scleral hemorrhage occasional Intraocular hemorrhage occasional Cardiac disorders Pericardial hemorrhage rare Vascular disorders Other hemorrhage occasional Respiratory, thoracic, and mediastinal disorders Epistaxis common Hemoptysis occasional Gastrointestinal disorders Lower gastrointestinal bleeding common Upper gastrointestinal bleeding common Oral/pharyngeal bleeding common Nausea common Abdominal pain common Retroperitoneal bleeding rare Hepatobiliary disorders Elevated blood bilirubin common Elevated gamma-glutamyl transferase common Elevated blood alkaline phosphatase occasional Elevated transaminases occasional Elevated aspartate aminotransferase occasional Skin and subcutaneous tissue disorders Skin Soft tissue bleeding common rash common pruritus common urticaria occasional musculoskeletal and connective tissue disorders intramuscular bleeding (without fascial compartment syndrome) rare intra-articular bleeding rare renal and urinary disorders naked eye visible hematuria/urethral bleeding common genital and breast disorders vaginal bleeding1 common systemic disorders and drug administration site disorders bleeding at puncture site common tests abnormal liver function tests common injuries, toxicities and surgical complications Surgical site bleeding Occasional subdural bleeding Rare surgical bleeding Rare1 Reporting rate based on female population in clinical trials. Vaginal bleeding is common in female patients under 50 years of age, but occasional in female patients over 50 years of age.
Adverse Reactions of Special Concern
Depending on the pharmacologic mechanism of action, this product may increase the risk of occult or significant bleeding from tissues and organs, which in turn may lead to anemia following bleeding. Signs, symptoms, and severity (including lethal outcomes) vary depending on the site, grade, or extent of bleeding and/or anemia (see [Drug Overdose], Bleeding Control).
Clinical studies have shown that mucosal bleeding (e.g., epistaxis, gastrointestinal bleeding, genitourinary bleeding) and anemia are more common in patients receiving long-term treatment with edoxaban compared with VKA therapy. Therefore, in addition to adequate clinical observation, proper judgment of laboratory findings of hemoglobin/erythrocyte pressure volume may help detect occult bleeding. The risk of bleeding may be elevated in certain patient groups, e.g., patients with uncontrolled severe arterial hypertension and/or patients undergoing combination therapy that affects hemostasis (see Bleeding Risk in [Precautions]). Menstrual bleeding may be increased and/or prolonged. Complications of bleeding may manifest as weakness, pallor, dizziness, headache or unexplained swelling, dyspnea, and unexplained shock. Known complications of this product have been reported secondary to severe bleeding, such as fascial compartment syndrome and renal failure due to inadequate blood perfusion. Therefore, the possibility of bleeding should be considered when evaluating the condition of any patient on anticoagulation therapy.
Contraindications
Patients with hypersensitivity to the active ingredient or other excipients of this product.
Patients with clinically significant active bleeding.
Patients with liver disease with coagulation disorders and clinically relevant bleeding risk.
Lesions or conditions with significant risk of major bleeding, such as current or recent gastrointestinal ulcers, malignancies with a high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial hemorrhage, known or suspected esophageal varices, arteriovenous malformations, vascular aneurysms or major intravertebral or intracerebral vascular malformations.
Uncontrollable severe hypertension.
Concomitant therapy with any other anticoagulant, such as UFH, low molecular heparin (enoxaparin, dalteparin, etc.), heparin derivatives (sodium fondaparinux, etc.), oral anticoagulants (warfarinux, dabigatranate, rivaroxaban, apixaban, etc.) is contraindicated, except in the special case of conversion to oral anticoagulant therapy or administration of the dose of normal heparin (UFH) required to maintain central venous or arterial catheter patency.
Pregnant and lactating women (see [Pregnant and lactating women’s medication]).
【Caution】.
This product 15 mg is not indicated for use alone, which may result in inadequate efficacy, and should only be used in combination with an appropriate amount of VKA during conversion from this product 30 mg (in the presence of one or more clinical factors contributing to elevated exposure; see Table 1, [Dosage]) to VKA (see Table 2, [Dosage]).
Discontinuation of this product in patients with NVAF will increase the risk of stroke
Early discontinuation of any oral anticoagulant in the absence of adequate alternative anticoagulation therapy will elevate the risk of ischemic events. If this product is discontinued for reasons other than pathological bleeding or completed therapy, another anticoagulant needs to be considered for administration.
Risk of bleeding
Edoxaban increases the risk of bleeding and can lead to severe, potentially fatal bleeding. As with other anticoagulants, caution is advised in patients with an increased risk of bleeding. If severe bleeding occurs, discontinue administration of this product (see [Adverse Reactions] and [Drug Overdose]).
Clinical studies have shown that mucosal bleeding (e.g., epistaxis, gastrointestinal bleeding, genitourinary bleeding) and anemia are more common in patients receiving long term treatment with edoxaban compared to VKA therapy. Therefore, in addition to adequate clinical observation, proper judgment of laboratory findings of hemoglobin/erythrocyte pressure volume may help to detect occult bleeding.
Several subgroups of patients (described below) are at increased risk of bleeding. After initiation of therapy, monitor these patients closely for signs and symptoms of bleeding complications and anemia (see [Adverse Reactions]). Look for bleeding sites in cases of unexplained hemoglobin or decreased blood pressure.
Spinal/epidural hematomas may occur in patients treated with edoxaban while undergoing epidural anesthesia or spinal puncture. These risks need to be considered when scheduling patients for spinal surgery and evaluating factors that may put these patients at increased risk for epidural or spinal hematomas.
The anticoagulant effect of this product cannot be reliably monitored using standard laboratory tests.
There are no specific antagonists for edoxaban (see [Drug Overdose]).
Hemodialysis does not significantly alter the clearance of edoxaban (see [Pharmacokinetics]).
Geriatric Patients
Combination of this product with acetylsalicylic acid (ASA) in elderly patients has a potentially higher risk of bleeding (see [Drug Interactions]) and should be used with caution.
Renal impairment
Compared to subjects with normal renal function, plasma AUC was increased by 32%, 74%, and 72% in subjects with mild renal impairment (CrCL > 50-80 mL/min), moderate renal impairment (CrCL 30-50 mL/min), and severe renal impairment (CrCL < 30 mL/min but no dialysis), respectively (see [Dosage] for dose adjustments).
This product is not recommended for patients with end-stage renal disease or dialysis (see [Dosage] and [Pharmacokinetics]).
Renal function in patients with NVAF
There is a trend toward reduced efficacy of edoxaban in the presence of elevated creatinine clearance compared to well-managed warfarin therapy with the drug (see [Clinical Trials]). Therefore, edoxaban should only be used in NVAF patients with high creatinine clearance after careful assessment of the patient’s risk of thromboembolism and bleeding.
Renal function assessment: All patients treated with this product should have creatinine clearance (CrCL) monitored at the start of and during treatment (see [DOSAGE]).
Hepatic impairment
This product is not recommended for patients with severe hepatic impairment (see [Dosage] and [Pharmacokinetics]).
This product should be used with caution in patients with mild or moderate hepatic impairment (see [DOSAGE AND ADMINISTRATION]).
Clinical trials have not included patients with elevated liver enzymes (ALT/AST > 2 x ULN) or total bilirubin ≥ 1.5 x ULN. Therefore, this product should be used with caution in this population (see [DOSAGE] and [PHARMACOLOGY]). Liver function should be checked before starting treatment with this product.
Regular monitoring of liver function is recommended for patients treated with this product for more than 1 year.
Discontinuation for surgery and other interventions
If anticoagulation therapy must be discontinued to reduce the risk of bleeding during surgery or other interventions, the drug must be discontinued at least 24 hours prior to the intervention to reduce the risk of bleeding.
The elevated risk of bleeding must be weighed against the urgency of the intervention when deciding whether to delay an intervention until 24 hours after the last dose of edoxaban. Considering that anticoagulant therapy with this product takes effect in 1 to 2 hours, it should be reintroduced as soon as it is determined that adequate hemostasis has been achieved after a surgical or other interventional procedure. If oral medication cannot be taken during or after a surgical intervention, consider giving a non-oral anticoagulant, followed by a switch to oral administration of this product once daily (see [Dosage]).
Interaction with Other Drugs Affecting Hemostasis
Combination of drugs that affect hemostasis may increase the risk of bleeding. This includes acetylsalicylic acid (ASA), P2Y12 platelet inhibitors, other antithrombotic agents, thrombolytic therapy, selective 5-hydroxytryptamine reuptake inhibitors (SSRIs) or 5-hydroxytryptamine norepinephrine reuptake inhibitors (SNRIs), and chronic nonsteroidal anti-inflammatory drugs (NSAIDs class of drugs) (see [Drug Interactions]).
Patients with prosthetic heart valves and moderate-to-severe mitral stenosis
Edoxaban has not been studied in patients with prosthetic heart valves with or without atrial fibrillation and in the first 3 months after implantation of a bioprosthetic heart valve, or in patients with moderate or severe mitral stenosis. Therefore, it is not recommended for use in these patients.
Patients with hemodynamically unstable PE or those requiring thrombolysis or pulmonary artery tamponade
The safety and efficacy of edoxaban have not been studied in patients with hemodynamically unstable PE or those who may require thrombolysis or pulmonary artery tamponade; therefore, edoxaban is not recommended as an alternative therapy to regular heparin in such patients with PE.
Patients with active cancer
The efficacy and safety of edoxaban in the treatment and/or prevention of VTE in patients with active cancer has not been established.
Laboratory tests for coagulation parameters
Although edoxaban therapy does not require routine monitoring, anticoagulant effects can be assessed by calibrated quantitative assays of anticoagulant factor Xa, which can be helpful in clinical decision making in special circumstances, such as drug overdose and emergency surgery (see [Pharmacokinetics]).
By inhibiting factor Xa, edoxaban prolongs standard coagulation tests such as prothrombin time (PT), INR, and activated partial thromboplastin time (aPTT). The observed changes in coagulation test times at the intended therapeutic dose were small, with a high degree of variability, and were not meaningful for monitoring the anticoagulant effects of edoxaban.
Effect on driving and mechanical handling ability
This product has no or almost no effect on driving and mechanical ability.
Pregnant women and nursing mothers
Women of childbearing age
Women of childbearing age should use contraception during treatment with edoxaban.
Pregnancy
The safety and efficacy of edoxaban in pregnant women have not been established. Animal studies have shown reproductive toxicity (see [Pharmacologic Toxicology]). This product is contraindicated in women during pregnancy due to potential reproductive toxicity and risk of endogenous bleeding, and evidence that edoxaban can cross the placenta (see [Contraindications]).
Lactation
The safety and efficacy of edoxaban in women who are breastfeeding has not been established. Data from animal studies indicate that edoxaban can be secreted into breast milk. Therefore, this product is contraindicated in nursing women (see [Contraindications]). A decision must be made whether to discontinue breast-feeding or to discontinue edoxaban therapy.
Fertility
No specific studies have been conducted in humans to evaluate the effects of edoxaban on fertility. In a study of fertility in male and female rats, no effect was observed. (See [Pharmacology and Toxicology]).
Pediatric Dosage]
The safety and efficacy of this product in pediatric and adolescent patients under 18 years of age have not been determined and no data are available.
Geriatric Use
No dose reduction is required (see [Pharmacokinetics]).
Drug Interactions]
Edoxaban is mainly absorbed in the upper gastrointestinal tract (GI). Therefore, drugs or diseases that increase gastric emptying and intestinal motility may reduce the dissolution and absorption of edoxaban.
Pgp inhibitor
Edoxaban is a substrate for the efflux transport protein Pgp. Pharmacokinetic (PK) studies have shown an increase in edoxaban plasma concentrations when edoxaban is combined with Pgp inhibitors (cyclosporine, dronedarone, erythromycin, ketoconazole, quinidine, or verapamil). The dose of edoxaban in combination with cyclosporine, dronedarone, erythromycin or ketoconazole should be reduced to 30 mg once daily. Clinical data suggest that edoxaban does not require dose reduction when combined with quinidine, verapamil, or amiodarone (see [Dosage]).
Edoxaban has not been studied in combination with other P-gp inhibitors (including HIV protease inhibitors).
A dose of 30 mg once daily is required when combining with the following Pgp inhibitors.
Cyclosporine: The AUC and Cmax of edoxaban were increased by 73% and 74%, respectively, when cyclosporine single dose 500 mg was combined with edoxaban single dose 60 mg.
Dronedarone: Dronedarone 400 mg twice daily for 7 days, combined with a single dose of edoxaban 60 mg on day 5 showed an 85% and 46% increase in the AUC and Cmax of edoxaban, respectively.
Erythromycin: Erythromycin 500 mg four times daily for 8 days, combined with a single dose of edoxaban 60 mg on day 7 showed an 85% and 68% increase in AUC and Cmax of edoxaban, respectively.
Ketoconazole: Ketoconazole 400 mg once daily for 7 days, combined with a single dose of edoxaban 60 mg on day 4 showed an 87% and 89% increase in AUC and Cmax of edoxaban, respectively.
The recommended dose of 60 mg once daily is used in combination with the following Pgp inhibitors.
Quinidine: Quinidine 300 mg once daily on days 1 and 4, 3 times daily on days 2 and 3, and a single dose of edoxaban 60 mg in combination with edoxaban on day 3 showed a 77% and 85% increase in AUC and Cmax, respectively, 24 hours after edoxaban administration.
Verapamil: Verapamil 240 mg once daily for 11 days, combined with a single dose of edoxaban 60 mg on day 10 showed an approximate 53% increase in the AUC and Cmax of edoxaban.
Amiodarone: Amiodarone 400 mg combined with edoxaban 60 mg once daily showed a 40% increase in AUC and a 66% increase in Cmax. The change was not clinically significant. The ENGAGE AF-TIMI 48 study for the treatment of NVAF showed similar efficacy and safety results in subjects with and without amiodarone.
P-gp inducers
The combination of edoxaban with the P-gp inducer rifampicin resulted in a lower mean AUC and shorter half-life of edoxaban, and its pharmacodynamic effects may be reduced. The combination of edoxaban with other P-gp inducers (e.g., phenytoin sodium, carbamazepine, phenobarbital, or Guangyelian) may result in a decrease in edoxaban plasma concentrations. Caution should be exercised when combining edoxaban with P-gp inducers.
P-gp substrates
Digoxin: Edoxaban Cmax was increased by 17% after multiple combinations of edoxaban 60 mg once daily (days 1 to 14) with digoxin 0.25 mg twice daily (days 8 and 9) and 0.25 mg once daily (days 10 to 14), with no significant effect on AUC and renal clearance at steady state. In addition, in a study of the effect of edoxaban on digoxin pharmacokinetics (PK), the results showed an increase in digoxin Cmax of approximately 28% and an increase in AUC of 7%. These results are not clinically significant. No dose adjustment is required when this product is used in combination with digoxin.
Anticoagulants, antiplatelet agents, NSAIDs and SSRIs/SNRIs
Anticoagulants: Edoxaban is contraindicated in combination with other anticoagulants due to increased risk of bleeding (see [Contraindications]).
Acetylsalicylic acid (ASA): Prolonged bleeding time with ASA (100 mg or 325 mg) in combination with edoxaban compared to the drug alone. The steady-state Cmax and AUC of edoxaban were increased by 35% and 32%, respectively, when combined with high-dose ASA (325 mg). Long-term co-administration of edoxaban with high-dose ASA (325 mg) is not recommended. Combination with ASA at doses higher than 100 mg should be done under medical supervision.
Combinations with ASA (low dose ≤ 100 mg/day), other antiplatelet agents, and thienopyridines were allowed in clinical studies and resulted in an approximately 2-fold increase in major bleeding events compared to non-combinations, but to a similar extent in the edoxaban and warfarin groups (see [Precautions]). The combination of low-dose ASA (≤100 mg) did not affect the peak or total exposure of edoxaban after a single dose or at steady state.
Edoxaban can be combined with low-dose ASA (≤ 100 mg/day).
Platelet Inhibitors: The ENGAGE AF-TIMI 48 study allowed the combination of thienopyridines (e.g., clopidogrel), and the risk of clinically relevant bleeding was increased with the combination, but the risk of bleeding was lower in the edoxaban group than in the warfarin group (see [Caution]).
Experience with edoxaban in combination with dual antiplatelet therapy or thrombolytic agents is limited.
NSAIDs: Bleeding time was prolonged with naproxen in combination with edoxaban compared with edoxaban alone. Naproxen had no effect on the Cmax and AUC of edoxaban. Clinical studies have shown that the combination with NSAIDs led to increased clinically relevant bleeding. Long-term combination of edoxaban with NSAIDs is not recommended.
SSRIs/SNRIs: As with other anticoagulants, there is a potential for increased bleeding risk in patients when combined with SSRIs or SNRIs due to the reported effects on platelets.
Effects of edoxaban on other drugs
The Cmax of digoxin increased by 28% when combined with edoxaban; however, there was no effect on AUC. Edoxaban had no effect on Cmax or AUC of quinidine.
The Cmax and AUC of verapamil decreased by 14% and 16%, respectively, after the combination of edoxaban and verapamil.
[Drug overdose].
Edoxaban overdose may result in bleeding. Experience with overdose is very limited.
There are no specific antagonists to counteract the effects of edoxaban.
In the case of edoxaban overdose, activated charcoal should be used as early as possible to reduce its absorption. This recommendation is based on the data available for standard treatment of overdose and similar compounds, and there are no edoxaban clinical research programs that have specifically studied the use of activated charcoal to reduce edoxaban absorption.
Management of Bleeding
If bleeding complications occur in patients receiving edoxaban, the next dose of edoxaban should be delayed appropriately or should be discontinued. The half-life of edoxaban is approximately 10-14 hours (see [Pharmacokinetics]). Management should be individualized according to the severity and location of bleeding. Appropriate symptomatic treatment, such as mechanical compression (e.g., for severe epistaxis), surgical hemostasis using bleeding control procedures, rehydration and hemodynamic support, blood products (concentrated red blood cells or fresh frozen plasma, depending on the associated anemia or coagulation abnormality), or platelets, should be administered as needed.
For life-threatening bleeding that cannot be controlled by transfusion or hemostatic measures, administration of 50 IU/kg factor IV prothrombin complex (PCC) reverses the effects of this product 30 minutes after completion of the infusion.
Recombinant human coagulation factor VIIa (r-FVIIa) may also be used. However, clinical experience with this agent in patients treated with edoxaban is limited.
Depending on the local situation, a coagulation specialist should be consulted in the event of major bleeding.
Fisetin sulfate and vitamin K do not affect the anticoagulant activity of edoxaban.
There is no experience with the use of antifibrinolytics (tranexamic acid, aminocaproic acid) in patients treated with edoxaban, nor is there any scientific basis or dosing experience with the beneficial use of systemic hemostatic agents (desmopressin, peptidase). Edoxaban has a high plasma protein binding rate and is not easily dialyzed.
Clinical trials]
Pharmacodynamic effects
Edoxaban has a rapid onset of action within 1 to 2 hours, which is consistent with the peak concentration (Cmax). Its pharmacodynamic effect can be predicted by anticoagulant factor Xa assay and correlated with the dose and concentration of edoxaban. Edoxaban may prolong clotting times (e.g., prothrombin time (PT) and activated partial thromboplastin time (aPTT)) due to FXa inhibition. At therapeutic doses, these coagulation test times changed as expected; however, such changes were small, had a high degree of variability, and were not significant for monitoring the anticoagulant effects of edoxaban.
Effect of Switching from Rivaroxaban, Dabigatran, or Apixaban to Edoxaban on Coagulation Markers
In clinical pharmacology studies, healthy subjects received rivaroxaban 20 mg once daily, dabigatran 150 mg twice daily, or apixaban 5 mg twice daily and were switched to a single dose of edoxaban 60 mg on day 4 to determine the effect on prothrombin time (PT) and other coagulation biomarkers (e.g., anti-FXa, aPTT). In the rivaroxaban and apixaban groups, PT after switching to edoxaban on day 4 was the same as on day 3. For the dabigatran group, the aPTT effect was stronger after treatment with dabigatran and then switching to edoxaban than after edoxaban monotherapy. The reason for this may be the subsequent effect of dabigatran treatment, but did not lead to prolonged bleeding time.
Based on the above data, when switching from the above anticoagulant to edoxaban, edoxaban may be given starting at the next scheduled dosing time point of the previous anticoagulant (see [Dosage]).
Clinical efficacy and safety
Prevention of stroke and embolism in the body circulation
A clinical study of edoxaban in atrial fibrillation demonstrated the efficacy and safety of two dose groups of edoxaban compared with warfarin for the prevention of stroke and circulatory embolism in non-valvular atrial fibrillation subjects with an intermediate to high risk of stroke and somatic embolic events (SEE).
The pivotal study ENGAGE AFTIMI 48 (a phase 3 event-driven, randomized, multicenter, double-blind, double-model, parallel-group, non-inferiority design study) enrolled 21,105 subjects with a mean CHADS2 score of 2.8 who were randomized to either the edoxaban 30 mg once-daily treatment group, or the edoxaban 60 mg once-daily treatment group, or the warfarin treatment group. In both edoxaban treatment arms, the dose was halved if the subject had one or more of the following clinical factors: moderate renal impairment (CrCL 30-50 mL/min), low body weight (£ 60 kg), or a combination of specific Pgp inhibitors (verapamil, quinidine, and dronedarone).
The primary efficacy endpoint was a composite endpoint of stroke (ischemic or hemorrhagic) and SEE. Secondary efficacy endpoints included the composite endpoint of stroke, SEE and cardiovascular (CV) mortality; the major adverse cardiovascular event (MACE), the composite endpoint of non-fatal MI, non-fatal stroke, non-fatal SEE and death due to CV causes or bleeding; and the composite endpoint of stroke, SEE and all-cause mortality.
The median study drug exposure in the edoxaban 60 mg and 30 mg groups was 2.5 years. Median study follow-up for the edoxaban 60 mg and 30 mg groups was 2.8 years. median subject-year exposure for the 60 mg and 30 mg treatment groups was 15,471 and 15,840, respectively; median subject-year follow-up for the 60 mg and 30 mg treatment groups was 19,191 and 19,216, respectively.
The median TTR (time within the target INR range of 2.0 to 3.0) rate for the warfarin group was 68.4%.
The primary efficacy analysis was designed to show that the time to first stroke or SEE in the modified intent-to-treat (mITT) population during treatment or within 3 days of the last dose was non-inferior to the warfarin group in the edoxaban group. The results of the study showed that the edoxaban 60 mg group was non-inferior to the warfarin group for stroke or SEE (the primary efficacy endpoint) (the upper 97.5% CI for HR was below the prespecified non-inferiority threshold of 1.38) (Table 4).
Table 4 Stroke and body circulation embolic events in the ENGAGE AF-TIMI 48 study (mITT, during treatment)
Primary endpoint Edoxaban 60 mg (dose reduced to 30 mg) (N = 7,012) Warfarin
(N = 7,012) First stroke/SEEa n182232 event rate (%/yr)b1.181.50HR (97.5% CI) 0.79 (0.63, 0.99) Non-inferiority P valuec<0.0001 First ischemic stroke n135144 event rate (%/yr)b0.870.93HR (95% CI ) 0.94 (0.75, 1.19) First hemorrhagic stroke n4076 Event rate (%/yr)b0.260.49HR (95% CI)0.53 (0.36, 0.78) First SEE n (%/yr)a8 (0.05)13 (0.08)HR (95% CI)0.62 (0.26, 1.50) Abbreviations: HR = risk ratio compared with warfarin, CI = confidence interval, n = number of events, mITT = modified intention-to-treat, N = number of cases of subjects in the mITT population, SEE = somatic circulatory embolic events, yr = years.
a 1 subject may be counted in multiple rows.
b Event rate (%/yr) was calculated as number of events/subjects-years exposure cases.
c Bilateral P values are based on a non-inferiority cut-off of 1.38.
The number of cases of subjects in the ITT population (superiority analysis set) who had an adjudicated stroke or SEE throughout the study period was 296 in the 60 mg group (1.57% per year) and 337 in the warfarin group (1.80% per year). The HR for the edoxaban 60 mg group was 0.87 (99% CI: 0.71, 1.07, with a superiority p value of 0.08) compared with subjects in the warfarin-treated group.
Subgroup analysis showed that the primary endpoint event rate for subjects (weight ≤60 kg, moderate renal impairment or combined use of Pgp inhibitors) in the 60 mg treatment group dosed down to 30 mg in the ENGAGE AFTIMI 48 study was 2.29% per year compared to 2.66% per year in the warfarin group [HR (95% CI): 0.86 (0.66, 1.13)].
The efficacy results (including dose adjusted subjects when necessary) for the prespecified major subgroups (including age, weight, sex, renal function status, previous stroke or TIA, diabetes mellitus and P-gp inhibitors) were generally consistent with the primary efficacy results for the overall population in the trial.
In the warfarin group, the clinical study centers with shorter mean time to target range (TTR) INR control (lowest 3 quartiles, INR TTR ≤57.7% to ≤73.9%) had a primary endpoint risk ratio (edoxaban 60 mg vs. warfarin) of 0.73 to 0.80. The clinical study centers with the best warfarin treatment control (effective treatment range INR values of quartile 4 > 73.9%), the value was 1.07.
Edoxaban was statistically significant compared with warfarin in terms of the interaction effect on the primary study endpoint (stroke/SEE) and renal function (P value: 0.0042; mITT, for the entire study period).
Ischemic stroke/SEE by creatinine clearance category in patients with NVAF from the ENGAGE AF-TIMI 48 study is shown in Table 5. event rates were reduced with elevated CrCL in both treatment groups.
Table 5 Number of ischemic stroke/SEE events by creatinine clearance category in the ENGAGE AF-TIMI 48 study, mITT analysis set for the entire study period
CrCL subgroup (mL/min) Edoxaban 60 mg
(N = 7,012) Warfarin
(N = 7,012) n number of events events
Incidence
(%/year) n number of events events
Incidence
(%/year) HR (95% CI) ≥ 30 ～ ≤ 501,302,631.891,305672.050.93 (0.66, 1.31)> 50 ～ ≤ 702,093851.512,106951.700.88 (0.66, 1.18)> 70 ～ ≤ 901,661,450.991, 703501.080.92 (0.61, 1.37)> 90 to ≤ 110927271.08960260.981.10 (0.64, 1.89)> 110 to ≤ 130497141.01469100.781.27 (0.57, 2.85)> 130462100.7841830.25 — * Abbreviations: n = number of subject cases; mITT population for the entire study period; n = number of patients in the subgroup.
* HR was not calculated if the number of events in a treatment group < 5.
Within the renal function subgroup, the secondary efficacy endpoint results were consistent with the primary endpoint results.
Efficacy testing was performed for the entire study period of ITT.
The number of subjects with stroke and SEE was lower in the edoxaban 60 mg treatment group than in the warfarin group (1.57% and 1.80% per year, respectively), with an HR of 0.87 (99% CI: 0.71, 1.07, with a superiority p value of 0.0807).
The HR (99% CI) for stroke, SEE, and CV mortality was 0.87 (0.76, 0.99), MACE was 0.89 (0.78, 1.00), and stroke, SEE, and all-cause mortality was 0.90 (0.80, 1.01) in the edoxaban 60 mg treatment group compared with the warfarin group for the composite endpoint.
The all-cause mortality (adjudicated deaths) outcome in the ENGAGE AF-TIMI 48 study was 769 (3.99% per year) in the edoxaban 60 mg group (dose reduced to 30 mg) compared with 836 (4.35% per year) in the warfarin group [HR (95% CI): 0.91 (0.83, 1.01)].
All-cause mortality (adjudicated deaths) in the renal function subgroup (edoxaban vs. warfarin): CrCL 30 to ≤ 50 mL/min [HR (95% CI): 0.81 (0.68, 0.97)]; CrCL > 50 to < 80 mL/min [HR (95% CI): 0.87 (0.75, 1.02)]; CrCL ≥ 80 mL/min [HR (95% CI): 1.15 (0.95, 1.40)].
Mortality from cardiovascular events was lower in the edoxaban 60 mg group (dose reduced to 30 mg) than in the warfarin group [HR (95% CI): 0.86 (0.77, 0.97)].
Efficacy determination of cardiovascular mortality in the renal function subgroup (edoxaban vs. warfarin): CrCL 30 to ≤ 50 mL/min [HR (95% CI): 0.80 (0.65, 0.99)]; CrCL > 50 to < 80 mL/min [HR (95% CI): 0.75 (0.62, 0.90)]; CrCL ≥ 80 mL/min [HR (95% CI): 1.16 (0.92, 1.46)].
Safety of NVAF patients in the ENGAGE AF-TIMI 48 study
The primary safety endpoint was major bleeding.
The risk of major bleeding (2.75% and 3.43% per year, respectively) [HR (95% CI): 0.80 (0.71, 0.91); p = 0.0009], ICH (0.39% and 0.85% per year, respectively) [HR (95% CI): 0.47 (0.34, 0.63); p < 0.0001] in the edoxaban 60 mg treatment group , the risk of other types of bleeding was significantly lower than in the warfarin group (see Table 6).
The number of fatal bleeding events was significantly lower in the edoxaban 60 mg treatment group than in the warfarin group (0.21% and 0.38%) [HR (95% CI): 0.55 (0.36, 0.84); p value for superiority 0.0059], mainly due to a reduction in fatal ICH bleeding [HR (95% CI): 0.58 (0.35, 0.95); p = 0.0312].
Table 6 Bleeding events in the ENGAGE AF-TIMI 48 study (safety analysis during treatment)
Edoxaban 60 mg
(dose reduced to 30 mg)
(n = 7,012) Warfarin
(n = 7,012) Major bleeding n418524 Event rate (%/yr)a2.753.43HR (95% CI)0.80 (0.71, 0.91) P value 0.0009 ICHb n61132 Event rate (%/yr)a0.390.85HR (95% CI)0.47 (0.34, 0.63) Fatal bleeding n3259 Event rate (%/yr)a0.210.38HR (95% CI)0.55 (0.36, 0.84) Clinically relevant non-major bleeding n1,2141,396 Event rate (%/yr)a8.6710.15HR (95% CI)0.86 (0.80, 0.93) Any confirmed bleedingc n1,8652, 114 Event rate (%/yr)a14.1516.40HR (95% CI)0.87 (0.82, 0.92) Abbreviations: ICH = intracranial hemorrhage, HR = risk ratio compared with warfarin, the
CI = confidence interval, CRNM = clinically relevant nonmajor bleeding, n = number of cases of subjects with an event; N = number of cases of subjects in the safety population, yr = year.
a Event rate (%/yr) calculated as number of events/subjects-years exposure cases.
b ICH includes major hemorrhagic stroke, subarachnoid hemorrhage, epidural/subdural hemorrhage, and ischemic stroke with major hemorrhagic transformation. All ICH reported in the adjudicated cerebrovascular and non-intracranial hemorrhage eCRF tables and confirmed by the adjudicator are counted in the ICH total.
c “Any confirmed bleeding” includes clinically significant bleeding events as defined by these adjudicators.
Note: If one subject has an event of the type described above, that subject may be counted in multiple subgroup categories. This analysis includes the first event in each classification.
Major, fatal, and intracranial hemorrhagic events by creatinine clearance category in NVAF patients studied in ENGAGE AF-TIMI 48 are shown in Tables 7, 8, and 9, respectively. event rates decreased in both treatment groups at elevated CrCL.
Table 7 Number of major bleeding events by creatinine clearance category in the ENGAGE AF-TIMI 48 study (during treatmenta safety analysis)
CrCL subgroup (mL/min) Edoxaban 60 mg
(n = 7,012) Warfarin
(n = 7,012) n Number of events Events
Incidence
(%/year) n Number of events Events
Incidence
(%/year) HR (95% CI) ≥ 30 ～ ≤ 501,302963.911,3051285.230.75 (0.58, 0.98)> 50 ～ ≤ 702,0931483.312,1061713.770.88 (0.71, 1.10)> 70 ～ ≤ 901, 6611082.881,7031193.080.93 (0.72, 1.21)> 90 ～ ≤ 110927291.33960562.480.54 (0.34, 0.84)> 110 ～ ≤ 130497201.70469242.140.79 (0.44, 1.42)> 130462131.18418212.080.58 (0.29, 1.15)
Table 8 Number of lethal bleeding events by creatinine clearance in the ENGAGE AF-TIMI 48 study (during treatmenta safety analysis)
CrCL subgroup (mL/min) Edoxaban 60 mg
(n = 7,012) Warfarin
(n = 7,012) n Number of events Events
Incidence
(%/year) n Number of events Events
Incidence
(%/year) HR (95% CI) ≥ 30 ～ ≤ 501,30290.361,305180.720.51 (0.23, 1.14)> 50 ～ ≤ 702,09380.182,106230.500.35 (0.16, 0.79)> 70 ～ ≤ 901,661,100.261, 70390.231.14 (0.46, 2.82)> 90 ～ ≤ 11092720.0996030.13–*> 110 ～ ≤ 13049710.0846950.44–*> 13046220.1841800.00–*
Table 9 Number of intracranial hemorrhage events by creatinine clearance classification in the ENGAGE AF-TIMI 48 study (during treatmenta safety analysis)
CrCL subgroup (mL/min) Edoxaban 60 mg
(n = 7,012) Warfarin
(n = 7,012) n Number of events Events
Incidence
(%/year) n Number of events Events
Incidence
(%/year) HR (95% CI) ≥ 30 ～ ≤ 501,302160.641,305351.400.45 (0.25, 0.81)> 50 ～ ≤ 702,093190.422,106511.100.38 (0.22, 0.64)> 70 ～ ≤ 901,661170.441, 703350.890.50 (0.28, 0.89)> 90 ～ ≤ 11092750.2396060.260.87 (0.27, 2.86)> 110 ～ ≤ 13049720.1746930.26–*> 13046210.0941810.10–* Abbreviations: n = number of subject cases; mITT population for the entire study period; n = number of patients in the subgroup
* HR was not calculated if the number of events in a treatment group < 5.
a
Treatment period: time from the first dose of study drug to the last dose + 3 days.
In the ENGAGE AF TIMI 48 study, subgroup analysis showed that major bleeding events occurred in 104 subjects (3.05% per year) in the edoxaban 60 mg treatment group dose reduced to 30 mg (weight ≤60 kg, moderate renal impairment or combined use of P gp inhibitors), and in 166 subjects (4.85% per year) in the warfarin group dose reduced [HR (95% CI): 0.63 (0.50, 0.81)].
In the ENGAGE AFTIMI 48 study, a significant improvement in net clinical benefit (first stroke, SEE, major bleeding, or all-cause death; mITT population, entire study period) was seen in the edoxaban 60 mg treatment group compared with the warfarin group, HR (95% CI): 0.89 (0.83, 0.96); p = 0.0024.
In the ENGAGE AF-TIMI 48 study, 469 Chinese subjects were randomized to the edoxaban 30 mg once daily, edoxaban 60 mg once daily, or warfarin treatment groups. The results of the subgroup analysis in the Chinese population were consistent with the global results, with the edoxaban 60 mg dose group having a lower annual incidence of stroke or embolic events in the body circulation compared with the warfarin group, 1.82% and 6.02 % (HR: 0.32; 97.5% CI: 0.11 to 0.90), respectively, and fewer major bleeding events, 2.77% and 5.79%/year (HR: 0.49 ; 95% CI: 0.22 to 1.09) (Table 10).
Table 10 Primary efficacy and safety results of the ENGAGE AF-TIMI 48 study (Chinese population)
Endpoint Edoxaban 60 mg (dose reduced to 30 mg) Warfarin first stroke/SEE a) n/N6/15019/163 event rate (%/yr) 1.826.02HR (97.5% CI) 0.32 (0.11, 0.90) Major bleeding b) n/N9/15018/163 event rate (%/yr) 2.775. 79HR (95% CI) 0.49 (0.22, 1.09) Abbreviations: HR = risk ratio compared with warfarin, CI = confidence interval, n = number of events, N = number of subjects in the mITT or safety analysis set, SEE = body circulation embolic event, yr = year.
a) During-treatment mITT analysis set (mITT = modified intention-to-treat analysis set)
b) Intertreatment safety analysis set
DVT treatment, PE treatment and recurrent DVT and PE (VTE) prophylaxis
Clinical studies of edoxaban in VTE subjects have confirmed the efficacy and safety of DVT and PE treatment and relapse prevention.
In the HokusaiVTE pivotal study, 8,292 subjects were enrolled and received initial heparin therapy (enoxaparin or regular heparin) followed by randomization to edoxaban 60 mg once daily or a control drug. In the control group, subjects received initial heparin and warfarin combination therapy, adjusted to a target INR (2.0 to 3.0), followed by warfarin monotherapy. The investigators determined the duration of treatment to range from 3 to 12 months based on the clinical characteristics of the patients.
The majority of patients in the edoxaban treatment group were Caucasian (69.6%) and Asian (21.0%), 3.8% were black, and 5.3% were of other races.
For subjects treated for at least 3 months, 3,718 (91.6%) were in the edoxaban group and 3,727 (91.4%) in the warfarin group; for subjects treated for at least 6 months, 3,495 (86.1%) were in the edoxaban group and 3,491 (85.6%) in the warfarin group; for subjects treated for 12 months, 1,643 (40.5%) were in the edoxaban group , 1,659 (40.4%) in the warfarin group.
The primary efficacy endpoint was symptomatic VTE recurrence, defined as a composite endpoint of recurrent symptomatic DVT, nonfatal symptomatic PE, and fatal PE among subjects during the 12-month study period. Secondary efficacy endpoints included the composite clinical outcome of recurrent VTE and all-cause death.
Subjects with one or more clinical factors (moderate renal impairment (CrCL 30-50 mL/min); weight ≤ 60 kg; and combination with specific Pgp inhibitors) were given edoxaban 30 mg once daily.
The Hokusai-VTE study confirmed (Table 11) that the primary efficacy outcome (recurrent VTE) was non-inferior in the edoxaban group compared with the warfarin group: recurrent VTE occurred in 130/4,118 subjects (3.2%) in the edoxaban group and 146/4,122 subjects (3.5%) in the warfarin group [HR (95% CI). 0.89 (0.70, 1.13); non-inferiority p < 0.0001]. The median TTR (time within the target INR range of 2.0 to 3.0) in the warfarin group was 65.6%. Among subjects reporting PE (with or without DVT), VTE recurrence occurred in 47 (2.8%) subjects in the edoxaban group and 65 (3.9%) subjects in the warfarin group [HR (95% CI): 0.73 (0.50, 1.06)].
Table 11 Efficacy results of the HokusaiVTE study – mITT population throughout the study period
Primary endpointa Edoxaban 60 mg (dose reduced to 30 mg) (n = 4,118) Warfarin
(n = 4,122) HR (95% CI)b
P valuec All subjects reporting symptomatic recurrent VTEc, n (%) 130 (3.2)146 (3.5) 0.89 (0.70, 1.13) P value < 0.0001 (non-inferiority) PE with or without DVT73 (1.8)83 (2.0) Fatal PE or death where PE could not be excluded24 (0.6)24 (0.6) Non-fatal PE49 (1.2)59 (1.4) DVT only57 (1.4)63 (1.5) Abbreviations: CI = confidence interval; DVT = deep vein thrombosis; mITT = modified intention-to-treat; HR = risk ratio compared with warfarin; n = number of cases of subjects with an event; N = number of cases of subjects in the mITT population; PE = pulmonary embolism; VTE = venous thrombosis embolism.
a. The primary efficacy endpoint is adjudicated symptomatic recurrent VTE (i.e., DVT, nonfatal PE, and fatal PE composite endpoint).
b. HR, based on a Cox proportional risk regression model with two-sided CI , including treatment and the following randomization stratification factors as covariates: diagnosis given (PE with or without DVT, DVT only), baseline risk factors (transient, all others), and need for edoxaban/edoxaban placebo 30 mg at randomization.
c. P-values are based on a pre-specified non-inferiority cut-off of 1.5.
VTE recurrence occurred in 15 cases (2.1%) in the edoxaban group and 22 cases (3.1%) in the warfarin group among subjects whose dose was adjusted to 30 mg (mainly subjects with low body weight or poor renal function) [HR (95% CI): 0.69 (0.36, 1.34)].
The secondary composite endpoint of VTE recurrence and all-cause death occurred in 138 (3.4%) subjects in the edoxaban group and 158 (3.9%) in the warfarin group [HR (95% CI): 0.87 (0.70, 1.10)].
All-cause death (adjudicated death) was reported in 136 (3.3%) subjects in the edoxaban 60 mg group (dose reduced to 30 mg) and 130 (3.2%) subjects in the warfarin group in the Hokusai-VTE study.
Subgroup analysis of subjects with pre-set PE showed that 447 (30.6%) subjects in the edoxaban group and 483 (32.2%) subjects in the warfarin group had definite PE and NTproBNP ≥ 500 pg/mL. 14 (3.1%) subjects in the edoxaban and 30 (6.2%) subjects in the warfarin group achieved the primary efficacy outcome [HR (95% CI): 0.50 (0.26, 0.94)].
The efficacy results for the prespecified primary subgroups (including age, weight, sex, and renal functional status), including dose reduction subjects when necessary, were consistent with the primary efficacy results for the overall population in the trial.
Safety of patients with VTE (DVT and PE) in the Hokusai-VTE study
The primary safety endpoint was clinically relevant bleeding (major bleeding or clinically relevant non-major bleeding).
Bleeding events that were centrally adjudicated in the safety analysis during treatment are shown in Table 12.
The risk of the primary safety endpoint (clinically relevant bleeding, a composite endpoint of major bleeding and clinically relevant non-major bleeding (CRNM)) was significantly lower in the edoxaban group compared with the warfarin group. Clinically relevant bleeding was 349/4,118 (8.5%) in the edoxaban group and 423/4,122 (10.3%) in the warfarin group, respectively [HR (95% CI): 0.81 (0.71, 0.94); p-value for superiority 0.004].
Table 12 Bleeding events in the HokusaiVTE study (during treatmenta safety analysis)
Edoxaban 60 mg (dose reduced to 30 mg)
(n = 4,118) Warfarin
(n = 4,122) Clinically relevant bleeding (major bleeding and CRNM)b, n (%) n349 (8.5)423 (10.3) HR (95% CI) 0.81 (0.71, 0.94) P value 0.004 (superiority) Major bleeding, n (%) n56 (1.4)66 (1.6) HR (95% CI) 0.84 (0.59, 1.21) Fatal ICH06 (0.1) Non-fatal ICH5 (0.1)12 (0.3) Clinically relevant non-major bleeding n298 (7.2)368 (8.9) HR (95% CI)0.80 (0.68, 0.93) All bleeding n895 (21.7)1,056 (25.6) HR (95% CI)0.82 (0.75 , 0.90) Abbreviations: ICH = intracranial hemorrhage, HR = risk ratio compared with warfarin; CI = confidence interval; N = number of cases in subjects in safety population; n = number of events; CRNM = clinically relevant nonmajor bleeding
a Treatment period: time from the first dose of study drug to the last dose + 3 days.
b Primary safety endpoint: clinically relevant bleeding (a composite endpoint of major bleeding and clinically relevant non-major bleeding).
Subgroup analysis showed that in the Hokusai-VTE study, major bleeding or CRNM events occurred in 58 (7.9%) in the edoxaban group and 92 (12.8%) in the warfarin group in subjects who had a dose reduction to 30 mg because of body weight ≤ 60 kg, moderate renal impairment, or coadministration of a P-gp inhibitor [HR (95%): 0.62 (0.44, 0.86) .
The Hokusai-VTE study showed a net clinical benefit (VTE recurrence, major bleeding, or all-cause death; mITT population throughout the study period) of 1.00 (0.85, 1.18) for edoxaban compared with warfarin.
In the Hokusai-VTE study, 486 Chinese subjects received initial heparin therapy (enoxaparin or plain heparin) followed by randomization to edoxaban 60 mg once daily or initial heparin combined with warfarin until an INR of 2.0-3.0 followed by warfarin alone. The results of the subgroup analysis in the Chinese population were consistent with the global results, with a lower rate of symptomatic VTE recurrence in the edoxaban 60 mg dose group compared with the warfarin group, at 3.3% and 4.6 % (HR: 0.72; 95% CI: 0.29, 1.82), and fewer clinically relevant bleeding events (major bleeding and clinically relevant non-major bleeding) (HR: 0.63; 95% CI: 0.36, 1.11) (Table 13).
Table 13 Key efficacy and safety results of the Hokusai-VTE study (Chinese population)
Endpoint edoxaban 60 mg (dose reduced to 30 mg) Warfarin symptomatic VTE recurrence in all subjects a) n/N8/24311/241 event rate (%) 3.34.6HR (95% CI) 0.72 (0.29, 1.82) Clinically relevant bleeding (major bleeding and CRNM) b) n/N20/24331/241 event rate ( %) 8.212.9HR (95% CI) 0.63 (0.36, 1.11) Abbreviations: HR = risk ratio compared with warfarin; CI = confidence interval l; N = number of subjects in mITT or safety analysis set; n = number of events; CRNM = clinically relevant non-major bleeding
a) mITT during the entire study (mITT = modified intention-to-treat analysis set)
b) safety analysis set during treatment
Patients receiving cardioversion
In a multicenter, prospective, randomized, open, using blinded endpoint evaluation study (ENSURE-AF), 2199 subjects with non-valvular atrial fibrillation (not taking and having taken oral anticoagulants) scheduled for cardioversion were randomized 1:1, comparing edoxaban 60 mg once-daily treatment with enoxaparin/warfarin treatment (, with a treatment target INR of 2.0 to 3.0), with a mean TTR of 70.8% in the warfarin group. As a result, a total of 2149 subjects were treated with edoxaban (N = 1067) or enoxaparin/warfarin (N = 1082). Subjects in the edoxaban group received edoxaban 30 mg once daily if one or more of the following clinical factors were present: moderate renal impairment (CrCL 30-50 mL/min), low body weight (£ 60 kg), or combination with a specific P-gp inhibitor. The majority of patients in the edoxaban and warfarin groups underwent cardioversion (83.7% and 78.9%, respectively) or self-recovery (6.6% and 8.6%, respectively). The study used either TEE-guided cardioversion (within 3 days of the start of cardioversion) or conventional cardioversion (at least 21 days prior to treatment). Subjects continued treatment for 28 days after cardioversion.
The primary efficacy endpoint of the study was the composite endpoint of all strokes, body circulation embolic events, myocardial infarction, and cardiovascular mortality. A total of 5 events (0.5%, 95% CI 0.15% to 1.06%) occurred in subjects in the edoxaban group (N = 1095) and 11 events (1.0%, 95% CI 0.50% to 1.78%) in subjects in the warfarin group (N = 1104); the ratio (OR) was 0.46 (95% CI 0.12 to 1.43). For the entire study period of the ITT analysis set, the mean duration of treatment was 66 days.
The primary safety endpoint of the study was the composite endpoint of major bleeding and clinically relevant non-major bleeding (CRNM). A total of 16 events (1.5%, 95% CI 0.86% to 2.42%) occurred in subjects in the edoxaban group (N = 1067) and 11 events (1.0%, 95% CI 0.51% to 1.81%) in subjects in the warfarin group (N = 1082); the ratio (OR) was 1.48 (95% CI 0.64 to 3.55); safety during treatment Analysis set.
This exploratory study demonstrated a lower incidence of major and clinically relevant nonmajor bleeding and thromboembolism in both treatment groups during cardioversion therapy.
Pharmacology and Toxicology]
Pharmacological effects
Edoxaban is a selective inhibitor of coagulation factor Xa (FXa), and its anticoagulant effect does not require the participation of antithrombin III. Edoxaban can inhibit free FXa and thrombinogenase activity and inhibit thrombin-induced platelet aggregation. Inhibition of coagulation factor Xa in the coagulation cascade reduces thrombin production and inhibits thrombus formation.
Toxicological studies
Genotoxicity
Edoxaban and its human-specific metabolite M-4 showed positive results in the in vitro chromosomal aberration test and negative results in the Ames test, the rat in vitro DNA synthesis test, the human lymphocyte micronucleus test, the rat liver micronucleus test, and the rat bone marrow micronucleus test.
Reproductive toxicity
Fertility and early embryonic development toxicity were not observed in rats given edoxaban orally at doses up to 1000 mg/kg/day (162 times the human administered dose of 60 mg/day, based on body surface area conversion).
In pregnant rats and rabbits, oral administration of edoxaban was 16 and 8 times the human dose, respectively, based on body surface area and AUC, and no embryo-fetal growth toxicity was observed. Edoxaban was secreted in the milk of rats.
Carcinogenicity
In mice given edoxaban orally for 104 weeks at a dose of 500 mg/kg/day, the exposure (AUC) was 3 times (male) and 6 times (female) the human exposure (AUC) at a clinical dose of 60 mg/day, respectively, and no carcinogenicity was observed. In rats, oral administration of edoxaban at doses of 600/400 mg/kg/day (males) and 200 mg/kg/day (females) for 104 weeks resulted in 8 times (males) and 14 times (females) the human exposure at the clinical dose of 60 mg/day, respectively, and no carcinogenicity was observed.
Pharmacokinetics]
Absorption
Edoxaban reaches peak plasma concentration within 1~2 hours after being absorbed. The absolute bioavailability is about 62%. Food causes a variable increase in peak exposure, but the effect on total exposure is minimal. edoxaban can be taken with food or alone in the ENGAGE AF-TIMI 48 and Hokusai-VTE studies. edoxaban is extremely difficult to dissolve at a pH of 6.0 or higher. Coadministration with proton pump inhibitors did not produce a meaningful effect on edoxaban exposure.
Distribution
A biphasic distribution was observed. The mean (SD) volume of distribution was 107 (19.9) L.
The in vitro plasma protein binding rate was approximately 55%. No clinically relevant accumulation (accumulation ratio 1.14) was observed after once-daily administration of edoxaban. steady-state concentrations were achieved within 3 days.
Biotransformation
The predominant form in plasma is the prototype edoxaban drug. Edoxaban is metabolized by hydrolysis (mediated by carboxylesterase 1), coupling, or CYP3A4/5-mediated oxidation (< 10%). In healthy subjects, edoxaban had three active metabolites, with the major metabolite from hydrolysis (M4) being active at exposures below 10% of the parent compound. Exposure to the other metabolites was less than 5%. Edoxaban is a substrate of the efflux P-glycoprotein (P-gp) transporter protein, but not of the uptake transporter protein (e.g., organic anion transporter polypeptide OATP1B1, organic anion transporter OAT1 or OAT3, or organic cation transporter OCT2). Its active metabolites are substrates of OATP1B1.
Clearance
In healthy subjects, the predicted total clearance was 22 (±3) L/hour; 50% was cleared by the kidneys (11 L/hour). Renal clearance was approximately 35% of the administered dose. The remaining routes of clearance were metabolism and biliary/small intestinal excretion. The t½ for oral administration is 10 to 14 hours.
Linearity/non-linearity
The pharmacokinetics of edoxaban are approximately dose-dependent in healthy subjects at doses in the range of 15 mg to 60 mg.
Special Populations
Geriatric patients
In combination with renal function and body weight, a population pharmacokinetic analysis of the pivotal phase 3 study in NVAF patients (ENGAGE AF-TIMI 48) showed no additional clinically significant effect of age on the pharmacokinetics of edoxaban.
Gender
Population pharmacokinetic analysis of the Phase 3 study in patients with NVAF (ENGAGE AF-TIMI 48), taking weight into account, showed no additional clinically significant effect of gender on the pharmacokinetics of edoxaban.
Race
Population pharmacokinetic analysis of the ENGAGE AF-TIMI 48 study showed that peak and total exposures in Asian patients were comparable to those in non-Asian patients.
Renal Impairment
Compared to subjects with normal renal function, plasma AUC was increased by 32%, 74% and 72% in subjects with mild (CrCL > 50 to 80 mL/min), moderate (CrCL 30 to 50 mL/min) and severe renal impairment (CrCL < 30 mL/min but no dialysis), respectively. In patients with renal impairment, metabolic profiles were altered and higher amounts of active metabolites were formed.
Edoxaban plasma concentrations were linearly correlated with anti-FXa activity, regardless of renal function.
Total exposure was 93% higher in ESRD subjects on peritoneal dialysis than in healthy subjects.
Population PK models showed that exposure among patients with severe renal impairment (CrCL of 15-29 mL/min) was approximately twice that of patients with normal renal function.
Anti-FXa activity by CrCL
The anti-clotting factor Xa activity of edoxaban when used for each indication according to CrCL is shown in Table 14.
Table 14 Anti-FXa activity of edoxaban by creatinine clearance
Edoxaban
Dose CrCL
(mL/min) Edoxaban
Anti-FXa activity
After administration (IU/mL)1 Edoxaban
Anti-FXa activity
Before administration (IU/mL)2 Median value [range: 2.5% to 97.5%] Stroke and body circulation embolism prevention: NVAF30 mg QD ≥ 30 ~ ≤ 502.92
[0.33 to 5.88] 0.53
[0.11 to 2.06] 60 mg QD*
> 50 ～ ≤ 704.52
[0.38～7.64]0.83
[0.16～2.61]> 70 ～ ≤ 904.12
[0.19～7.55]0.68
[0.05～2.33]> 90 ～ ≤ 1103.82
[0.36～7.39]0.60
[0.14～3.57]> 110 ～ ≤ 1303.16
[0.28～6.71]0.41
[0.15～1.51]> 1302.76
[0.12～6.10]0.45
[0.00 to 3.10] Treatment of DVT and PE, prevention of recurrence of DVT and PE (VTE) 30 mg QD ≥ 30 ~ ≤ 502.21
[0.14 to 4.47] 0.22
[0.00～1.09]60 mg QD*> 50 ～ ≤ 703.42
[0.19～6.13]0.34
[0.00～3.10]> 70 ～ ≤ 902.97
[0.24～5.82]0.24
[0.00～1.77]> 90 ～ ≤ 1102.82
[0.14～5.31]0.20
[0.00～2.52]> 110 ～ ≤ 1302.64
[0.13～5.57]0.17
[0.00～1.86]> 1302.39
[0.10～4.92]0.13
[0.00 to 2.43]* Reduced dose to 30 mg due to low body weight ≤ 60 kg or use of specific P-glycoprotein (P-gp) inhibitors in combination.
1 Post-administration values, equivalent to Cmax (post-administration samples were collected 1 to 3 hours after edoxaban administration)
2 Pre-dose value, equivalent to Cmin
Although edoxaban therapy does not require routine monitoring, anticoagulation can be assessed by calibrated quantitative anti-factor Xa assays, and edoxaban exposure can be useful for clinical decision making in special circumstances, such as drug overdose and emergency surgery (see [Precautions]).
Hemodialysis
Total edoxaban exposure was reduced by less than 9% with a 4-hour hemodialysis session.
Hepatic impairment
The pharmacokinetics and pharmacodynamics in patients with mild to moderate hepatic impairment were comparable to those of the corresponding healthy controls. Edoxaban has not been studied in patients with severe hepatic impairment (see [DOSAGE]).
Body weight
In the ENGAGE AF-TIMI 48 study, a population pharmacokinetic analysis of NVAF patients showed a 40% increase in Cmax and 13% increase in AUC in patients with low body weight (55 kg) compared to patients with high body weight (84 kg). 50%, with similar efficacy and reduced bleeding events compared to the warfarin group.
Pharmacokinetic/pharmacodynamic relationships
PT, INR, aPTT and anticoagulation factor Xa were linearly correlated with edoxaban concentration.
Storage
Store under 30℃ in a sealed container.
Package
Polyvinyl chloride/aluminum foil blister pack.
15mg: 7 tablets/box, 14 tablets/box.
30mg: 7tablets/box, 14tablets/box, 28tablets/box, 98tablets/box.
60mg: 7tablets/box, 14tablets/box, 28tablets/box, 98tablets/box.
【Validity】36 months.
Executive Standard】Imported drug registration standard JX20180241.
【Approval number】.
【Manufacturing Company
Company Name: Daiichi Sankyo Europe GmbH
Production Address: Luitpoldstrasse 1, 85276, Pfaffenhofen, Bayern, Germany
Hotline：400-656-3228
Fax: 021-60397399
Website: http://www.daiichisankyo.com.cn