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brand savaysa 60 mg tablet

In stock Manufacturer DAIICHI SANKYO, 65597020330
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Uses

Embolism Associated with Atrial Fibrillation

Edoxaban tosylate is used to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Current evidence suggests that edoxaban is at least as effective as well-controlled warfarin therapy in the prevention of stroke and systemic embolism and is associated with a lower risk of bleeding and cardiovascular death than warfarin. However, the benefit of edoxaban in reducing ischemic stroke appears to be strongly dose- and plasma-concentration dependent, and the drug should not be used in patients with a creatinine clearance exceeding 95 mL/minute because of an increased risk of ischemic stroke in such patients.(See Reduced Efficacy in Nonvalvular Atrial Fibrillation Patients with Creatinine Clearance Exceeding 95 mL/minute under Warnings/Precautions: Warnings, in Cautions.)

The American College of Chest Physicians (ACCP), the American College of Cardiology (ACC), the American Heart Association (AHA), the American Stroke Association (ASA), and other experts currently recommend that antithrombotic therapy be administered to all patients with nonvalvular atrial fibrillation (i.e., atrial fibrillation in the absence of rheumatic mitral stenosis, a prosthetic heart valve, or mitral valve repair) who are considered to be at increased risk of stroke, unless such therapy is contraindicated. Recommendations regarding choice of antithrombotic therapy are based on a patient's relative risk for stroke and bleeding. In general, oral anticoagulant therapy (traditionally warfarin) is recommended in patients who have a moderate to high risk for stroke and acceptably low risk of bleeding, while aspirin or no antithrombotic therapy may be considered in patients at low risk of stroke. Although many risk stratification methods have been used, patients considered to be at increased risk of stroke generally include those with prior ischemic stroke or transient ischemic attack (TIA), advanced age (e.g., 75 years or older), history of hypertension, diabetes mellitus, or congestive heart failure. In addition, population-based studies suggest that female sex is an important risk factor for stroke in patients with atrial fibrillation, particularly in patients 75 years of age or older, and AHA and ASA recommend the use of risk stratification tools that account for age- and sex-specific differences in stroke risk. One such tool is the CHA2DS2-VASc score, an extension of the CHADS2 system (which considers the risk factors congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, and prior stroke/TIA) that adds extra points for female sex (1 point); previous myocardial infarction, peripheral arterial disease, or aortic plaque (1 point); and age 65-74 years (1 point) or 75 years or older (2 points).

The risk of thromboembolism in patients with atrial flutter is not as well established as it is in those with atrial fibrillation. In addition, many patients with atrial flutter have alternating periods of atrial fibrillation. Experts state that antithrombotic therapy in patients with atrial flutter generally should be managed in the same manner as in patients with atrial fibrillation.

Although warfarin traditionally has been used for oral anticoagulation in patients with atrial fibrillation at increased risk of stroke, non-vitamin K antagonist oral anticoagulants such as edoxaban may provide certain advantages over warfarin (e.g., rapid onset of action, predictable anticoagulant effect, no requirement for coagulation monitoring, less potential for drug-drug and drug-food interactions), and are considered by some experts to be useful alternatives to warfarin in selected patients. The non-vitamin K antagonist oral anticoagulants may be particularly useful in patients at moderate to high risk of stroke who are unable to comply with warfarin monitoring requirements or in whom a consistent therapeutic response to warfarin has not been achieved (e.g., because of drug or food interactions), while warfarin may continue to be preferred in patients who are optimally managed with well-controlled international normalized ratios (INRs) (e.g., INR in therapeutic range more than 70% of the time). Warfarin generally should remain the treatment of choice in patients with severe renal impairment pending clinical outcomes data with the non-vitamin K antagonist oral anticoagulants in these patients. Because of the lack of direct, comparative studies, the relative efficacy and safety of the non-vitamin K antagonist anticoagulants (e.g., apixaban, dabigatran, edoxaban, rivaroxaban) for the prevention of stroke in patients with nonvalvular atrial fibrillation remain to be fully elucidated. Some evidence from indirect comparisons suggests that there may be important differences (e.g., bleeding risk) between these agents; however, results of such analyses should be interpreted with caution because of possible confounding factors (e.g., differences in study design and methods, patient populations, and anticoagulation control). Selection of an appropriate anticoagulant for patients with nonvalvular atrial fibrillation should be individualized based on the absolute and relative risks of stroke and bleeding; costs; patient compliance, preference, tolerance, and comorbidities; and other clinical factors such as renal function and degree of INR control if the patient has been taking warfarin.

Efficacy and safety of edoxaban for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation have been established in a randomized, double-blind, double-dummy trial (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 [ENGAGE AF-TIMI 48]). In this trial, edoxaban was compared with warfarin in 21,105 patients with nonvalvular atrial fibrillation who were at moderate-to-high risk of stroke (Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke [doubled] [i.e., CHADS2] score of at least 2). Patients received one of 2 fixed dosages of edoxaban (30 or 60 mg daily) or warfarin (dosage-adjusted to achieve therapeutic INR of 2-3) for a median of 2.5 years; for those in the edoxaban treatment groups, dosage was reduced by 50% (from 60 to 30 mg or 30 to 15 mg) if any of the following conditions anticipated to increase drug exposure, and thus bleeding, were present: estimated creatinine clearance of 30-50 mL/minute, body weight of 60 kg or less, or concomitant use of the potent P-glycoprotein inhibitors verapamil, quinidine, or dronedarone.

Edoxaban was noninferior to warfarin in preventing stroke and systemic embolism and was associated with lower rates of bleeding. At a median follow-up of 2.8 years, both dosage regimens of edoxaban demonstrated noninferiority to warfarin for the primary composite outcome of time to first occurrence of stroke (ischemic or hemorrhagic) or a systemic embolic event; annualized rates of the primary end point were 1.5% with warfarin, 1.61% with edoxaban 30 mg, and 1.18% with edoxaban 60 mg. The effect of edoxaban on the primary outcome was attributable principally to a marked reduction in hemorrhagic stroke; the rate of ischemic stroke was similar between edoxaban 60 mg and warfarin, and substantially higher with edoxaban 30 mg than with warfarin. The primary efficacy analysis was performed on the modified intent-to-treat population, which included all patients who underwent randomization and received at least one dose of study drug during the treatment period. In a prespecified superiority analysis that was subsequently conducted on the intent-to-treat population, both dosage regimens of edoxaban failed to demonstrate superiority over warfarin in reducing the rate of stroke or systemic embolism. With regard to the primary safety end point in this trial, major bleeding was substantially reduced with edoxaban (at both dosage levels) compared with warfarin. Other bleeding end points (i.e., intracranial bleeding, life-threatening bleeding, clinically relevant nonmajor bleeding) also favored edoxaban, with the exception of GI bleeding, which occurred at a higher rate in patients receiving the 60-mg dose of edoxaban compared with warfarin. The reduction in major bleeding with edoxaban compared with warfarin was even greater in patients who required a reduction in edoxaban dosage, and no apparent loss of efficacy was observed.

The comparison between edoxaban and warfarin in the ENGAGE AF-TIMI 48 trial was based on well-controlled warfarin therapy; patients who received warfarin achieved a mean time in the therapeutic INR range (2-3) of 65%, which is higher than that reported with warfarin anticoagulation in other trials of non-vitamin K antagonist anticoagulants (e.g., dabigatran, apixaban, rivaroxaban) in patients with nonvalvular atrial fibrillation (e.g., 55-64%).

At the end of the ENGAGE AF-TIMI 48 trial, patients were switched to open-label anticoagulant therapy with the use of a transition plan that was specifically incorporated into the protocol to minimize the risk of stroke due to inadequate anticoagulation.(See Risk of Thrombosis Following Premature Discontinuance of Therapy under Warnings/Precautions: Warnings, in Cautions.) The transition plan included a period of overlap between edoxaban (at half the initial dosage used in the controlled trial) and warfarin until a therapeutic INR of 2 was achieved or for 14 days (whichever occurred first) in patients who switched from edoxaban to warfarin therapy. Similar rates of stroke and bleeding were observed across all treatment groups during the 30-day period following the end of the trial.

A strong relationship between plasma concentrations of edoxaban and the drug's effectiveness was observed in the ENGAGE AF-TIMI 48 trial. Patients who received the low dosage of edoxaban (30 mg daily) had a 64% higher rate of ischemic stroke compared with those who received the high dosage of the drug (60 mg daily). Because plasma edoxaban concentrations are affected by renal function, patients with good renal function are likely to have a lesser response to edoxaban due to lower plasma concentrations at a given dosage than those with mildly impaired renal function. When results of the ENGAGE AF-TIMI 48 trial were evaluated based on creatinine clearance, the relative benefits of edoxaban versus warfarin in reducing the rate of ischemic stroke decreased as renal function improved to the point where warfarin was more effective than edoxaban at creatinine clearances exceeding 95 mL/minute. Based on these findings, edoxaban should not be used in patients with a creatinine clearance exceeding 95 mL/minute.(See Reduced Efficacy in Nonvalvular Atrial Fibrillation Patients with Creatinine Clearance Exceeding 95 mL/minute under Warnings/Precautions: Warnings, in Cautions.)

Safety and efficacy of edoxaban have not been established in patients with mechanical heart valves or moderate to severe mitral stenosis; the drug is not recommended in such patients.(See Patients with Prosthetic Heart Valves or Mitral Stenosis under Warnings/ Precautions: Other Warnings and Precautions, in Cautions.)

Deep-Vein Thrombosis and Pulmonary Embolism

Treatment

Edoxaban is used for the treatment of deep-vein thrombosis (DVT) and/or pulmonary embolism (PE) following initial treatment with a parenteral anticoagulant for 5-10 days.

Efficacy and safety of edoxaban for this use have been established in a randomized, double-blind noninferiority trial (Hokusai VTE) in more than 8000 adults with acute venous thromboembolism. In this trial, edoxaban demonstrated noninferiority to warfarin in reducing the risk of recurrent venous thromboembolism and was associated with substantially reduced rates of clinically important bleeding. The relative efficacy and safety of edoxaban versus other non-vitamin K antagonist oral anticoagulants (e.g., apixaban, dabigatran, rivaroxaban) for the treatment of venous thromboembolism remain to be established.

The Hokusai VTE trial was conducted in a broad population of patients with acute venous thromboembolism, including those with provoked (i.e., associated with a temporary risk factor) or unprovoked venous thromboembolism, and those with severe PE. All patients received initial therapy with heparin (enoxaparin or unfractionated heparin) on an open-label basis for at least 5 days; blinded treatment consisted of either edoxaban (60 mg daily, initiated after the heparin regimen was discontinued) or warfarin (initiated concurrently with heparin and dose-adjusted to achieve a therapeutic INR of 2-3), which was continued for a total of 3-12 months depending on the clinical situation. For those in the edoxaban treatment group, dosage was reduced to 30 mg daily if any of the following conditions anticipated to increase drug exposure, and thus bleeding, were present: estimated creatinine clearance of 30-50 mL/minute, body weight of 60 kg or less, or concomitant use of the potent P-glycoprotein inhibitors verapamil, quinidine, azithromycin, clarithromycin, erythromycin, oral itraconazole, or oral ketoconazole. The primary composite end point of DVT or nonfatal or fatal PE occurred in 3.2% of patients receiving edoxaban and 3.5% of those receiving warfarin during the 12-month trial period. The primary efficacy analysis was performed on a modified intent-to-treat population, which included all patients who underwent randomization and received at least one dose of study drug during the treatment period. With respect to the primary safety outcome, clinically relevant major or nonmajor bleedingoccurred less frequently in patients receiving edoxaban than those receiving warfarin (8.5 versus 10.3%). Among patients who required a dosage reduction of edoxaban, bleeding rates were decreased without an apparent loss of efficacy. Patients who received warfarin in the trial achieved a median time in therapeutic INR range (2-3) of 65.6%.

Dosage and Administration

General

Prior to initiating therapy with edoxaban tosylate, renal function should be assessed. Creatinine clearance should be calculated using the Cockcroft-Gault method as dosage recommendations for edoxaban are based on estimated creatinine clearance. Patients with nonvalvular atrial fibrillation who have a creatinine clearance exceeding 95 mL/minute should not receive the drug because of evidence indicating that efficacy may be reduced in such patients.(See Reduced Efficacy in Nonvalvular Atrial Fibrillation Patients with Creatinine Clearance Exceeding 95 mL/minute under Warnings/Precautions: Warnings, in Cautions.)

Routine coagulation monitoring (e.g., prothrombin time [PT], activated partial thromboplastin time [aPTT], international normalized ratio [INR]) is not necessary during edoxaban therapy because of the drug's predictable pharmacokinetic and pharmacodynamic effects. However, in certain situations, such as in the case of overdosage or in patients with hemorrhagic or thromboembolic complications or those requiring emergency surgery, it may be useful to assess the degree of anticoagulation. Although edoxaban has been shown to produce concentration-dependent increases in aPTT, PT, and INR, these tests are not useful for monitoring the anticoagulant effects of edoxaban because of a high degree of inconsistency, insensitivity, and variability in results.

Administration

Edoxaban is administered orally without regard to food.(See Description.)

If a dose of edoxaban is missed, the missed dose should be taken as soon as possible on the same day, followed by resumption of the regular schedule; the dose should not be doubled to make up for the missed dose.

Dosage

Dosage of edoxaban tosylate monohydrate is expressed in terms of edoxaban.

Embolism Associated with Atrial Fibrillation

For the prevention of stroke and systemic embolism in adults with nonvalvular atrial fibrillation who have a creatinine clearance of 51-95 mL/minute, the recommended initial dosage of edoxaban is 60 mg once daily. Dosage should be reduced to 30 mg daily in patients with creatinine clearance of 15-50 mL/minute.(See Dosage and Administration: Special Populations.) The drug should not be used in patients with creatinine clearance exceeding 95 mL/minute.

Deep-Vein Thrombosis and Pulmonary Embolism

Treatment

The recommended dosage of edoxaban for the treatment of deep-vein thrombosis (DVT) and/or pulmonary embolism (PE) is 60 mg once daily following 5-10 days of initial therapy with a parenteral anticoagulant.

Dosage should be reduced to 30 mg once daily in patients with creatinine clearance of 15-50 mL/minute, body weight of 60 kg or less, and/or in those receiving concomitant therapy with certain drugs that are potent P-glycoprotein inhibitors. In the Hokusai VTE trial, dosage of edoxaban was reduced in patients receiving concomitant therapy with verapamil, quinidine, or short-term treatment with azithromycin, clarithromycin, erythromycin, oral ketoconazole, or oral itraconazole.(See P-glycoprotein Inhibitors under Drug Interactions: Drugs Affecting Efflux Transport Systems.)

The optimum duration of anticoagulant therapy should be determined by the individual clinical situation (e.g., location of thrombi, presence or absence of precipitating factors for thrombosis, presence of cancer, risk of bleeding). In general, the American College of Chest Physicians (ACCP) states that anticoagulant therapy for venous thromboembolism should be continued beyond the acute treatment period for at least 3 months and possibly longer in patients with a high risk of recurrence and low risk of bleeding.

Transitioning from Other Anticoagulant Therapy

When transitioning from a vitamin K antagonist (e.g., warfarin) to edoxaban therapy, the manufacturer states that the vitamin K antagonist should be discontinued and edoxaban initiated as soon as the INR is 2.5 or less. When transitioning from other oral anticoagulants, the current anticoagulant should be discontinued and edoxaban initiated at the time of the next scheduled dose of the other anticoagulant.

When transitioning from a low molecular weight heparin to edoxaban, the low molecular weight heparin should be discontinued and edoxaban initiated at the time of the next scheduled dose of the low molecular weight heparin. In patients currently receiving heparin by continuous IV infusion, the heparin infusion should be discontinued and edoxaban initiated 4 hours later.

Transitioning to Other Anticoagulant Therapy

When transitioning from edoxaban to warfarin therapy, a parenteral or oral conversion strategy can be used. In the parenteral method, edoxaban is discontinued and a parenteral anticoagulant and warfarin are initiated simultaneously at the time of the next scheduled dose of edoxaban; the parenteral anticoagulant is then discontinued once a stable INR of at least 2 is reached. The oral conversion strategy is similar to the end-of-trial transition plan that was used in the ENGAGE AF-TIMI trial and involves the use of a half-dose edoxaban bridging regimen with overlapping warfarin therapy. In this method, the current dose of edoxaban is decreased by 50% (60 to 30 mg or 30 to 15 mg) and warfarin is initiated simultaneously. The 2 drugs are administered concomitantly until a stable INR of at least 2 is achieved; once this occurs, edoxaban should be discontinued and warfarin continued. INR values should be monitored at least once a week, with testing performed just prior to the daily dose of edoxaban to minimize the effect of the drug on the INR.

When transitioning from edoxaban to other anticoagulants, including parenteral anticoagulants or non-vitamin K-antagonist oral anticoagulants, edoxaban should be discontinued and the other anticoagulant initiated at the time of the next scheduled dose of edoxaban.

Managing Anticoagulation in Patients Requiring Invasive Procedures

To minimize the risk of bleeding, edoxaban should be temporarily discontinued at least 24 hours prior to surgery or other invasive procedure. If surgery cannot be delayed, the potential increased risk of bleeding should be weighed against the urgency of the intervention. Edoxaban may be resumed postoperatively as soon as adequate hemostasis has been established; decisions regarding when to restart therapy should take into account the onset of the drug's pharmacodynamic effects (1-2 hours). If oral administration is not possible, a parenteral anticoagulant should be administered in the interim until edoxaban therapy can be resumed.(See Risk of Thrombosis Following Premature Discontinuance of Therapy under Warnings/Precautions: Warnings, in Cautions.)

Special Populations

Hepatic Impairment

No dosage adjustment is necessary in patients with mild (Child-Pugh class A) hepatic impairment. Use of edoxaban is not recommended in patients with moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment.(See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Renal Impairment

Dosage of edoxaban should be reduced to 30 mg once daily in patients with a creatinine clearance of 15-50 mL/minute, regardless of indication. The drug is not recommended in patients with a creatinine clearance of less than 15 mL/minute.(See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Body Weight

Edoxaban exposure is increased in patients with low body weight (less than 60 kg), which may increase the risk of bleeding. The manufacturer makes no dosage adjustment recommendations based on weight in patients with nonvalvular atrial fibrillation. When used for the treatment of venous thromboembolism, dosage of edoxaban should be reduced to 30 mg once daily in patients who weigh 60 kg or less.

Cautions

Contraindications

Active pathologic bleeding.

Warnings/Precautions

Warnings

Reduced Efficacy in Nonvalvular Atrial Fibrillation Patients with Creatinine Clearance Exceeding 95 mL/minute

Edoxaban tosylate should not be used in patients with nonvalvular atrial fibrillation who have a creatinine clearance exceeding 95 mL/minute; the manufacturer states that alternative anticoagulants should be used in such patients. Reduced antithrombotic efficacy was observed in the principal efficacy trial of the drug (ENGAGE AF-TIMI 48) in patients with nonvalvular atrial fibrillation who had a creatinine clearance exceeding 95 mL/minute. In particular, the rate of ischemic stroke was substantially increased in such patients who were receiving edoxaban 60 mg daily compared with warfarin-treated patients who had a similar level of renal function.(See Uses: Embolism Associated with Atrial Fibrillation.)

Risk of Thrombosis Following Premature Discontinuance of Therapy

Premature discontinuance of any anticoagulant therapy, including edoxaban, in the absence of adequate alternative anticoagulation increases the risk of thromboembolic events. When transitioning patients from one anticoagulant therapy to another, it is important to ensure continuous anticoagulation while minimizing the risk of bleeding. Particular caution is advised when switching patients from a factor Xa inhibitor to warfarin therapy because of the slow onset of action of warfarin.

If discontinuance of edoxaban is required for reasons other than pathologic bleeding or completion of a course of therapy, coverage with an alternative anticoagulant should be considered.(See Dosage and Administration: Dosage.) Patients should be advised about the importance of adhering to the therapeutic regimen and instructed on steps to take if doses are missed.(See Advice to Patients.)

Spinal/Epidural Hematoma

Patients receiving anticoagulants are at risk of developing an epidural or spinal hematoma when concomitant neuraxial (epidural/spinal) anesthesia or spinal puncture is employed; such complications can result in long-term or permanent paralysis. The risk of these adverse events is increased by use of indwelling epidural catheters or by concomitant use of drugs affecting hemostasis, such as nonsteroidal anti-inflammatory agents (NSAIAs), platelet inhibitors, or other anticoagulants. Risk also may be increased in patients with a history of traumatic or repeated epidural or spinal punctures or a history of spinal deformity or spinal surgery.

Although optimal timing between the administration of edoxaban and neuraxial procedures is not known, the manufacturer states that removal of an indwelling epidural or intrathecal catheter should be delayed for at least 12 hours after the last administered dose of edoxaban, and at least 2 hours should elapse following removal of the catheter prior to administration of the next edoxaban dose.

Patients receiving edoxaban in the setting of epidural or spinal anesthesia should be monitored frequently for manifestations of neurologic impairment (e.g., numbness or weakness of the legs, bowel or bladder dysfunction). If neurologic compromise is noted, urgent diagnosis and treatment are necessary. Clinicians should consider the potential benefits versus risks of neuraxial intervention in patients who are currently receiving or will receive anticoagulants.

Other Warnings and Precautions

Bleeding

Edoxaban increases the risk of hemorrhage and can cause serious, potentially fatal, bleeding. Patients should be promptly evaluated if any manifestations of blood loss occur during therapy. The drug should be discontinued if active pathological bleeding occurs. (See Cautions: Contraindications.) However, minor or ''nuisance'' bleeding is a common occurrence in patients receiving any anticoagulant and should not readily lead to treatment discontinuance.(See Risk of Thrombosis Following Premature Discontinuance of Therapy under Warnings/Precautions: Warnings, in Cautions.)

Bleeding complications were the most common adverse effects of edoxaban in clinical trials. In the principal efficacy trial of edoxaban in patients with nonvalvular atrial fibrillation (ENGAGE AF-TIMI 48), major bleeding (i.e., clinically overt bleeding at a critical organ/site or accompanied by a hemoglobin decrease of at least 2 g/dL when adjusted for transfusions or fatal bleeding) occurred at a rate of 2.75% per year with edoxaban 60 mg and 1.61% per year with edoxaban 30 mg; these rates were substantially lower than the rate of major bleeding in patients who received warfarin (3.43% per year). The rate of major GI bleeding was substantially higher with edoxaban 60 mg compared with warfarin (1.51 versus 1.23%), but the lower dosage of edoxaban (30 mg) was associated with the lowest rate of major GI bleeding (0.82%). In a dose-ranging study in patients with atrial fibrillation receiving edoxaban daily in 1 or 2 divided doses (twice-daily dosing currently not FDA-labeled), trough edoxaban concentrations and the frequency of bleeding complications were higher with 30 mg twice daily than with 60 mg once daily. In the Hokusai VTE trial in patients with acute venous thromboembolism, clinically relevant bleeding (major or nonmajor) occurred in 8.5% of patients receiving edoxaban 60 mg, which was substantially lower than the rate in patients receiving warfarin (10.3%).

Risk of bleeding may be increased in patients with renal impairment, low body weight (e.g., less than 60 kg), or in those receiving concomitant drugs that affect hemostasis (e.g., aspirin or other antiplatelet drugs, other anticoagulants, chronic use of NSAIAs). (See Drug Interactions.) Edoxaban therapy should be temporarily interrupted prior to surgery or other invasive procedure to minimize the risk of bleeding.(See Managing Anticoagulation in Patients Requiring Invasive Procedures under Dosage and Administration: Dosage.)

There is no specific reversal agent for edoxaban; anticoagulant effects can be expected to persist for approximately 24 hours after the drug is discontinued. Preliminary findings from a study in healthy individuals suggest that prothrombin complex concentrate (PCC) may be an effective reversal agent for edoxaban. In this study, administration of a 4-factor PCC reversed the effects of edoxaban 60 mg in a dose-dependent manner. At the highest dose studied (50 unit/kg), the PCC completely reversed bleeding duration and endogenous thrombin potential and partially reversed prothrombin time. Protamine sulfate, vitamin K, and tranexamic acid are not expected to be effective in reversing the anticoagulant effects of edoxaban. Edoxaban is not appreciably removed by dialysis.

Patients with Prosthetic Heart Valves or Mitral Stenosis

Safety and efficacy of edoxaban have not been evaluated in patients with mechanical heart valves or moderate to severe mitral stenosis; use of the drug is not recommended in such patients.

Specific Populations

Pregnancy

Category C.

There are no adequate or well-controlled studies of edoxaban in pregnant women. In animal studies, edoxaban was not teratogenic at exposure levels 49 times the maximum recommended human dose; however, fetotoxic effects, including gallbladder abnormalities, postimplantation pregnancy loss, spontaneous abortion, decreased live fetuses, and decreased fetal weight, occurred at maternally toxic doses. Edoxaban should be used during pregnancy only if the potential benefits justify the potential risks to the fetus.

Lactation

Edoxaban is distributed into milk in rats; it is not known whether the drug is distributed into human milk. Because of the potential for serious adverse reactions to edoxaban in nursing infants, the manufacturer states that a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Pediatric Use

Safety and efficacy of edoxaban have not been established in pediatric patients.

Geriatric Use

No substantial differences in efficacy and safety have been observed in geriatric patients 65 years of age or older relative to younger adults in clinical trials of edoxaban. In the ENGAGE AF-TIMI 48 trial, 74% of patients were 65 years of age or older, and 41% were 75 years of age or older. In the Hokusai VTE trial, 32% of patients were 65 years of age or older, and 14% were 75 years of age or older.

Hepatic Impairment

Mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment does not appear to affect pharmacokinetics or pharmacodynamics of edoxaban. Data on the drug are lacking in patients with severe hepatic impairment (Child-Pugh class C).(See Dosage and Administration: Special Populations.)

Edoxaban should not be used in patients with moderate or severe hepatic impairment because of the possibility of intrinsic coagulation abnormalities in such patients.

Renal Impairment

Edoxaban is eliminated renally.(See Description.) Clearance of edoxaban is decreased, and consequently, plasma concentrations are increased in patients with renal impairment. In a dedicated pharmacokinetic study in individuals with various degrees of renal dysfunction, systemic exposure of edoxaban was increased by 32, 74, and 72% in those with creatinine clearances of 51-79 mL/minute, 30-50 mL/minute, and less than 30 mL/minute, respectively, compared with that in individuals with normal renal function (creatinine clearance of at least 80 mL/minute). Systemic exposure of edoxaban was increased by 93% in patients undergoing peritoneal dialysis. Patients with creatinine clearance less than 15 mL/minute were not evaluated.

Renal function should be evaluated prior to initiating edoxaban therapy and periodically thereafter when clinically indicated. Assessment of renal function should include calculation of estimated creatinine clearance using the Cockcroft-Gault method. Recommendations regarding use and dosage of edoxaban are based on creatinine clearance.(See Dosage and Administration.) As renal function improves, plasma concentrations of edoxaban may decrease and potentially decrease efficacy of the drug.(See Reduced Efficacy in Nonvalvular Atrial Fibrillation Patients with Creatinine Clearance Exceeding 95 mL/minute under Warnings/Precautions: Warnings, in Cautions.)

Hemodialysis does not substantially contribute to clearance of edoxaban. Following a 4-hour hemodialysis session, total drug exposure was reduced by less than 7%.

Common Adverse Effects

In studies in patients with nonvalvular atrial fibrillation, the most common adverse effects of edoxaban were bleeding and anemia. In studies in patients with acute venous thromboembolism, the most common adverse effects of the drug were bleeding, rash, abnormal liver function tests, and anemia.

Drug Interactions

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Edoxaban tosylate is minimally metabolized by cytochrome P-450 (CYP) 3A4; drug interactions are unlikely with inhibitors or inducers of this isoenzyme.

In vitro studies indicate that edoxaban does not inhibit the major CYP isoenzymes (CYP1A2, 2A6, 2B6, 2C8/9, 2C19, 2D6, 2E1, or 3A4) nor induce CYP1A2 or CYP3A4; drug interactions involving these pathways are unlikely.

Drugs Affecting Efflux Transport Systems

Edoxaban is a substrate of the efflux transporter P-glycoprotein, but does not appear to be a substrate of other major uptake transporters such as organic anion transporters OAT1 and OAT3, organic cation transporter OCT2, or organic anion transporting polypeptide OATP1B1. In vitro studies indicate that edoxaban does not induce the P-glycoprotein transporter. In addition, the drug does not substantially inhibit P-glycoprotein, OAT1, OAT3, OCT1, OCT2, OATP1B1, or OATP1B3.

P-glycoprotein Inhibitors

Concomitant use of edoxaban with P-glycoprotein inhibitors may potentially increase edoxaban exposure; the potential for clinically important effects depends on the degree of P-glycoprotein inhibition. Drug interaction studies have demonstrated substantially increased peak plasma concentrations and systemic exposure of edoxaban when coadministered with the following potent P-glycoprotein inhibitors: ketoconazole, quinidine, verapamil, erythromycin, cyclosporine, and dronedarone. Concomitant administration of edoxaban with amiodarone, also a potent P-glycoprotein inhibitor, increased systemic exposure of edoxaban to a more modest extent. When coadministered with drugs with weaker affinity for the P-glycoprotein transporter (e.g., atorvastatin, digoxin), pharmacokinetics of edoxaban were only slightly altered.

The manufacturer states that based on criteria used in clinical studies, dosage of edoxaban should be reduced in patients with acute venous thromboembolism who are receiving certain P-glycoprotein inhibitors; in the Hokusai VTE trial, dosage of edoxaban was reduced for concomitant therapy with verapamil, quinidine, azithromycin, clarithromycin, erythromycin, oral itraconazole, and oral ketoconazole.(See Dosage and Administration: Dosage.) In patients with nonvalvular atrial fibrillation, no edoxaban dosage adjustment is necessary for concomitant P-glycoprotein inhibitors since patients in whom such dosages were adjusted in the ENGAGE AF-TIMI 48 trial had lower plasma edoxaban concentrations than those who received the full dosage of the drug.

P-glycoprotein Inducers

Concomitant use of edoxaban with P-glycoprotein inducers may potentially decrease edoxaban exposure. Systemic exposure of edoxaban was substantially reduced when the drug was coadministered with rifampin, a known P-glycoprotein inducer; the manufacturer states that concomitant use of edoxaban and rifampin should be avoided.

Drugs Affecting Hemostasis

Concomitant use of drugs that affect hemostasis (e.g., aspirin or other antiplatelet agents, other anticoagulants, fibrinolytics, nonsteroidal anti-inflammatory agents [NSAIAs]) can increase the risk of bleeding associated with edoxaban.(See Bleeding under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Anticoagulant Agents

When edoxaban was administered concomitantly with enoxaparin, no substantial changes in the pharmacokinetics of either drug were observed.

Because of the risk of bleeding, long-term concomitant use of edoxaban and other anticoagulants is not recommended; however, short-term concomitant therapy may be necessary in patients transitioning from one anticoagulant to another.

Antiplatelet Agents

In a study in healthy individuals, bleeding time was increased by approximately twofold from baseline when edoxaban and aspirin (100 or 325 mg) were administered concomitantly relative to administration of either drug alone. The higher dose of aspirin (325 mg) increased peak plasma concentrations and systemic exposure of edoxaban, but the lower aspirin dose did not affect pharmacokinetics of edoxaban. The anticoagulant effects of edoxaban (i.e., activated partial thromboplastin time [aPTT], prothrombin time [PT], international normalized ratio [INR], anti-factor Xa activity, intrinsic factor Xa activity) were not altered by aspirin.

In clinical studies, patients who received edoxaban and aspirin concurrently had increased rates of clinically relevant bleeding; patients requiring chronic treatment with aspirin during edoxaban therapy should be carefully monitored for bleeding.

NSAIAs

In a study in healthy individuals, concomitant administration of edoxaban and naproxen (500 mg) increased bleeding time by approximately twofold from baseline relative to administration of either drug alone. Naproxen did not alter the pharmacokinetics or anticoagulant effects (i.e., as indicated by aPTT, PT, INR, anti-factor Xa activity, intrinsic factor Xa activity) of edoxaban.

In clinical studies, patients who received edoxaban and NSAIAs concurrently had increased rates of clinically relevant bleeding; patients requiring long-term treatment with an NSAIA during edoxaban therapy should be carefully monitored for bleeding.

Amiodarone

Peak plasma concentrations and systemic exposure of edoxaban increased by approximately 66 and 40%, respectively, when the drug was administered concomitantly with amiodarone.(See Drug Interactions: Drugs Affecting Efflux Transport Systems.)

Atorvastatin

Peak plasma concentrations of edoxaban were decreased by 14.2% and systemic exposure increased by 1.7% when the drug was administered concomitantly with atorvastatin.(See Drug Interactions: Drugs Affecting Efflux Transport Systems.)

Azole Antifungals

Peak plasma concentrations and systemic exposure of edoxaban were substantially increased with concomitant administration of ketoconazole. Dosage of edoxaban should be reduced when administered concomitantly with oral itraconazole or oral ketoconazole in patients with venous thromboembolism.(See Drug Interactions: Drugs Affecting Efflux Transport Systems.)

Cyclosporine

Peak plasma concentrations and systemic exposure of edoxaban were substantially increased with concomitant administration of cyclosporine.(See Drug Interactions: Drugs Affecting Efflux Transport Systems.)

Digoxin

In healthy individuals, concomitant administration of edoxaban and digoxin did not substantially affect peak plasma concentrations or systemic exposure of edoxaban. Although peak plasma concentrations of digoxin were increased by 28%, such concentrations remained within the established therapeutic range. Clinically important changes in the pharmacodynamics of either drug were not observed.

Dronedarone

Dronedarone increased peak plasma concentrations and systemic exposure of edoxaban by approximately 46 and 85%, respectively.(See Drug Interactions: Drugs Affecting Efflux Transport Systems.)

Esomeprazole

Peak plasma concentrations of edoxaban were decreased with concomitant administration of esomeprazole; however, systemic exposure of edoxaban was not substantially affected.

Macrolide Antibiotics

Peak plasma concentrations and systemic exposure of edoxaban were substantially increased with concomitant administration of erythromycin. Dosage of edoxaban should be reduced when the drug is administered concomitantly with erythromycin, azithromycin, or clarithromycin in patients with venous thromboembolism.(See Drug Interactions: Drugs Affecting Efflux Transport Systems.)

Quinidine

Quinidine increased peak plasma concentrations and systemic exposure of edoxaban by approximately 85 and 77%, respectively, but edoxaban did not affect pharmacokinetics of quinidine. Dosage of edoxaban should be reduced when the drug is administered concomitantly with quinidine in patients with venous thromboembolism.(See Drug Interactions: Drugs Affecting Efflux Transport Systems.)

Verapamil

Verapamil increased peak plasma concentrations and systemic exposure of edoxaban by approximately 53%; pharmacokinetic parameters of verapamil were altered to only a slight extent. Dosage of edoxaban should be reduced when the drug is administered concomitantly with verapamil in patients with venous thromboembolism.(See Drug Interactions: Drugs Affecting Efflux Transport Systems.)

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