of ethical [15:95 mL/minute Strong relationship between plasma concentrations of edoxaban and effectiveness observed. 1 Because plasma concentrations are affected by renal function, patients with good renal function may have reduced response due to lower plasma concentrations. 1 In principal efficacy trial in patients with nonvalvular atrial fibrillation (ENGAGE AF-TIMI 48), ischemic stroke occurred more frequently in patients with Cl cr >95 mL/minute who received edoxaban 60 mg daily versus warfarin. 1 (See Boxed Warning.) Do not use in nonvalvular atrial fibrillation patients with Cl cr >95 mL/minute; use alternative anticoagulant agents in such patients. 1 Risk of Thrombosis Following Premature Discontinuance of Therapy Premature discontinuance of any oral anticoagulant, including edoxaban, increases risk of thromboembolic events in the absence of adequate alternative anticoagulation. 1 5 11 (See Boxed Warning.) When transitioning patients from one anticoagulant therapy to another, ensure continuous anticoagulation while minimizing risk of bleeding. 83 Particular caution advised when switching patients from a factor Xa inhibitor to warfarin therapy because of the slow onset of action of warfarin. 83 (See Dosage under Dosage and Administration.) If discontinuing edoxaban required for reasons other than pathologic bleeding or completion of a course of therapy, consider coverage with an alternative anticoagulant. 1 (See Managing Anticoagulation in Patients Requiring Invasive Procedures under Dosage and Administration.) Advise patients regarding importance of adhering to therapeutic regimen and on steps to take if doses are missed. 1 (See Advice to Patients.) Spinal/Epidural Hematoma Epidural or spinal hematoma reported with concurrent use of anticoagulants and neuraxial (spinal/epidural) anesthesia or spinal puncture procedures. 1 Such hematomas have resulted in neurologic injury, including long-term or permanent paralysis. 1 (See Boxed Warning.) Delay removal of indwelling epidural or intrathecal catheters for 12 hours after a dose of edoxaban and wait 2 hours after catheter removal before administering next dose. 1 Frequently monitor for signs of neurologic impairment (e.g., numbness or weakness in lower limbs, bowel or bladder dysfunction). 1 If neurologic compromise noted, diagnose and treat immediately. 1 Carefully consider potential benefits versus risks of neuraxial intervention in patients who are currently receiving or will receive anticoagulants. 1 Other Warnings and Precautions Bleeding Risk of serious, potentially fatal, bleeding. 1 2 16 83 Promptly evaluate if any manifestations of blood loss occur during therapy. 1 Discontinue if active pathological bleeding occurs. 1 (See Contraindications under Cautions.) However, should not readily discontinue anticoagulation for commonly occurring minor or nuisance bleeding. 83 (See Risk of Thrombosis Following Premature Discontinuance of Therapy under Cautions.) Risk of bleeding may be increased in patients with renal impairment, low body weight (e.g., 60 kg), or in those receiving concomitant drugs that affect hemostasis (e.g., aspirin or other antiplatelet drugs, other anticoagulants, chronic use of NSAIAs). 1 10 32 33 (See Interactions.) Limited data suggest increased risk of bleeding in patients receiving 60-mg daily dosage in 2 divided doses (currently not an FDA-labeled dosage) versus once daily. 14 Temporarily interrupt therapy prior to surgery or other invasive procedure to minimize risk of bleeding. 1 (See Managing Anticoagulation in Patients Requiring Invasive Procedures under Dosage and Administration.) No specific reversal agent for edoxaban; anticoagulant effects expected to persist for approximately 24 hours after the drug is discontinued. 1 35 Preliminary findings from a study in healthy individuals suggest that 4-factor prothrombin complex concentrate (PCC) may be an effective reversal agent for edoxaban. 34 Protamine sulfate, vitamin K, and tranexamic acid are not expected to be effective. 1 In addition, the drug is not appreciably removed by dialysis. 1 35 Patients with Prosthetic Heart Valves or Mitral Stenosis Efficacy and safety not established; use not recommended. 1 Specific Populations Pregnancy Category C. 1 No adequate or well-controlled studies in pregnant women. 1 Not teratogenic, but fetotoxic effects observed in animals. 1 Use during pregnancy only if potential benefits justify potential risks to the fetus. 1 Lactation Distributed into milk in rats; not known whether distributed into human milk. 1 Discontinue nursing or the drug. 1 Pediatric Use Safety and efficacy not established in pediatric patients. 1 Geriatric Use No substantial differences in efficacy and safety relative to younger adults. 1 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. 1 No clinical experience with the drug in patients with severe hepatic impairment (Child-Pugh class C). 1 (See Hepatic Impairment under Dosage and Administration.) Do not use in patients with moderate or severe hepatic impairment because of possibility of intrinsic coagulation abnormalities in such patients. 1 Renal Impairment Edoxaban is eliminated renally. 1 Clearance is decreased, and consequently, plasma concentrations are increased in patients with renal impairment. 1 24 Evaluate renal function prior to initiating therapy and periodically thereafter when clinically indicated. 1 80 Calculate estimated Cl cr using the Cockcroft-Gault method. 1 83 Recommendations regarding use and dosage of edoxaban are based on Cl cr . 1 (See Dosage and Administration.) As renal function improves, plasma edoxaban concentrations may decrease and potentially decrease efficacy of the drug. 1 (See Reduced Efficacy in Nonvalvular Atrial Fibrillation Patients with Cl cr >95 mL/minute under Cautions.) Hemodialysis does not substantially contribute to clearance of edoxaban. 1 23 Common Adverse Effects Patients with nonvalvular atrial fibrillation: Bleeding, anemia. 1 Patients with acute DVT and/or PE: Bleeding, rash, abnormal liver function tests, anemia. 1 Interactions for Savaysa Minimally metabolized by CYP3A4. 1 Does not inhibit CYP1A2, 2A6, 2B6, 2C8/9, 2C19, 2D6, 2E1, or 3A4; does not induce CYP1A2 or CYP3A4. 1 Substrate of the efflux transporter P-glycoprotein (P-gp), 1 22 30 31 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. 22 Does not induce P-gp nor inhibit P-gp, OAT1, OAT3, OCT1, OCT2, OATP1B1, or OATP1B3. 1 22 Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes Inhibitors or inducers of CYP3A4: Pharmacokinetic interactions unlikely. 1 Substrates of major CYP isoenzymes (e.g., CYP1A2, 2A6, 2B6, 2C8/9, 2C19, 2D6, 2E1, 3A4): Pharmacokinetic interactions unlikely. 1 Drugs Affecting Efflux Transport Systems Inhibitors of P-gp: Potential pharmacokinetic interaction (increased edoxaban exposure); potential for clinically important effects depends on the degree of P-gp inhibition. 1 22 24 30 31 Reduce edoxaban dosage in patients with acute venous thromboembolism who are receiving certain P-gp inhibitors based on clinical studies. 1 (See Dosage under Dosage and Administration.) In patients with nonvalvular atrial fibrillation, no dosage adjustment necessary for concomitant P-gp inhibitor use since patients who received such dosage adjustment in clinical studies had lower plasma edoxaban concentrations than those who received the full dosage of the drug. 1 Inducers of P-gp: Potential pharmacokinetic interaction (decreased edoxaban exposure). 1 Drugs Affecting Hemostasis Potential increased risk of hemorrhage. 1 8 Promptly evaluate any manifestations of bleeding. 1 Specific Drugs Drug Interaction Comments Antiarrhythmic agents, class III (amiodarone, dronedarone) Amiodarone: Increased peak plasma concentrations and systemic exposure of edoxaban by 66 and 40%, respectively Dronedarone: Increased peak plasma concentrations and systemic exposure of edoxaban by 46 and 85%, respectively Anticoagulants, other Potential increased risk of hemorrhage 1 Enoxaparin: No substantial changes in pharmacokinetics of either drug 29 Long-term concomitant anticoagulants not recommended; short-term concomitant therapy may be necessary in patients switching anticoagulants 1 Promptly evaluate if bleeding manifestations occur 1 Antifungals, azole (oral itraconazole, oral ketoconazole) Potential for increased peak plasma concentrations and systemic exposure of edoxaban 1 Oral itraconazole or ketoconazole: Reduce edoxaban dosage to 30 mg daily for DVT or PE 1 Antiplatelet agents (e.g., aspirin) Potential increased risk of hemorrhage 1 Aspirin (100 or 325 mg): Increased bleeding time; higher aspirin dose increased peak plasma concentrations and systemic exposure of edoxaban, but pharmacodynamic indices not affected 1 33 Carefully monitor for bleeding in patients requiring long-term concomitant aspirin 1 Promptly evaluate if bleeding manifestations occur 1 Atorvastatin 14.2% decrease in peak plasma edoxaban concentration; 1.7% increase in edoxaban systemic exposure 1 31 Cyclosporine Potential for substantially increased peak plasma concentrations and systemic exposure of edoxaban 1 Digoxin Peak plasma concentrations and systemic exposure of edoxaban not substantially altered 1 30 31 Peak plasma concentrations of digoxin increased by 28%, but remained within established therapeutic range 1 30 Clinically important changes in pharmacodynamics of either drug not observed 30 Esomeprazole Peak plasma concentrations of edoxaban decreased, but systemic exposure not substantially affected 1 Fibrinolytics Potential increased risk of hemorrhage 1 Promptly evaluate if bleeding manifestations occur 1 Macrolides (azithromycin, clarithromycin, erythromycin) Potential for substantially increased peak plasma concentrations and systemic exposure of edoxaban 1 31 Reduce edoxaban dosage to 30 mg daily when treating DVT or PE 1 NSAIAs (e.g., naproxen) Potential increased risk of hemorrhage 1 32 Naproxen: Increased bleeding time; 1 33 pharmacokinetics and pharmacodynamics of edoxaban not altered 33 Carefully monitor for bleeding in patients requiring long-term concomitant treatment with an NSAIA 1 Promptly evaluate if bleeding occurs 1 Quinidine Edoxaban peak plasma concentration and systemic exposure increased by approximately 85 and 77%, respectively; quinidine pharmacokinetics not affected 1 31 Reduce edoxaban dosage to 30 mg daily when treating DVT or PE 1 Rifampin Potential for substantially reduced systemic exposure of edoxaban 1 Avoid concomitant use 1 Verapamil Edoxaban peak plasma concentration and systemic exposure increased by approximately 53%; pharmacokinetics of verapamil slightly altered 1 31 Reduce edoxaban dosage to 30 mg daily when treating DVT or PE 1 Savaysa Pharmacokinetics Absorption Bioavailability Rapidly absorbed following oral administration; peak plasma concentrations occur within 1 3 hours. 1 26 27 28 31 Absolute bioavailability approximately 62%. 1 24 Not known whether bioavailability is altered when edoxaban crushed and/or mixed with food, liquids, or administered through feeding tubes. 1 Food Food delays absorption, but does not substantially affect systemic exposure. 1 27 Distribution Extent Distributed into milk in rats; not known whether distributed into human milk. 1 Plasma Protein Binding Approximately 55%. 1 9 28 Elimination Metabolism Undergoes minimal metabolism by hydrolysis, conjugation, and CYP3A4 oxidation. 1 Main metabolite is formed by hydrolysis. 1 Elimination Route Approximately 50% excreted unchanged in urine; remainder is metabolized and eliminated through biliary and intestinal routes. 1 22 No substantial accumulation with multiple dosing. 1 Not appreciably removed by dialysis. 1 Half-life Approximately 10 14 hours. 1 Special Populations Systemic exposure increased by 32, 74, and 72% in patients with Cl cr of 51 79 mL/minute, 30 50 mL/minute, and]} FEATURED: CAR-T Cell Therapy Overview Mechanism of Action KTE-C19 Studies KTE-C19 Cancer Targets Adverse Events Manufacturing Drug Status Rx Availability Prescription only C Pregnancy Category Risk cannot be ruled out N/A CSA Schedule Not a controlled drug 2 years Approval History FDA approved 2015 Manufacturer Daiichi Sankyo Drug Class Factor Xa inhibitors Related Drugs Atrial Fibrillation diltiazem , Xarelto , propranolol , digoxin , sotalol , flecainide , More... Prevention of Thromboembolism in Atrial Fibrillation aspirin , warfarin , Xarelto , Eliquis , Coumadin , More... Deep Vein Thrombosis Xarelto , Eliquis , Pradaxa , apixaban , Lovenox , enoxaparin , More... Pulmonary Embolism Xarelto , Eliquis , Pradaxa , apixaban , rivaroxaban , heparin , More... Savaysa Rating 1 User Review 1.0 /10 1 User Review 1.0 Rate it!} } is known
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