Savaysa® (Edoxaban)
New Drug Evaluation
Manufacturer:
Daiichi Sankyo
Drug Class:
Anticoagulant (Factor Xa Inhibitor)
Pharmacology:
Edoxaban is a selective inhibitor of factor Xa, which inhibits prothrombinase activity to result in prevention of the conversion of prothrombin to thrombin, inhibition of subsequent thrombin-induced platelet aggregation, and suppression of resultant thrombus formation.
Pharmacokinetics:
Edoxaban has a half-life of 10 to 14 hours, a time to peak of 1 to 2 hours, a mean absolute bioavailability of 62%, and a volume of distribution of 107 liters. It undergoes moderate protein binding (approximately 55%) and is minimally metabolized (less than 10%) via hydrolysis and CYP3A4 conjugation and oxidation. The parent drug and predominant metabolite (M-4) are both excreted in the urine, with a clearance approximately 50% that of total body clearance.
Clinical Trials:
ENGAGE AF-TIMI 48
ClincalTrials.gov Identifier: NCT00781391
Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation-Thrombolysis In Myocardial Infarction study 48
This Phase 3 clinical trial demonstrated the non-inferiority of edoxaban in comparison to warfarin for the prevention of stroke and thromboembolism in approximately 20,500 patients with atrial fibrillation. Ruff CT, Giugliano RP, Antman EM, et al. Evaluation of the novel factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation: design and rationale for the Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation-Thrombolysis In Myocardial Infarction study 48 (ENGAGE AF-TIMI 48). Am Heart J. 2010;160(4):635-41. Hokusai-VTE ClinicalTrials.gov Identifier: NCT00986154 This Phase 3 clinical trial, similar to the ENGAGE AF-TIMI 48 trial, demonstrated the non-inferiority of edoxaban in the treatment of symptomatic venous thromboembolism. Büller HR, Décousus H, Grosso MA, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369(15):1406-15. Drug Interactions: Anticoagulant/Antiplatelet/Thrombolytic Agents: may enhance the anticoagulant effect of edoxaban to result in an increased risk for bleeding. P-Glycoprotein Inhibitors: May increase serum edoxaban concentrations and result in an increased risk for bleeding. (Examples: quinidine, verapamil, amiodarone, and atorvastatin) NSAIDs/Salicylates: May enhance the anticoagulant effect of edoxaban and increase the risk for bleeding (specifically gastrointestinal). Rifampin: May decrease the serum concentration of edoxaban, resulting in reduced efficacy. Adverse Reactions: Hemorrhage Skin rash Anemia Decreased hemoglobin Interstitial pulmonary disease (potentially confounded by concomitant amiodarone therapy and infectious pneumonia Comparison of Oral Anticoagulants: Warfarin Mechanism: Inhibits formation of vitamin K-dependent clotting factors. Monitoring parameters: PT/INR required at regularly scheduled intervals. Reversal: Vitamin K or PCC/FFP if major bleeding. Dosing considerations: Daily dosing effective, no adjustment for renal/hepatic impairment. Other: Therapeutic effect is not seen for 5 to 7 days, half-life is ~ 40 hours. Dabigatran Mechanism: Direct thrombin inhibition. Monitoring parameters: Routine lab monitoring not required. Reversal: No specific antidote, ~ 60% dialyzable. Dosing considerations: Twice-daily dosing required, renal adjustment required, contraindicated in CrCl ≤ 30 mL/min. Other: Half-life is 12 to 17 hours Rivaroxaban Mechanism: Direct factor Xa inhibition. Monitoring parameters: Routine lab monitoring not required. Reversal: No specific antidote, not dialyzable. Dosing considerations: Frequency depends on indication, but can be up to twice-daily, renal and hepatic adjustment required. Other: Half-life 5 to 9 hours, interacts with CYP3A4 and P-glycoprotein substrates/inhibitors. Apixaban Mechanism: Direct factor Xa inhibition. Monitoring parameters: Routine lab monitoring not required. Reversal: No specific antidote, not dialyzable. Dosing considerations: Twice-daily dosing required, renal and hepatic adjustment required, avoid if CrCl < 25 mL/min. Other: Half-life is ~ 8 to 15 hours, also carries CYP3A4/P-glycoprotein interactions. Edoxaban Mechanism: Direct factor Xa inhibition. Monitoring parameters: Routine lab monitoring not required. Reversal: No specific antidote, not dialyzable. Dosing considerations: Dose reduction if < 60 kg, concomitant P-glycoprotein inhibitor, or CrCl 15 to 50 mL/min, contraindicated if CrCl < 15 mL/min or in NVAF if CrCl > 95 mL/min. Other: Half-life is 10 to 14 hours, interacts with P-glycoprotein substrates/inhibitors. Appropriate Dosage: Deep Vein Thrombosis/Pulmonary Embolism 60 mg once daily after 5 to …show more content…
In addition, the documented clinical trials have demonstrated only non-inferiority of the drug in comparison to warfarin or parenteral anticoagulants. Although the drug is likely eligible for significant manufacturer-sponsored rebates, the ultimate purchase price is likely to be much greater than the aforementioned options, precluding any realizable cost benefits. As such, except in the case of widespread unavailability of comparative therapies, I believe the purchasing and utilization of the drug should be
New Drug Evaluation
Manufacturer:
Daiichi Sankyo
Drug Class:
Anticoagulant (Factor Xa Inhibitor)
Pharmacology:
Edoxaban is a selective inhibitor of factor Xa, which inhibits prothrombinase activity to result in prevention of the conversion of prothrombin to thrombin, inhibition of subsequent thrombin-induced platelet aggregation, and suppression of resultant thrombus formation.
Pharmacokinetics:
Edoxaban has a half-life of 10 to 14 hours, a time to peak of 1 to 2 hours, a mean absolute bioavailability of 62%, and a volume of distribution of 107 liters. It undergoes moderate protein binding (approximately 55%) and is minimally metabolized (less than 10%) via hydrolysis and CYP3A4 conjugation and oxidation. The parent drug and predominant metabolite (M-4) are both excreted in the urine, with a clearance approximately 50% that of total body clearance.
Clinical Trials:
ENGAGE AF-TIMI 48
ClincalTrials.gov Identifier: NCT00781391
Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation-Thrombolysis In Myocardial Infarction study 48
This Phase 3 clinical trial demonstrated the non-inferiority of edoxaban in comparison to warfarin for the prevention of stroke and thromboembolism in approximately 20,500 patients with atrial fibrillation. Ruff CT, Giugliano RP, Antman EM, et al. Evaluation of the novel factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation: design and rationale for the Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation-Thrombolysis In Myocardial Infarction study 48 (ENGAGE AF-TIMI 48). Am Heart J. 2010;160(4):635-41. Hokusai-VTE ClinicalTrials.gov Identifier: NCT00986154 This Phase 3 clinical trial, similar to the ENGAGE AF-TIMI 48 trial, demonstrated the non-inferiority of edoxaban in the treatment of symptomatic venous thromboembolism. Büller HR, Décousus H, Grosso MA, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369(15):1406-15. Drug Interactions: Anticoagulant/Antiplatelet/Thrombolytic Agents: may enhance the anticoagulant effect of edoxaban to result in an increased risk for bleeding. P-Glycoprotein Inhibitors: May increase serum edoxaban concentrations and result in an increased risk for bleeding. (Examples: quinidine, verapamil, amiodarone, and atorvastatin) NSAIDs/Salicylates: May enhance the anticoagulant effect of edoxaban and increase the risk for bleeding (specifically gastrointestinal). Rifampin: May decrease the serum concentration of edoxaban, resulting in reduced efficacy. Adverse Reactions: Hemorrhage Skin rash Anemia Decreased hemoglobin Interstitial pulmonary disease (potentially confounded by concomitant amiodarone therapy and infectious pneumonia Comparison of Oral Anticoagulants: Warfarin Mechanism: Inhibits formation of vitamin K-dependent clotting factors. Monitoring parameters: PT/INR required at regularly scheduled intervals. Reversal: Vitamin K or PCC/FFP if major bleeding. Dosing considerations: Daily dosing effective, no adjustment for renal/hepatic impairment. Other: Therapeutic effect is not seen for 5 to 7 days, half-life is ~ 40 hours. Dabigatran Mechanism: Direct thrombin inhibition. Monitoring parameters: Routine lab monitoring not required. Reversal: No specific antidote, ~ 60% dialyzable. Dosing considerations: Twice-daily dosing required, renal adjustment required, contraindicated in CrCl ≤ 30 mL/min. Other: Half-life is 12 to 17 hours Rivaroxaban Mechanism: Direct factor Xa inhibition. Monitoring parameters: Routine lab monitoring not required. Reversal: No specific antidote, not dialyzable. Dosing considerations: Frequency depends on indication, but can be up to twice-daily, renal and hepatic adjustment required. Other: Half-life 5 to 9 hours, interacts with CYP3A4 and P-glycoprotein substrates/inhibitors. Apixaban Mechanism: Direct factor Xa inhibition. Monitoring parameters: Routine lab monitoring not required. Reversal: No specific antidote, not dialyzable. Dosing considerations: Twice-daily dosing required, renal and hepatic adjustment required, avoid if CrCl < 25 mL/min. Other: Half-life is ~ 8 to 15 hours, also carries CYP3A4/P-glycoprotein interactions. Edoxaban Mechanism: Direct factor Xa inhibition. Monitoring parameters: Routine lab monitoring not required. Reversal: No specific antidote, not dialyzable. Dosing considerations: Dose reduction if < 60 kg, concomitant P-glycoprotein inhibitor, or CrCl 15 to 50 mL/min, contraindicated if CrCl < 15 mL/min or in NVAF if CrCl > 95 mL/min. Other: Half-life is 10 to 14 hours, interacts with P-glycoprotein substrates/inhibitors. Appropriate Dosage: Deep Vein Thrombosis/Pulmonary Embolism 60 mg once daily after 5 to …show more content…
In addition, the documented clinical trials have demonstrated only non-inferiority of the drug in comparison to warfarin or parenteral anticoagulants. Although the drug is likely eligible for significant manufacturer-sponsored rebates, the ultimate purchase price is likely to be much greater than the aforementioned options, precluding any realizable cost benefits. As such, except in the case of widespread unavailability of comparative therapies, I believe the purchasing and utilization of the drug should be