Edoxaban

Edoxaban, an oral direct factor Xa inhibitor, is in development for thromboprophylaxis, including prevention of stroke and systemic embolism in patients with atrial fibrillation (AF). P-glycoprotein (P-gp), an efflux transporter, modulates absorption and excretion of xenobiotics. Edoxaban is a P-gp substrate, and several cardiovascular (CV) drugs have the potential to inhibit P-gp and increase drug exposure. /The objective of the study was/ to assess the potential pharmacokinetic interactions of edoxaban and 6 cardiovascular drugs used in the management of AF and known P-gp substrates/inhibitors. Drug-drug interaction studies with edoxaban and CV drugs with known P-gp substrate/inhibitor potential were conducted in healthy subjects. In 4 crossover, 2-period, 2-treatment studies, subjects received edoxaban 60 mg alone and coadministered with quinidine 300 mg (n = 42), verapamil 240 mg (n = 34), atorvastatin 80 mg (n = 32), or dronedarone 400 mg (n = 34). Additionally, edoxaban 60 mg alone and coadministered with amiodarone 400 mg (n = 30) or digoxin 0.25 mg (n = 48) was evaluated in a single-sequence study and 2-cohort study, respectively. Edoxaban exposure measured as area under the curve increased for concomitant administration of edoxaban with quinidine (76.7%), verapamil (52.7%), amiodarone (39.8%), and dronedarone (84.5%), and exposure measured as 24 hr concentrations for quinidine (11.8%), verapamil (29.1%), and dronedarone (157.6%) also increased. Administration of edoxaban with amiodarone decreased the 24-hr concentration for edoxaban by 25.7%. Concomitant administration with digoxin or atorvastatin had minimal effects on edoxaban exposure. Coadministration of the P-gp inhibitors quinidine, verapamil, and dronedarone increased edoxaban exposure. Modest/minimal effects were observed for amiodarone, atorvastatin, and digoxin.

The oral direct factor Xa inhibitor edoxaban is a P-glycoprotein (P-gp) substrate metabolized via carboxylesterase-1 and cytochrome P450 (CYP) 3A4/5. The effect of rifampin-induced induction of P-gp and CYP3A4/5 on transport and metabolism of edoxaban through the CYP3A4/5 pathway was investigated in a single-dose edoxaban study. This was a phase 1, open-label, two-treatment, two-period, single-sequence drug interaction study in healthy adults. All subjects received a single oral 60 mg edoxaban dose in period 1, and 7 days of 600 mg rifampin (2 x 300 mg capsules once daily) with a single oral edoxaban 60 mg dose administered concomitantly on day 7 in period 2. A 6-day washout period separated the treatments. Plasma concentrations of edoxaban and its metabolites M4 and M6 were measured, and limited assessments of pharmacodynamic markers of coagulation were performed. In total, 34 healthy subjects were enrolled; 32 completed the study. Coadministration of rifampin with edoxaban decreased edoxaban exposure but increased active metabolite exposure. Rifampin increased apparent oral clearance of edoxaban by 33% and decreased its half-life by 50%. Anticoagulant effects based on the prothrombin time (PT) and the activated partial thromboplastin time (aPTT) with and without rifampin at early time points were maintained to a greater-than-expected degree than with edoxaban exposure alone, presumably because of an increased contribution from the active metabolites. Edoxaban was well tolerated in this healthy adult population. Rifampin reduced exposure to edoxaban while increasing exposure to its active metabolites M4 and M6. PT and aPTT at early time points did not change appreciably; however, the data should be interpreted with caution.

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.

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.

For more Interactions (Complete) data for Edoxaban (19 total), please visit the HSDB record page.

Edoxaban is associated with serum aminotransferase elevations greater than 3 times the upper limit of normal in 2% to 5% of treated patients. This rate is similar or lower than rates with warfarin or comparator arms. The elevations are generally transient and not associated with symptoms or jaundice. In premarketing studies, no instances of clinically apparent liver injury were reported, but there was little experience in large numbers of patients treated for extend periods of time. In large health care databases, the rate of liver injury has been somewhat less with edoxaban than rivaroxaban and apixaban, but the numbers of patients treated with edoxaban has been limited and the nature of the liver injury not described.

IDENTIFICATION AND USE: Edoxaban is a white to pale yellowish-white crystalline powder. It is used to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. It is also used for the treatment of deep vein thrombosis (DVT) and pulmonary embolism following 5 to 10 days of initial therapy with a parenteral anticoagulant. HUMAN STUDIES: Overdose of the drug increases the risk of 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. However, minor or "nuisance" bleeding is a common occurrence in patients receiving any anticoagulant and should not readily lead to treatment discontinuance. Edoxaban and its human-specific metabolite, M-4 were not genotoxic in in vitro human lymphocytes micronucleus test. ANIMAL STUDIES: Edoxaban was not carcinogenic when administered daily to mice and rats by oral gavage for up to 104 weeks. Edoxaban showed no effects on fertility and early embryonic development in rats at doses of up to 1000 mg/kg/day. In a rat pre- and post-natal developmental study, edoxaban was administered orally during the period of organogenesis and through lactation day 20 at doses up to 30 mg/kg/day. Vaginal bleeding in pregnant rats and delayed avoidance response (a learning test) in female offspring were seen at 30 mg/kg/day. Embryo-fetal development studies were conducted in pregnant rats and rabbits during the period of organogenesis. In rats, no malformation was seen when edoxaban was administered orally at doses up to 300 mg/kg/day. Increased post-implantation loss occurred at 300 mg/kg/day, but this effect may be secondary to the maternal vaginal hemorrhage seen at this dose in rats. In rabbits, no malformation was seen at doses up to 600 mg/kg/day. Embryo-fetal toxicities occurred at maternally toxic doses, and included absent or small fetal gallbladder at 600 mg/kg/day, and increased post-implantation loss, increased spontaneous abortion, and decreased live fetuses and fetal weight at doses equal to or greater than 200 mg/kg/day. Edoxaban and its human-specific metabolite, M-4, were genotoxic in in vitro chromosomal aberration tests but were not genotoxic in the in vitro bacterial reverse mutation (Ames test), in in vivo rat bone marrow micronucleus test, in in vivo rat liver micronucleus test, and in in vivo unscheduled DNA synthesis tests.

Patients with impaired kidney function have a higher risk of toxicity. The efficacy of hemodialysis in enhancing edoxaban clearance has not been established.

/SIGNS AND SYMPTOMS/ Overdose of Savaysa increases the risk of bleeding.

/SIGNS AND SYMPTOMS/ 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. However, minor or "nuisance" bleeding is a common occurrence in patients receiving any anticoagulant and should not readily lead to treatment discontinuance.

/CASE REPORTS/ The main adverse effect of anticoagulant therapy is bleeding, and major bleeding, including intracranial, gastrointestinal, and retroperitoneal bleeding, has been reported as an adverse effect of edoxaban, a direct oral anticoagulant (DOAC). Bleeding during systemic anticoagulation with edoxaban presents a therapeutic conundrum, because there is currently no safe or efficacious reversal agent to stop major bleeding. A 51-year-old woman had multiple traumatic injuries, including lower limb fractures. On day 8, she developed deep venous thrombosis, and edoxaban was administered orally. On day 38, she developed fungemia, which was treated with an antifungal drug. On day 43, she presented with dyspnea. Chest computed tomography scan showed bilateral diffuse ground-glass opacities in the whole lung fields. The results of the subsequent workup (i.e., serum levels of the antineutrophil cytoplasmic antibody, antinuclear antibody, and antiglomerular basement membrane antibody) and microbiological study were unremarkable. Based on these findings, her condition was diagnosed as diffuse alveolar hemorrhage (DAH) associated with edoxaban therapy. The lung opacities disappeared spontaneously after edoxaban therapy was discontinued. DAH is a dangerous complication associated with edoxaban therapy. DOACs, including edoxaban, should be prescribed with caution, especially for patients in a critical condition.

/CASE REPORTS/ Factor-Xa inhibitors like edoxaban have been shown to have comparable or superior rates of stroke and systemic embolization prevention to warfarin while exhibiting lower clinically significant bleeding rates. The authors report a case of a man who presented with delayed, recurrent intracranial hemorrhage months after successful deep brain stimulator placement for Parkinson disease while on edoxaban for atrial fibrillation. Further reports on the use of novel anticoagulants after intracranial surgery are acutely needed to help assess the true relative risk they pose.

For more Human Toxicity Excerpts (Complete) data for Edoxaban (9 total), please visit the HSDB record page.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Edoxaban was not carcinogenic when administered daily to mice and rats by oral gavage for up to 104 weeks. The highest dose tested (500 mg/kg/day) in male and female mice was 3 and 6 times, respectively, the human exposure (AUC) at the human dose of 60 mg/day, and the highest doses tested in male (600/400 mg/kg/day) and female (200 mg/kg/day) rats were 8 and 14 times, respectively, the human exposure at the human dose of 60 mg/day.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Edoxaban showed no effects on fertility and early embryonic development in rats at doses of up to 1000 mg/kg/day (162 times the human dose of 60 mg/day normalized to body surface area).

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ In a rat pre- and post-natal developmental study, edoxaban was administered orally during the period of organogenesis and through lactation day 20 at doses up to 30 mg/kg/day, which is up to 3 times the human exposure when based on AUC. Vaginal bleeding in pregnant rats and delayed avoidance response (a learning test) in female offspring were seen at 30 mg/kg/day.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Embryo-fetal development studies were conducted in pregnant rats and rabbits during the period of organogenesis. In rats, no malformation was seen when edoxaban was administered orally at doses up to 300 mg/kg/day, or 49 times the human dose of 60 mg/day normalized to body surface area. Increased post-implantation loss occurred at 300 mg/kg/day, but this effect may be secondary to the maternal vaginal hemorrhage seen at this dose. In rabbits, no malformation was seen at doses up to 600 mg/kg/day (49 times the human exposure at a dose of 60 mg/day when based on AUC). Embryo-fetal toxicities occurred at maternally toxic doses, and included absent or small fetal gallbladder at 600 mg/kg/day, and increased post-implantation loss, increased spontaneous abortion, and decreased live fetuses and fetal weight at doses equal to or greater than 200 mg/kg/day, which is equal to or greater than 20 times the human exposure.

For more Non-Human Toxicity Excerpts (Complete) data for Edoxaban (6 total), please visit the HSDB record page.

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.

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.

Savaysa is contraindicated in patients with: Active pathological bleeding.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

Emergency and supportive measures. 1. If significant bleeding occurs, attempt to identify the source of bleeding and provide local control or hemostasis if possible. Give intravenous volume replacement as needed and closely monitor hemodynamics. obtain immediate neurosurgical consult if intracranial bleeding is suspected. 2. Administer specific antidote as directed. 3. For severe or life-threatening bleeding, use a specific reversal agent ... or consider one of the prothrombin complex concentrates (PCCs) or activated PPC (APPC). for dabigatran, APCC is the preferred agent, for factor Xa inhibitors, a 4-factor PCC is preferred. The utility of these concentrates is limited by the stoichiometric ration needed to over come the effects of the newer direct anticoagulants. 4. Fresh-frozen plasma is likely of limited utility given volume constraints and sheer amount that would be required to over come drug effect, but may have a role for coagulopathies caused by dilution or DIC. 5. Consider platelet transfusion for patient son concurrent antiplatelet agents. 6. Desmopressin enhances hemostasis by increasing the release of von Willebrand factor and can be considered as a adjunct. ... 7. Packed red blood cell transfusion should be administered as indicated for blood loss. 8. Take care not to precipitate hemorrhage in severely anticoagulated patients. Proper fall precautions should be taken and invasive procedures should be avoided if possible. /Anticoagulants, newer/

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including edoxaban tosylate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Edoxaban tosylate/

Factor Xa Inhibitors

MEDICATION