アピキサバン

Current evidence suggests that addition of apixaban to standard antiplatelet therapy (e.g., aspirin, clopidogrel) does not substantially reduce the rate of recurrent ischemic events in patients with acute coronary syndrome (ACS) and may increase the risk of major, sometimes fatal, bleeding. /NOT included in US product label/

In a study in healthy individuals, concomitant administration of apixaban and enoxaparin had no effect on the pharmacokinetics of apixaban, but had an additive effect on anti-factor Xa activity. The increased pharmacodynamic effect was considered to be modest. When administration of apixaban and enoxaparin was separated by 6 hours in this study, the additive effect on anti-factor Xa activity was attenuated.

In the principal efficacy study of apixaban, bleeding risk was increased in patients who received concomitant apixaban and aspirin therapy. Additionally, a placebo-controlled study of patients with acute coronary syndromes was terminated early after an increased risk of bleeding was observed in patients receiving apixaban in combination with aspirin and clopidogrel. In drug interaction studies in healthy individuals, apixaban did not substantially alter the pharmacokinetics of aspirin, and a pharmacodynamic interaction was not observed with such concomitant therapy.

Concomitant use of apixaban and drugs that affect hemostasis (e.g., aspirin or other antiplatelet drugs, heparin or other anticoagulants, fibrinolytics, selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), nonsteroidal anti-inflammatory agents (NSAIAs)) increases the risk of bleeding.

For more Interactions (Complete) data for Apixaban (11 total), please visit the HSDB record page.

Apixaban is associated with serum aminotransferase elevations greater than 3 times the upper limit of normal in 1% to 2% of treated patients. This rate is similar or lower than rates with warfarin or comparator arms. In premarketing studies, no instances of clinically apparent liver injury were reported, but subsequent to its approval and more wide scale use, several reports of mild but clinically apparent liver injury have been published. The liver injury arose within days of starting apixaban and the pattern of liver enzyme elevations was hepatocellular. Immunoallergic and autoimmune features were not present. In most cases, recovery was rapid once apixaban was stopped. In one analysis of a national health care database, the incidence of hospitalization for acute liver injury after initiation of apixaban therapy was 1 per 2,200 patients treated, a rate similar to that of rivaroxaban.

As an anticoagulant, apixaban's most common adverse effect is bleeding (1% to 10%). The risk of major bleeding is 3% or less, and clinically relevant nonmajor bleeding is 2% to 4%. Other less common adverse effects include nausea (3%), gingival hemorrhage (1% or less), hematuria (2% or less), hypermenorrhea (1%), anemia (3%), bruise (1% to 2%), hematoma (1% to 2%), postprocedural hemorrhage (1% or less), rectal hemorrhage (1% or less), increased serum transaminases (1% or less), aspartate aminotransferase increased (1% or less), gamma-glutamyltransferase increased (1% or less), epistaxis (4% or less), and hemoptysis (1% or less). In rare instances (less than 1%), it can cause a hypersensitivity reaction.

IDENTIFICATION AND USE: Apixaban white to pale-yellow powder formulated into a film-coated tablet. Apixaban is indicated in patients to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. It is also indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery. It is also indicated for the treatment of PE and for the treatment of DVT. Finally, apixaban is indicated it patients to reduce the risk of recurrent DVT and PE following initial therapy. HUMAN EXPOSURE AND TOXICITY: Premature discontinuation of any oral anticoagulant, including apixaban, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from apixaban to warfarin in clinical trials in atrial fibrillation patients. Apixaban increases the risk of hemorrhage and can cause serious, potentially fatal, bleeding. The drug should be discontinued if active pathological hemorrhage occurs. Epidural or spinal hematomas may occur in patients treated with apixaban who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: use of indwelling epidural catheters concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants a history of traumatic or repeated epidural or spinal punctures a history of spinal deformity or spinal surgery. Apixaban should not be used in people with mechanical heart valves. ANIMAL STUDIES: Single dose oral studies in mice (up to 4000 mg/kg), rats (up to 4510 mg/kg), dogs (up to 1500 mg/kg) and cynomolgus monkeys (up to 300 mg/kg) revealed no other drug-related effects than those related to the pharmacodynamic action of apixaban. In particular some monkeys died due to excessive bleeding after blood sampling. Apixaban was not carcinogenic when administered to mice and rats for up to 2 years. The systemic exposures (AUCs) of unbound apixaban in male and female mice at the highest doses tested (1500 and 3000 mg/kg/day) were 9 and 20 times, respectively, the human exposure of unbound drug at the MRHD of 10 mg/day. Systemic exposures of unbound apixaban in male and female rats at the highest dose tested (600 mg/kg/day) were 2 and 4 times, respectively, the human exposure. Apixaban had no effect on fertility in male or female rats when given at doses up to 600 mg/kg/day, a dose resulting in exposure levels that are 3 and 4 times, respectively, the human exposure. Apixaban administered to female rats at doses up to 1000 mg/kg/day from implantation through the end of lactation produced no adverse findings in male offspring (F1 generation) at doses up to 1000 mg/kg/day, a dose resulting in exposure that is 5 times the human exposure. Adverse effects in the F1-generation female offspring were limited to decreased mating and fertility indices at 1000 mg/kg/day. Apixaban was neither mutagenic in the bacterial reverse mutation (Ames) assay, nor clastogenic in Chinese hamster ovary cells in vitro, in a 1-month in vivo/in vitro cytogenetics study in rat peripheral blood lymphocytes, or in a rat micronucleus study in vivo.

/SIGNS AND SYMPTOMS/ Apixaban increases the risk of hemorrhage and can cause serious, potentially fatal, bleeding. The drug should be discontinued if active pathological hemorrhage occurs.

/SIGNS AND SYMPTOMS/ Epidural or spinal hematomas may occur in patients treated with Eliquis who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: use of indwelling epidural catheters concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants a history of traumatic or repeated epidural or spinal punctures a history of spinal deformity or spinal surgery optimal timing between the administration of Eliquis and neuraxial procedures is not known. Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.

/SIGNS AND SYMPTOMS/ Apixaban increases the risk of hemorrhage and can cause serious, potentially fatal, bleeding. The drug should be discontinued if active pathological hemorrhage occurs.

/CASE REPORTS/ Left atrial appendage (LAA) thrombus is associated with atrial fibrillation (AF) and is a powerful predictor of cardiogenic thromboembolism. Warfarin is an established anticoagulant therapy for patients with LAA thrombus to prevent thromboembolic complications. Apixaban is superior to warfarin in the prevention of thromboembolic complications in patients with AF, and there are case reports showing apixaban-associated resolution of LAA thrombus; however, the efficacy and safety of apixaban for the treatment of LAA thrombus remains unproven. Here we report a patient who experienced embolic stroke while taking apixaban for the treatment of LAA thrombus. Thrombolysis therapy was initiated at the onset of stroke and the patient recovered remarkably. Apixaban is known to make thrombi mobile and/or fragile by shifting the coagulation/fibrinolysis balance to a relative predominance of fibrinolytic activity; therefore, it is necessary to monitor for thromboembolic complications after the initiation of apixaban for the treatment of pre-existing LAA thrombus.

For more Human Toxicity Excerpts (Complete) data for Apixaban (7 total), please visit the HSDB record page.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Apixaban

vLess-DILI-concern

4

Adverse reactions

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Acute Exposure/ Single dose oral studies in mice (up to 4000 mg/kg), rats (up to 4510 mg/kg), dogs (up to 1500 mg/kg) and cynomolgus monkeys (up to 300 mg/kg) revealed no other drug-related effects than those related to the pharmacodynamic action of apixaban. In particular some monkeys died due to excessive bleeding after blood sampling.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Apixaban was not carcinogenic when administered to mice and rats for up to 2 years. The systemic exposures (AUCs) of unbound apixaban in male and female mice at the highest doses tested (1500 and 3000 mg/kg/day) were 9 and 20 times, respectively, the human exposure of unbound drug at the MRHD of 10 mg/day. Systemic exposures of unbound apixaban in male and female rats at the highest dose tested (600 mg/kg/day) were 2 and 4 times, respectively, the human exposure.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Apixaban administered to female rats at doses up to 1000 mg/kg/day from implantation through the end of lactation produced no adverse findings in male offspring (F1 generation) at doses up to 1000 mg/kg/day, a dose resulting in exposure that is 5 times the human exposure. Adverse effects in the F1-generation female offspring were limited to decreased mating and fertility indices at 1000 mg/kg/day.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Apixaban had no effect on fertility in male or female rats when given at doses up to 600 mg/kg/day, a dose resulting in exposure levels that are 3 and 4 times, respectively, the human exposure.

/GENOTOXICITY/ Apixaban was neither mutagenic in the bacterial reverse mutation (Ames) assay, nor clastogenic in Chinese hamster ovary cells in vitro, in a 1-month in vivo/in vitro cytogenetics study in rat peripheral blood lymphocytes, or in a rat micronucleus study in vivo.

/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/

EXPERIMENTAL: Non-specific hemostatic agents, namely activated prothrombin complex concentrate (aPCC), PCC and recombinant activated factor VII (rFVIIa), can be used, off-label, to reverse the effects of factor Xa inhibitors in the rare cases of severe hemorrhages, as no approved specific antidote is available. We have evaluated the ability of aPCC, PCC, and rFVIIa to reverse apixaban. Healthy volunteer whole blood was spiked with therapeutic or supra-therapeutic apixaban concentrations and two doses of aPCC, PCC, or rFVIIa. Tests performed included a turbidimetry assay for fibrin polymerization kinetics analysis, scanning electron microscopy for fibrin network structure observation, thrombin generation assay (TGA), thromboelastometry, prothrombin time and activated partial thromboplastin time. aPCC generated a dense clot constituted of thin and branched fibers similar to that of control without apixaban, increased fibrin polymerization velocity and improved quantitative (endogenous thrombin potential and peak height) as well as latency (clotting and lag times) parameters. Adding PCC also improved the fibrin and increased quantitative parameters, but fibrin polymerization kinetics and latency parameters were not corrected. Finally, rFVIIa improved latency parameters but failed to restore the fibrin network structure, fibrin polymerization velocity and quantitative parameters. aPCC was more effective than PCC or rFVIIa to reverse in vitro the effects of apixaban. aPCC rapidly triggered the development of an apparently normal fibrin network and corrected latency and quantitative parameters, whereas PCC or rFVIIa had only partial effect. ...

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