Table of Contents
Overview
Edoxaban is prescribed as a thromboprophylaxis (prevention of thrombosis or blood clots) in case of non-valvular atrial fibrillation, a condition causing irregular heartbeat. The drug is mainly prescribed to an individual to lower the risk of blood clot formation leading to strokes (blood supply interruption causing brain damage). The drug is specifically given to patients with atrial fibrillation or irregular heartbeats (heart rhythms), which are not caused by abnormalities in the heart valves.
The drug was approved by the United States Food and Drug Administration (USFDA) in January 2015 as thromboprophylaxis in non-valvular atrial fibrillation. The article discusses Edoxaban, its uses, side effects, drug dosage, contraindications, and clinical pharmacology.
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Chemical Name: N-(5-Chloropyridin-2-yl)-N′-[(1S,2R,4S)-4-(N,N-dimethyl carbamoyl)-2-(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamido)cyclohexyl] oxamide mono (4-methylbenzenesulfonate) monohydrate.
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Molecular Weight: 738.27
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Empirical Formula: C24H30ClN7O4S•C7H8O3S•H2O
Drug Group
The drug is an anticoagulant medication that belongs to the Xa inhibitors class of medications.
Indications
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Edoxaban is indicated for the treatment of strokes and blood clots in patients with non-valvular atrial fibrillation or irregular heartbeats, which are not related to heat valve problems.
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The drug is also indicated for treating pulmonary embolisms or lung blood clots.
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Edoxaban is also prescribed for deep vein thrombosis or clots formed in the legs.
Dose Form, Route, and Strength
Edoxaban is available in tablet form and can only be taken orally (through the mouth). It is available in the following strengths: 60 mg (milligrams), 30 mg, and 15 mg.
For Patients:
What Is Non-valvular Atrial Fibrillation?
Non-valvular atrial fibrillation is an irregular heartbeat or rhythm caused irrespective of the problem in the heart valves. Atrial fibrillation is a condition of the heart that causes various complications, such as strokes (blockage of blood flow to the brain).
Why is Edoxaban Prescribed?
Edoxaban is prescribed as a thromboprophylaxis (prevention of thrombosis or blood clots) in non-valvular atrial fibrillation, an irregular heartbeat caused irrespective of the problems in the heart valves. The drug is also used to treat conditions such as pulmonary embolism (blood clots in the lungs) and deep thrombosis (blood clots formed in legs) in individuals who have been receiving blood thinners (intravenously) for almost five to ten days.
How Should Edoxaban Be Used?
The drug is available as a tablet to be taken orally or through the mouth once a day, with or without a meal. It should be taken at regular intervals daily or as directed by the doctor or pharmacist. One must follow the label instructions carefully and consult the pharmacist or doctor if they cannot understand any part of the label or prescription.
The drug should be taken by the person exactly as directed by the doctor, meaning the frequency, dosage, and duration of the drug intake must not be altered without consulting the doctor.
However, if one cannot take the medication, they can crush the tablet in 60 to 90 milliliters or two to three ounces of water and take it immediately. If a person is using the gastric tube, the drug can be crushed, and the mixture can be given via gastric tube also. The doctor must be asked about the exact way of taking the drug, and the patient must strictly follow the instructions.
What Precautions Should Be Followed Before Taking Edoxaban?
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Any allergic reactions to the drug, Edoxaban's ingredients, or any other drug should be reported to the doctor.
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One must also inform the doctor if they have profuse and unstoppable bleeding in any body area. In such cases, the doctor will ask the person to stop taking the drug (Edoxaban).
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The doctor must also know about all the prescription or non-prescription drugs one is taking or planning to take, such as herbal products, nutritional supplements, or vitamins. In such cases, the doctor might need to modify the drug dosage or monitor the patient for side effects.
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One must inform the doctor if they are pregnant or planning to conceive or get pregnant during the treatment with Edoxaban.
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The doctor must be told about the past or present medical history of an individual, such as if they ever had or still have bleeding disorders, antiphospholipid syndrome (which causes blood clots), kidney, heart, or liver disease, cancer of the intestine or stomach, mechanical heart valve, or weight 60 kilograms or 132 pounds or less.
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If a person is undergoing any surgical or dental procedure, they must inform the doctor about taking Edoxaban. The drug needs to be discontinued due to the risk of bleeding before any surgical procedure.
What Are the Side Effects of Edoxaban?
Common Side Effects:
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Dizziness.
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Rash.
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Pale skin.
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Tiredness.
Serious Side Effects:
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Heavy flow vaginal bleeding.
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Bleeding gums.
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Pink, red, or brown urine.
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Nosebleeds.
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Black or red tarry stool.
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Blood in vomiting or coughing that appears like coffee grounds.
Drug Dosage and Administration
Adult Dosage for Nonvalvular Atrial Fibrillation:
The recommended drug dose of Edoxaban is 60 milligrams, to be taken orally once a day.
NOTE:
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CrCL or creatinine clearance levels should be assessed before initiating therapy.
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The recommended dose (60 milligrams once daily) in patients with CrCL greater than 50 to less than or equal to 95 milliliters per minute (mL/min).
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The drug is not recommended in patients with creatinine clearance levels greater than 95 milliliters per minute.
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The drug dosage should be reduced to 30 milligrams once daily in individuals with creatinineclearance of 15 to 50 mL/min.
Missed Dose
If a person misses the drug dose, they must take it as soon as they remember. However, if it is already time for the next dose, they must continue with the scheduled dose and skip the missed one. One should not take double the drug dosage to compensate for the missed one.
Overdose
In case of an overdose of the drug, one must contact the nearest poison control helpline. If the person collapses, has seizures, or has trouble breathing, then emergency medical help must be availed immediately.
Symptoms of Overdose:
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Blood in urine.
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Bruising or unusual breathing.
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Blood in vomiting.
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Black or blood-colored stool.
Drug Storage and Disposal
The drug should be stored in its airtight container, tightly packaged, away from children. It must be stored at 20 to 25 degrees Celsius or 68 to 77 degrees Fahrenheit, with excursions permitted to 15 to 30 degrees Celsius or 59 to 86 degrees Fahrenheit, away from excess moisture and heat.
Expired or unneeded drugs should be discarded safely so that pets or children do not accidentally consume them. One can contact the nearest pharmacist or garbage or recycling department to discard the drug through a takeback program. However, it needs access to this program and to follow the Food and Drug Administration's (FDA) guidelines and protocols for safe drug disposal.
For Doctors:
Clinical Pharmacology:
Mechanism of Action
The drug is a selective inhibitor of Factor Xa. It does not require antithrombin III for antithrombotic activity. The drug inhibits free Factor Xa, thrombin-induced platelet aggregation, and prothrombinase activity. Inhibition of Factor Xa in the coagulation cascade reduces thrombus formations and thrombin generation.
Pharmacodynamics
Factor Xa inhibition of Edoxaban causes prolonged clotting time tests, such as PT (prothrombin time) and aPTT (activated partial thromboplastin time). The changes observed in prothrombin time activated partial thromboplastin time and international normalized ratio test (INR) at the recommended therapeutic dose are small concerning a high degree of variability and, thus, are not useful in monitoring the drug’s anticoagulant effect. Also, after oral administration, the pharmacodynamic effects and peak drug concentrations (Cmax) can be seen between one to two hours and peak drug concentrations (Cmax).
Cardiac Electrophysiology:
The QT study in healthy women and men (aged 19 to 45 years) revealed no prolongation in QTc interval with Edoxaban with 90 and 180 milligrams.
Pharmacodynamic Interactions:
The co-administration of 100 or 325 milligrams of Aspirin and Edoxaban showed the same increase in bleeding time relative to that seen with either drug alone. Also, the co-administration of 500 milligrams of Naproxen (an NSAID or Non-steroidal anti-inflammatory drug) with Edoxaban showed an increase in bleeding time relative to that seen with either drug alone.
Pharmacokinetics
Absorption
Peak plasma drug concentrations are observed within one to two hours after oral administration. The bioavailability of the drug is 62 percent, and the total systemic exposure to the drug is not affected by the food. Edoxaban can be administered with or without food. No clinical data suggests the bioavailability of the drug upon crushing and mixing the drug into liquids or food or giving it through feeding tubes.
Distribution
The drug's volume of distribution (steady state) is 107 (19.9) liters. Also, the plasma protein binding (in vitro) is approximately 55 percent. No clinical data shows the drug's accumulation with a single daily dosing (accumulation ratio 1.14), and the steady state of the drug concentration is obtained within three days.
Metabolism
The unchanged drug is the predominant form in plasma. Minimal metabolism can be seen via hydrolysis, and it forms metabolite M-4, which is active and human-specific. Thus, it reaches exposure levels of approximately less than 10 percent of the parent compound in healthy subjects. Also, the exposure to the other metabolites is not more than five percent of the drug's exposure.
Excretion
The drug is excreted from the body through urine in an unchanged form. Its renal clearance is 11 liters (371 ounces) per hour, accounting for approximately 50 percent of its total clearance, which is 22 liters (743 ounces) per hour. The terminal elimination half-life of the drug post-oral administration is ten to 14 hours.
Ingredients
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Active Ingredient: Factor Xa inhibitor.
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Inactive Ingredients: Pregelatinized starch, Mannitol, Crospovidone, Magnesium stearate, hydroxypropyl cellulose, carnauba wax, and talc. The color coatings of the drug contain titanium dioxide, hypromellose, talc, polyethylene glycol 8000, iron oxide red (15 and 30 milligrams tablets), and iron oxide yellow (15 and 60 milligrams tablets).
Contraindications
The drug is strictly contraindicated in patients with active pathological bleeding or suffering from any bleeding disorder due to some abnormality in the clotting process of the blood.
Edoxaban is known to increase the risk of potentially serious bleeding that can be fatal as well. Thus, it is not recommended in such cases.
Drug Warnings and Precautions:
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Risk of Bleeding: The drug increases the risk of bleeding and has the potential to cause serious and potentially fatal bleeding. Therefore, the doctor must thoroughly evaluate a patient's blood loss signs or symptoms. Also, the drug is not recommended in patients with active pathological bleeding as its concomitant use affects the hemostasis and may increase the risk of bleeding further. These include Aspirin, antiplatelet agents, fibrinolytic therapy, other antithrombotic agents, and non-steroidal anti-inflammatory drugs (NSAIDs). Also, the anticoagulant effects of the drugs cannot be reversed, and it may persist for approximately 24 hours at the end of the last dose. These effects cannot be reliably monitored as well with standard laboratory testing. Also, there is no specific reversal agent available for the drug, and hemodialysis does not contribute to drug clearance.
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Reduced Efficacy in Nonvalvular Atrial Fibrillation Patients with Creatinine Clearance Greater than 95 mL/min: The drug should not be prescribed in patients with creatinine clearance of greater than 95 milliliters per minute, as 60 mg daily of the drug is known to cause an increased rate of ischemic stroke in patients with nonvalvular atrial fibrillation compared to patients treated with Warfarin. The doctor should prescribe another drug to treat the condition in such cases.
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Increased Risk of Stroke with Discontinuation of Edoxaban in Patients with Nonvalvular Atrial Fibrillation: Premature stopping of any oral anticoagulant without adequate alternative anticoagulation increases the risk of ischemic events. If the drug is discontinued for some other reason apart from pathological bleeding or drug course completion, another anticoagulant must be prescribed to avoid the risk of ischemic attacks.
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Patients with Moderate to Severe Mitral Stenosis or Mechanical Heart Valve Stenosis: The drug's safety and efficacy have not been established in patients with moderate to severe mitral or mechanical heart valve stenosis. Therefore, it is not recommended in such cases.
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Spinal or Epidural Anesthesia or Puncture: In the case of spinal or epidural anesthesia or spinal/epidural puncture, patients who are treated with antithrombotic agents to prevent thromboembolic complications, are at risk of developing an epidural or spinal hematoma resulting in long-term or permanent paralysis. The risk is further increased by the postoperative use of indwelling epidural catheters or the concomitant drugs that affect hemostasis. Intrathecal catheters or indwelling epidurals should be removed after more than 12 hours after the last administration of the drug. The next drug dose should be administered two hours post-removal of the catheter. The risk can also be increased by traumatic or repeated epidural or spinal puncture. The patient should be monitored frequently for signs and symptoms of neurological impairment, such as bowel or bladder dysfunction and numbness or weakness of the legs. If a doctor notices neurological compromise, immediate diagnosis and treatment are necessary. Also, before neuraxial intervention, the physician should consider the risk-benefit levels in anticoagulated individuals or those anticoagulated for thromboprophylaxis.
Drug Interactions:
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Amiodarone.
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Atorvastatin.
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Cyclosporine.
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Digoxin.
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Dronedarone.
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Erythromycin.
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Esomeprazole.
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Ketoconazole.
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Quinidine.
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Rifampin.
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Selective serotonin-reuptake inhibitors (Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, and Sertraline).
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Serotonin-norepinephrine reuptake inhibitors (Desvenlafaxine, Duloxetine, Levomilnacipran, Milnacipran).
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Venlafaxine.
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Verapamil.
Use in Specific Populations:
Pregnancy
The drug belongs to pregnancy category C, meaning it is potentially harmful to the fetus, and there are no well-controlled studies or adequate data on drug usage in pregnant women. Therefore, the drug should be cautiously prescribed to this population after weighing the potential benefits and risks associated with the drug. However, no major teratogenic effects have been established with Edoxaban usage in this category.
Breastfeeding
It is not yet established if the drug is excreted in human milk. However, the drug was found to be excreted in rats during animal studies. Therefore, the risk-benefit levels of the drug should be carefully evaluated before prescribing it to this population category.
Renal Impairment
About 50 percent of the drug is excreted through renal clearance. Therefore, the drug’s blood levels are elevated in patients with poor renal clearance compared to those with higher clearance. Renal function. Thus, it is recommended that Edoxaban dosage be reduced to 30 milligrams once per day in patients with creatinine clearance of 15 to 50 milliliters per minute. The clinical data of patients receiving the drug with creatinine clearance of fewer than 15 milliliters per minute is minimal. Therefore, the drug is not recommended as hemodialysis does not improve the clearance levels in these patients. With an improvement in renal function, Edoxaban blood levels decrease, and the risk for ischemic stroke increases in patients with non-valvular atrial fibrillation.
Hepatic Impairment
The drug is not recommended in patients with moderate to severe hepatic impairment due to some abnormalities in the blood's intrinsic coagulation initiated by the clotting factors (XI, IX, VIII). However, in patients with mild hepatic impairment, no dose reduction is required.
Geriatric Use
The drug should be prescribed to the senior population based on their renal function, and renal drug dosing guidelines must be followed to avoid any risks or complications.
Pediatric Use
The safety and effectiveness of the drug have yet to be established in this population group.
