Apixaban

Apixaban is an anticoagulant agent belonging to Factor Xa (FXa) inhibitor.

Apixaban is an anticoagulant used for the prophylaxis of stroke and systemic embolism in nonvalvular atrial fibrillation, and deep vein thrombosis (DVT) leading to pulmonary embolism (PE), including in patients after a hip or knee replacement surgery.

The absolute bioavailability of apixaban is approximately 50% for doses up to 10 mg of Apixaban. Food does not affect the bioavailability of apixaban. Maximum concentrations (Cmax) of apixaban appear 3 to 4 hours after oral administration of Apixaban. Apixaban is absorbed throughout the gastrointestinal tract. Plasma protein binding in humans is approximately 87%. The volume of distribution (Vss) is about 21 liters. About 25% of an orally administered apixaban dose is recovered in urine and feces as metabolites. Apixaban is metabolized mainly via CYP3A4 with minor contributions from CYP1A2, 2C8, 2C9, 2C19, and 2J2. Following oral administration, the apparent half-life is ~12 hours because of prolonged absorption.

Apixaban shows common side effects like Constipation, Dizziness, Skin rash, Stomach pain, Headache, Nausea, and vomiting.

Apixaban is available in the form of an Oral tablet.

Apixaban is available in India, the US, the UK, Finland, Ireland, Italy, Japan, Germany, Spain, France, Australia, and Russia.

Apixaban belonging to the Factor Xa (FXa) inhibitor, acts as an anticoagulant agent.

Apixaban inhibits platelet activation and fibrin clot formation via direct, selective, and reversible inhibition of free and clot-bound factor Xa (FXa). FXa, as part of the prothrombinase complex consisting also of factor Va, calcium ions, and phospholipid, catalyzes the conversion of prothrombin to thrombin. Thrombin both activates platelets and catalyzes the conversion of fibrinogen to fibrin.

The onset of action of Apixaban occurs within 3-4 hours.

The Duration of Action for Apixaban in the body is approximately 24 hours.

The Tmax was found within 3-4 hours following the administration of Apixaban.

Apixaban is available in the form of an Oral tablet.

Apixaban Oral tablet is taken by mouth usually two times a day.

Apixaban is an anticoagulant used for the prophylaxis of stroke and systemic embolism in nonvalvular atrial fibrillation, and deep vein thrombosis (DVT) leading to pulmonary embolism (PE), including in patients after a hip or knee replacement surgery.

Apixaban is an anticoagulant agent belonging to Factor Xa (FXa) inhibitor.

Apixaban selectively inhibits factor Xa in its free and bound forms, independent of antithrombin III. Apixaban also inhibits prothrombinase. These effects prevent the formation of a thrombus.

Apixaban is approved for use in the following clinical indications

• Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation

Apixaban is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

• Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery

Apixaban is 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.

• Treatment of Deep Vein Thrombosis

Apixaban is indicated for the treatment of DVT.

• Treatment of Pulmonary Embolism

Apixaban is indicated for the treatment of PE.

• Reduction in the Risk of Recurrence of DVT And PE

Apixaban is indicated to reduce the risk of recurrent DVT and PE following initial therapy.

• Adult Dose for Prevention of Thromboembolism in Atrial Fibrillation

5 mg orally 2 times a day

• Adult Dose for Thromboembolic Stroke Prophylaxis

5 mg orally 2 times a day

• Adult Dose for Pulmonary Embolism

Initial dose: 10 mg orally 2 times a day for 7 days

Maintenance dose: 5 mg orally 2 times a day

• Adult Dose for Deep Vein Thrombosis

Initial dose: 10 mg orally 2 times a day for 7 days

Maintenance dose: 5 mg orally 2 times a day

• Adult Dose for Deep Vein Thrombosis – Prophylaxis

Deep vein thrombosis (DVT) prophylaxis following hip or knee replacement surgery:

2.5 mg orally twice a day

Duration of therapy:

Hip replacement: 35 days

Knee replacement: 12 days

Comments: The initial dose should be taken 12 to 24 hours after surgery.

Recurrent DVT and pe risk reduction:

2.5 mg orally twice a day

• Adult Dose for Deep Vein Thrombosis Prophylaxis after Hip Replacement Surgery

Deep vein thrombosis (DVT) prophylaxis following hip or knee replacement surgery:

2.5 mg orally twice a day

Duration of therapy:

Hip replacement: 35 days

Knee replacement: 12 days

Comments: The initial dose should be taken 12 to 24 hours after surgery.

Recurrent DVT and pe risk reduction:

2.5 mg orally twice a day

• Adult Dose for Deep Vein Thrombosis Prophylaxis after Knee Replacement Surgery

Deep vein thrombosis (DVT) prophylaxis following hip or knee replacement surgery:

2.5 mg orally twice a day

Duration of therapy:

Hip replacement: 35 days

Knee replacement: 12 days

Recurrent DVT and pe risk reduction:

2.5 mg orally twice a day

Apixaban is available in various strengths as 2.5mg and 5mg.

Apixaban is available in the form of an Oral Tablet.

Dosage Adjustment in Kidney Patient

● Stroke and systemic embolism risk reduction in patients with nonvalvular atrial fibrillation: Age 80 years or older Serum creatinine 1.5 mg/dL or higher.

● Deep vein thrombosis prophylaxis after hip or knee replacement: No adjustment required.

● Deep vein thrombosis (DVT) and pulmonary embolism (PE) treatment: No adjustment required.

● Recurrent DVT and PE risk reduction: No adjustment required.

Dosage Adjustment in Hepatic impairment Patient

• Mild liver impairment (Child-Pugh A): No adjustment recommended
• Moderate liver impairment (Child-Pugh B): These patients may have intrinsic coagulation abnormalities and there is limited experience with apixaban in these patients; therefore, data is not available.
• Severe liver impairment (Child-Pugh C): Not recommended.

Avoid grapefruit products. Avoid herbs and supplements with anticoagulant/antiplatelet activity. (eg. garlic, ginger, bilberry, danshen, piracetam, and ginkgo biloba).

Apixaban is contraindicated in patients with

● Active pathological bleeding.

● Severe hypersensitivity reaction to Apixaban

• Increased Risk of Thrombotic Events After Premature Discontinuation

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. If Apixaban is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.

• Bleeding

Apixaban increases the risk of bleeding and can cause serious, potentially fatal, bleeding. Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin and other antiplatelet agents, other anticoagulants, heparin, thrombolytic agents, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and nonsteroidal anti-inflammatory drugs (NSAIDs). Advise patients of signs and symptoms of blood loss and to report them immediately or go to an emergency room. Discontinue Apixaban in patients with active pathological hemorrhage.

• Reversal of Anticoagulant Effect

An agent to reverse the anti-factor Xa activity of apixaban is available. The pharmacodynamic effect of Apixaban can be expected to persist for at least 24 hours after the last dose, i.e., for about two drug half-lives. Prothrombin complex concentrate (PCC) activated prothrombin complex concentrate or recombinant factor VIIa may be considered but have not been evaluated in clinical studies. When PCCs are used, monitoring for the anticoagulation effect of apixaban using a clotting test (PT, INR, or aPTT) or anti-factor Xa (FXa) activity is not useful and is not recommended. Activated oral charcoal reduces the absorption of apixaban, thereby lowering apixaban plasma concentration. Hemodialysis does not appear to have a substantial impact on apixaban exposure. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of apixaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving apixaban. There is no experience with systemic hemostatics (desmopressin) in individuals receiving Apixaban, and they are not expected to be effective as a reversal agent.

• Spinal/Epidural Anesthesia or Puncture

When neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents for the prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis. The risk of these events may be increased by the postoperative use of indwelling epidural catheters or the concomitant use of medicinal products affecting hemostasis. Indwelling epidural or intrathecal catheters should not be removed earlier than 24 hours after the last administration of Apixaban. The next dose of Apixaban should not be administered earlier than 5 hours after the removal of the catheter. The risk may also be increased by a traumatic or repeated epidural or spinal puncture. If a traumatic puncture occurs, delay the administration of Apixaban for 48 hours. Monitor patients frequently for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, or bowel or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment are necessary. Prior to neuraxial intervention, the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis.

• Patients With Prosthetic Heart Valves

The safety and efficacy of Apixaban have not been studied in patients with prosthetic heart valves. Therefore, the use of Apixaban is not recommended in these patients.

It is unknown whether Apixaban or its metabolites are excreted in human milk. Rats excrete apixaban in milk (12% of the maternal dose). Women should be instructed either to discontinue breastfeeding or to discontinue Apixaban therapy, considering the importance of the drug to the mother.

When used in pregnancy, there is also the potential for fetal or subclinical placental bleeding which may increase the risk of miscarriage, preterm delivery, fetal compromise, or stillbirth. The use of direct-acting oral anticoagulants during pregnancy and use in pregnant patients is not recommended.

Avoid grapefruit products. Avoid herbs and supplements with anticoagulant/antiplatelet activity. (eg. garlic, ginger, bilberry, danshen, piracetam, and ginkgo biloba).

• Common Adverse effects

Hemorrhage, heavy menstrual bleeding, gingival hemorrhage, nausea, hematuria, anemia, bruise, hematoma, rectal hemorrhage, hemoptysis.

• Other Adverse effects

Hypersensitivity reactions (including drug hypersensitivity, such as skin rash, and anaphylactic reactions, such as allergic edema) and syncope.

• Combined P-GP and Strong CYP3A4 Inhibitors

For patients receiving Apixaban 5 mg or 10 mg twice daily, the dose of Apixaban should be decreased by 50% when coadministered with combined P-GP and potent CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir).

For patients receiving Apixaban at a dose of 2.5 mg twice daily, avoid coadministration with combined P-GP and potent CYP3A4 inhibitors.

• Clarithromycin

Although clarithromycin is a combined P-GP and strong CYP3A4 inhibitor, pharmacokinetic data suggest that no dose adjustment is necessary with concomitant administration with Apixaban.

• Combined P-GP and Strong CYP3A4 Inducers

Avoid using Apixaban with combined P-GP and strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, St. John's wort) because such drugs will decrease exposure to Apixaban.

• Anticoagulants and Antiplatelet Agents

Coadministration of antiplatelet agents, fibrinolytic, heparin, aspirin, and chronic NSAID use increase the risk of bleeding.

The common side effects of Apixaban include the following

• Common

Constipation, Dizziness, Skin rash, Stomach pain, Headache, Nausea, and vomiting.

• Rare

• Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies of Apixaban in pregnant women. Treatment is likely to increase the risk of hemorrhage during pregnancy and delivery. Apixaban should be used during pregnancy only if the potential benefit outweighs the potential risk to the mother and fetus. Treatment of pregnant rats, rabbits, and mice after implantation until the end of gestation resulted in fetal exposure to apixaban but was not associated with an increased risk for fetal malformations or toxicity. No maternal or fetal deaths were attributed to bleeding. Increased incidence of maternal bleeding was observed in mice, rats, and rabbits at maternal exposures that were 19, 4, and 1 time, respectively, the human exposure of unbound drug, based on area under plasma concentration-time curve (AUC) comparisons at the maximum recommended human dose (MRHD) of 10 mg (5 mg twice daily).

• Nursing Mothers

It is unknown whether Apixaban or its metabolites are excreted in human milk. Rats excrete apixaban in milk (12% of the maternal dose). Women should be instructed either to discontinue breastfeeding or to discontinue Apixaban therapy, taking into account the importance of the drug to the mother.

• Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

• Geriatric Use

Of the total subjects in clinical studies of apixaban, >69% were 65 and older, and >31% were 75 and older. The effects of Apixaban on the risk of stroke and major bleeding compared to warfarin were maintained in geriatric subjects.

• Overdose of Apixaban increases the risk of bleeding. In controlled clinical trials, orally administered apixaban in healthy subjects at doses up to 50 mg daily for 3 to 7 days (25 mg twice daily for 7 days or 50 mg once daily for 3 days) had no clinically relevant adverse effects.
• In healthy subjects, administration of activated charcoal 2 and 6 hours after ingestion of a 20-mg dose of Apixaban reduced mean apixaban AUC by 50% and 27%, respectively. Thus, the administration of activated charcoal may be useful in the management of Apixaban overdose or accidental ingestion. An agent to reverse the anti-factor Xa activity of apixaban is available.

Pharmacodynamic

• Apixaban selectively inhibits factor Xa in its free and bound forms, independent of antithrombin II. Apixaban also inhibits prothrombinase. These effects prevent the formation of a thrombus.

Pharmacokinetics

• Absorption

The absolute bioavailability of apixaban is approximately 50% for doses up to 10 mg of Apixaban. Food does not affect the bioavailability of apixaban. Maximum concentrations (Cmax) of apixaban appear 3 to 4 hours after oral administration of Apixaban. Apixaban is absorbed throughout the gastrointestinal tract with the distal small bowel and ascending colon contributing about 55% of apixaban absorption. Apixaban demonstrates linear pharmacokinetics with dose-proportional increases in exposure for oral doses up to 10 mg. At doses ≥25 mg, apixaban displays dissolution-limited absorption with decreased bioavailability.

• Distribution

Plasma protein binding in humans is approximately 87%. The volume of distribution (Vss) is approximately 21 liters.

• Metabolism and Excretion

Approximately 25% of an orally administered apixaban dose is recovered in urine and feces as metabolites. Apixaban is metabolized mainly via CYP3A4 with minor contributions from CYP1A2, 2C8, 2C9, 2C19, and 2J2. O-demethylation and hydroxylation at the 3-oxopiperidinyl moiety are the major sites of biotransformation. Unchanged apixaban is the major drug-related component in human plasma; there are no active circulating metabolites. Apixaban is eliminated in both urine and feces. Renal excretion accounts for about 27% of total clearance. Biliary and direct intestinal excretion contributes to the elimination of apixaban in the feces. Following intravenous administration, apixaban is eliminated with a dominant half-life of ~ 5 hours. Following oral administration, the apparent half-life is ~12 hours because of prolonged absorption.

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