Apixan

APIXAN 2.5: Yellow, round shaped, biconvex, film-coated tablet debossed with IU1 on one side and plain on the other side.
Each film-coated tablet contains Apixaban 2.5 mg.
APIXAN 5: Pink, oval shaped, biconvex, film-coated tablet debossed with IU2 on one side and plain on the other side.
Each film-coated tablet contains Apixaban 5 mg.

Pharmacology: Pharmacodynamics: Apixaban, an anticoagulant, is a direct selective and reversible inhibitor of free and clot-bound Factor Xa (FXa). FXa as part of prothrombinase complex consisting also of Factor Va, calcium ions and phospholipid catalyzes the conversion of prothrombin to thrombin. Thrombin activates platelets and catalyzes the conversion of fibrinogen to fibrin. By inhibiting FXa, apixaban decreases thrombin generation and thrombus development, it does not require a cofactor (antithrombin III) for its antithrombotic activity.
Apixaban prolongs clotting tests such as prothrombin time (PT), International Normalized Ratio (INR), and activated partial thromboplastin time (aPTT) in a concentration-dependent manner.
Pharmacokinetics: Apixaban demonstrates linear, dose-proportional pharmacokinetics for oral doses up to 10 mg.
Absorption: The absolute bioavailability of apixaban is approximately 50%.
Peak plasma concentrations of apixaban appear approximately 3 to 4 hours after oral administration. Following administration of a single, crushed 5 mg apixaban tablet that was suspended in 60 mL D5W and delivered through a nasogastric tube, its bioavailability was similar to that of a whole tablet taken orally. Absorption of apixaban occurs throughout gastrointestinal tract, about 55% of the drug is absorbed in the distal small intestine and ascending colon. Food does not affect the pharmacokinetics (bioavailability and peak plasma concentrations) or pharmacodynamics of apixaban.
Distribution: Plasma protein binding in humans is approximately 87%. The volume of distribution (Vss) is approximately 21 liters.
Metabolism: Apixaban is metabolized mainly in the liver via CYP3A4/5 with minor contributions from CYP1A2, CYP2C8, CYP2C9, CYP2C19 and CYP2J2 to inactive metabolites. O-demethylation and hydroxylation at the 3-oxopiperidinyl moiety are the major sites of biotransformation. Apixaban is a substrate of transport proteins; p-glycoprotein (P-gp) and breast cancer resistant protein (BCRP). No active circulating metabolites have been identified.
Excretion: Apixaban is eliminated in both urine and feces. Renal excretion accounts for about 27% of total clearance. Biliary and direct intestinal excretion contributes to elimination of apixaban in the feces. An apparent half-life is approximately 12 hours (8-15 hours) following oral administration. Apixaban has a total clearance of approximately 3.3 L/hour.

Apixaban, a Factor Xa inhibitor, is indicated for: Prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective hip or knee replacement surgery.
Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF): Reduce the risk of stroke, systemic embolism, and death in patients with non-valvular atrial fibrillation with one or more risk factors, including patients unsuitable for warfarin. Compared to warfarin, apixaban also results in less bleeding, including cerebral hemorrhage.
Treatment of VTE: Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE); Prevention of recurrent DVT and PE.

Prevention of Venous Thromboembolic Events (VTE) in Elective Hip or Knee Replacement Surgery: The recommended dose is 2.5 mg orally twice daily. The initial dose should be taken 12 to 24 hours after surgery.
In patients undergoing hip replacement surgery, the recommended duration of treatment is 32-38 days.
In patients undergoing knee replacement surgery, the recommended duration of treatment is 10-14 days.
Prevention of Stroke and Systemic Embolism in NVAF: The recommended dose is 5 mg orally twice daily.
In patients with at least 2 of the following characteristics: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL (133 micromole/L), the recommended dose is 2.5 mg orally twice daily.
Treatment of DVT and PE: The recommended dose is 10 mg taken orally twice daily for 7 days, followed by 5 mg taken orally twice daily.
Prevention of Recurrent DVT and PE: The recommended dose is 2.5 mg taken orally twice daily after at least 6 months of treatment for DVT or PE.
Missed Dose: If a dose of apixaban tablets is not taken at the scheduled time, the dose should be taken as soon as possible on the same day and twice-daily administration should be resumed. The dose should not be doubled to make up for a missed dose.
Switching: Switching from warfarin or other VKA therapy to apixaban: Warfarin or other VKA therapy should be discontinued and apixaban started when the international normalized ratio (INR) is below 2.0.
Switching from apixaban to warfarin or other VKA therapy: Administration of apixaban should be continued for at least 48 hours after beginning warfarin or other VKA therapy. After 48 hours of co-administration of apixaban with warfarin or other VKA therapy (at usual starting doses), an INR should be obtained and then retested just prior to any next scheduled dose of apixaban. Co-administration of apixaban and warfarin or other VKA therapy should be continued until the INR is ≥2.0.
Switching from apixaban to other non-warfarin anti-coagulants (oral or parenteral): Discontinue apixaban and begin taking the other non-warfarin anticoagulant at the usual time of the next scheduled dose of apixaban.
Switching from other non-warfarin anti-coagulants (oral or parenteral) to apixaban: Discontinue the other non-warfarin anticoagulant and begin taking apixaban at the usual time of the next scheduled dose of the other non-warfarin anticoagulant.
Renal Impairment: For the prevention of VTE in elective hip or knee replacement surgery, for the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE, no dose adjustment is necessary.
For the prevention of stroke and systemic embolism in patients with NVAF: Serum creatinine <1.5mg/dl, no dose adjustment is necessary unless age ≥80 years and body weight ≤60 kg, then a dose reduction is needed.*
Serum creatinine ≥1.5 mg/dL (133 micromole/L) and associated with either age ≥80 years or body weight ≤60 kg, a dose reduction is necessary.*
*(See Prevention of Stroke and Systemic Embolism in NVAF as previously mentioned.)
In patients with creatinine clearance <15 mL/min, or in patients undergoing dialysis, there is no clinical experience therefore apixaban is not recommended.
Geriatrics patients ≥65 years of age with creatinine clearance <25 mL/min, apixaban is not recommended due to increased risk of bleeding.
Hepatic Impairment: It is not recommended in patients with severe hepatic impairment. No dose adjustment is required in patients with mild or moderate hepatic impairment.
Body Weight: No dose adjustment required, unless weighing ≤60 kg with criteria for dose reduction (age ≥80 years and/or having serum creatinine concentration ≥1.5 mg/dL) are met. (See Renal Impairment as previously mentioned.)
Gender/race/ethnicity: No dose adjustment required.
Elderly: NVAF: no dose adjustment required, unless criteria for dose reduction are met. (See Prevention of Stroke and Systemic Embolism in NVAF as previously mentioned.)
Pediatrics: The safety and efficacy of apixaban in children and adolescents below age 18 have not been established. No data are available.
Mode of Administration: Apixaban should be swallowed with water, with or without food.
For patients who are unable to swallow whole tablets, apixaban 2.5 or 5.0 mg tablets may be crushed and suspended in 60 ml of water, or 5% dextrose in water (D5W), or apple juice or mixed with apple puree and immediately administered orally.
Nasogastric tube administration, apixaban tablets may be crushed and suspended in 60 mL of water or D5W and immediately delivered.
Crushed apixaban tablets are stable in water, D5W, or apple juice or mixed with apple puree for up to 4 hours.

Overdose and Treatment: Overdose of apixaban may result in a higher risk of bleeding. Apixaban is not dialyzable due to its high plasma protein binding. There is no antidote for apixaban. In the event of overdosage, activated charcoal may be used to more rapidly decrease plasma concentrations of apixaban.

Avoid using apixaban in patients with these conditions: Hypersensitivity to apixaban or any component of this drug; Clinically significant active bleeding; Hepatic disease associated with coagulopathy and clinically relevant bleeding risk; Lesion or condition if considered a significant risk factor for major bleeding.
Concomitant treatment with any other anticoagulant agent e.g., unfractionated heparin (except when given at doses used to maintain an open central venous or arterial catheter), low molecular weight heparins, heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, rivaroxaban, dabigatran, etc.) except under specific circumstances of switching anticoagulant therapy to or from apixaban therapy.
Concomitant systemic use of apixaban with agents that are strong inhibitors of both CYP3A4 and P-gp.
The use in patients with creatinine clearance less than 15 mL/minute or receiving dialysis cannot be made.

Apixaban increases the risk of bleeding and can cause serious, potentially fatal, bleeding.
Concomitant use of drugs affecting hemostasis increases the risk of bleeding. Discontinue apixaban in patients with active pathological hemorrhage.
A specific antidote for apixaban is not available, the symptomatic and supportive treatments are depended on the bleeding severity. If ingestion occurred within 1 or 2 hours of presentation, activated oral charcoal should be considered for decreasing the plasma concentrations because of the high plasma protein binding of apixaban and it is not expected to be dialyzable. The following alternative options, 4-factor unactivated prothrombin concentrate (PCC) or 4-factor activated prothrombin concentrate (aPCC) or recombinant factor VIIa, may also be considered depending specific clinical scenario.
Premature discontinuation of apixaban in absence of any alternative anticoagulants will increase the risk of thrombotic events.
If it is needed to discontinue apixaban because of the other reasons other than the pathologic bleeding or completion of a course of the therapy, anticoagulant coverage with the alternative anticoagulants should be considered.
The dose should not be doubled to make up for a missed dose.
It is not recommended in patients with severe hepatic impairment.
It should be used with caution in patients with mild or moderate hepatic impairment (Child Pugh A or B).
Patients may bruise and/or bleed more easily and that longer than normal time may be required to stop bleeding.
Patients should be advised on how to recognize signs and symptoms of bleeding and to inform clinicians immediately.
Advice patients who have had neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural puncture, especially when they are receiving concomitant nonsteroidal anti-inflammatory agents (NSAIDs), platelet-aggregation inhibitors or other anticoagulants, to monitor for manifestations of epidural or spinal hematoma (e.g., numbness or weakness of the legs, bowel, or bladder dysfunction) and report them to clinicians immediately.
In patients who receive both apixaban and neuraxial anesthesia, avoid removal of epidural or intrathecal catheter for at least 24 hours following last apixaban dose; avoid apixaban administration for at least 5 hours following catheter removal. If traumatic puncture occurs, delay apixaban administration for at least 48 hours.
Hemodynamically unstable patients with acute PE or patients with PE who require thrombolysis or pulmonary embolectomy, the use of apixaban is not recommended.
The safety and efficacy of apixaban have not been studied in patients with prosthetic heart valves or significant rheumatic heart disease, the use of apixaban is not recommended in these patients.

Pregnancy: Apixaban is classified as Pregnancy Category B. There are no adequate and well controlled studies of apixaban in pregnant women. Animal studies have not demonstrated any evidence of fetotoxic effects but increased maternal bleeding was observed when apixaban was administered in pregnant animals at dose ranging from 1-19 times the human exposure at the maximum recommended dose. It 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.
Lactation: It is unknown whether apixaban or its metabolites are excreted in human milk. Rats excrete apixaban in their milk. Decision should be made either to discontinue breastfeeding or to discontinue apixaban therapy, taking into account the importance of the drug to the mother.

The use of apixaban may be associated with an increased risk of occult or overt bleeding. (See table.)

Click on icon to see table/diagram/image

Inhibitors of both CYP3A4 and P-gp increase exposure to apixaban and increase the risk of bleeding because apixaban is a substrate of both CYP3A4 and P-gp.
For patients receiving apixaban 5 mg or 10 mg twice daily, the dose of apixaban should be decreased by 50% when co-administered with drugs that are strong inhibitors of CYP3A4 and P-gp (e.g., ketoconazole, itraconazole, ritonavir, or clarithromycin).
For patients already receiving apixaban at a dose of 2.5 mg twice daily, avoid co-administration with strong dual inhibitors of CYP3A4 and P-gp.
Inducers of both CYP3A4 and P-gp, (e.g., rifampin, carbamazepine, phenytoin, St. John's wort) drugs will decrease exposure to apixaban and increase the risk of stroke and other thromboembolic events. Avoid concomitant use.
Co-administration of aspirin and other antiplatelet agents, fibrinolytics, heparin or other anticoagulants, selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs) and NSAIDs use will increases the risk of bleeding.

Special precaution for storage: No special requirements. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Store at temperature not exceeding 30°C.

Anticoagulants, Antiplatelets & Fibrinolytics (Thrombolytics)

B01AF02 - apixaban ; Belongs to the class of direct factor Xa inhibitors. Used in the treatment of thrombosis.

D