Genexiban

GENEXIBAN 2.5 MG: White to off-white colored, round shaped, biconvex, film-coated tablets debossed with "2.5" on one side and
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on the other side.
GENEXIBAN 5 MG: White to off-white colored, oval shaped, biconvex, film-coated tablets debossed with "5" on one side and
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on the other side.
Each film-coated tablet contains Apixaban 2.5 mg and Apixaban 5 mg.
Excipients/Inactive Ingredients: Hypromellose 5 CPS, anhydrous lactose, isopropyl alcohol, methylene chloride, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulphate, magnesium stearate, Opadry II white, purified water.

Pharmacology: Apixaban is a potent, oral, reversible, direct and highly selective active site inhibitor of factor Xa. It does not require antithrombin III for antithrombotic activity. Apixaban inhibits free and clot-bound factor Xa, and prothrombinase activity. Apixaban has no direct effects on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting factor Xa, apixaban prevents thrombin generation and thrombus development. Preclinical studies of apixaban in animal models have demonstrated antithrombotic efficacy in the prevention of arterial and venous thrombosis at doses that preserved haemostasis.
Pharmacodynamics: The pharmacodynamic effects of apixaban are reflective of the mechanism of action (FXa inhibition). As a result of FXa inhibition, apixaban prolongs clotting tests such as prothrombin time (PT), INR and activated partial thromboplastin time (aPTT). Changes observed in these clotting tests at the expected therapeutic dose are small and subject to a high degree of variability. They are not recommended to assess the pharmacodynamic effects of apixaban. In the thrombin generation assay, apixaban reduced endogenous thrombin potential, a measure of thrombin generation in human plasma.
Pharmacokinetics: Apixaban demonstrates linear pharmacokinetics with dose-proportional increases in exposure for oral doses up to 10 mg.
Absorption: The absolute bioavailability of apixaban is approximately 50% for doses up to 10 mg. Apixaban is rapidly absorbed with maximum concentrations (Cmax) appearing 3 to 4 hours after tablets intake. Intake with food does not affect apixaban AUC or Cmax at the 10 mg dose. Apixaban can be taken with or without food. 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. Apixaban exposure parameters exhibit low to moderate variability reflected by a within-subject and inter-subject variability of ~20% CV and ~30% CV respectively. Following oral administration of 10 mg of apixaban as 2 crushed 5 mg tablets suspended in 30 mL of water, exposure was similar to that after oral administration of 2 intact 5 mg tablets. Following oral administration of 10 mg of apixaban as 2 crushed 5 mg tablets mixed with 30 g of applesauce, the Cmax and AUC were 20% and 16% lower, respectively, when compared to administration of 2 intact 5 mg tablets. Following administration of a crushed 5 mg apixaban tablet that was suspended in 60 mL D5W and delivered through a nasogastric tube, exposure was similar to that seen in other clinical trials involving healthy volunteers receiving a single oral 5 mg tablet dose.
Distribution: Plasma protein binding in humans is approximately 87%. The volume of distribution (Vss) is approximately 21 liters.
Metabolism: Apixaban has multiple routes of elimination. Of the administered apixaban dose in humans, approximately 25% was recovered as metabolites, with the majority recovered in feces. 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.
Elimination: Apixaban is eliminated in both urine and feces. Renal excretion accounts for about 27% of total clearance. Additional contributions from biliary and direct intestinal excretion were observed in clinical and nonclinical studies, respectively. Apixaban has a total clearance of approximately 3.3 L/hour and an apparent half-life of approximately 12 hours following oral administration.
Apixaban is a substrate of transport proteins, P-gp and breast cancer resistance protein.
Drug interaction studies: In in vitro apixaban studies at concentrations significantly greater than therapeutic exposures, no inhibitory effect on the activity of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6, CYP3A4/5, or CYP2C19, nor induction effect on the activity of CYP1A2, CYP2B6, or CYP3A4/5 were observed. Therefore, apixaban is not expected to alter the metabolic clearance of co-administered drugs that are metabolized by these enzymes. Apixaban is not a significant inhibitor of P-gp. The effects of co-administered drugs on the pharmacokinetics of apixaban are summarized in Figure 1. (See Figure 1.)

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In dedicated studies conducted in healthy subjects, famotidine, atenolol, prasugrel, and enoxaparin did not meaningfully alter the pharmacokinetics of apixaban.
In studies conducted in healthy subjects, apixaban did not meaningfully alter the pharmacokinetics of digoxin, naproxen, atenolol, prasugrel, or acetylsalicylic acid. (See Figure 2.)

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Gender: A study in healthy subjects comparing the pharmacokinetics in males and females showed no meaningful difference.
Race: The results across pharmacokinetic studies in normal subjects showed no differences in apixaban pharmacokinetics among White/Caucasian, Asian, and Black/African American subjects. No dose adjustment is required based on race/ethnicity.
Hemodialysis in ESRD subjects: Systemic exposure to apixaban administered as a single 5 mg dose in ESRD subjects dosed immediately after the completion of a 4-hour hemodialysis session (postdialysis) is 36% higher when compared to subjects with normal renal function (Figure 2).
The systemic exposure to apixaban administered 2 hours prior to a 4-hour hemodialysis session with a dialysate flow rate of 500 mL/min and a blood flow rate in the range of 350 to 500 mL/min is 17% higher compared to those with normal renal function. The dialysis clearance of apixaban is approximately 18 mL/min. The systemic exposure of apixaban is 14% lower on dialysis when compared to not on dialysis. Protein binding was similar (92%-94%) between healthy controls and ESRD subjects during the on-dialysis and off-dialysis periods.

Prevention of VTE: elective hip or knee replacement surgery: 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 patient with non-valvular atrial fibrillation (NVAF): Apixaban is indicated to 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 intracranial hemorrhage.
Treatment of VTE: Apixaban is indicated for: Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE); Prevention of recurrent DVT and PE.

Apixaban can be taken with or without food. If a dose is missed, the patient should take apixaban immediately and then continue with twice daily administration as before.
Recommended dosage: Prevention of VTE: elective hip or knee replacement surgery: The recommended dose of apixaban is 2.5 mg taken 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 to 38 days.
In patients undergoing knee replacement surgery, the recommended duration of treatment is 10 to 14 days.
Prevention of stroke and systemic embolism: NVAF: The recommended dose of apixaban is 5 mg taken orally twice daily.
Age, body weight, serum creatinine: 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 of apixaban is 2.5 mg twice daily.
Treatment of DVT and PE: The recommended dose of apixaban 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 of apixaban is 2.5 mg taken orally twice daily after at least 6 months of treatment for DVT or PE.
Renal impairment: Prevention of VTE: elective hip or knee replacement surgery: No dose adjustment is necessary in patients with mild, moderate or severe (creatinine clearance 15-29 mL/min) renal impairment. Because there is limited clinical experience in patients with creatinine clearance <15 mL/min and no data in patients undergoing dialysis, apixaban is not recommended in these patients.
Prevention of stroke and systemic embolism: NVAF: No dose adjustment is recommended in patients with creatinine clearance 15 to 29 mL/min, except as described in Recommended dosage: Prevention of stroke and systemic embolism: NVAF as previously mentioned. Because there is no clinical experience in patients with creatinine clearance <15 mL/min, a dosing recommendation cannot be provided.
There are no data in patients undergoing dialysis, therefore, apixaban is not recommended in these patients.
Treatment of VTE: No dose adjustment is necessary in patients with mild, moderate, or severe (creatinine clearance 15-29 mL/min) renal impairment. Because there is limited clinical experience in patients with creatinine clearance <15 mL/min and no data in patients undergoing dialysis, apixaban is not recommended in these patients.
Hepatic impairment: Apixaban may be used with caution in patients with mild or moderate hepatic impairment (Child Pugh A or B). No dose adjustment is required in patients with mild or moderate hepatic impairment.
Apixaban is not recommended in patients with severe hepatic impairment.
Body weight: Prevention of VTE: elective hip or knee replacement surgery: No dose adjustment required.
Prevention of stroke and systemic embolism: NVAF: See Recommended dosage: Prevention of stroke and systemic embolism: NVAF as previously mentioned.
Treatment of VTE: No dose adjustment required.
Gender: No dose adjustment required.
Pediatric and adolescent: The efficacy and safety of apixaban in children below age 18 have not been established. No data are available.
Elderly: Prevention of VTE: elective hip or knee replacement surgery: No dose adjustment required.
Prevention of stroke and systemic embolism: NVAF: See Recommended dosage: Prevention of stroke and systemic embolism: NVAF as previously mentioned.
Treatment of VTE: No dose adjustment required.
Converting from or to parenteral anticoagulants: In general, switching treatment from parenteral anticoagulants to apixaban (and vice versa) can be done at the next scheduled dose.
Converting from or to warfarin or other vitamin K antagonists (VKA): When converting patients from warfarin or other VKA therapy to apixaban, discontinue warfarin or other VKA therapy and start apixaban when the international normalized ratio (INR) is below 2.0.
When converting from apixaban to warfarin or other VKA therapy, continue apixaban for 48 hours after the first dose of warfarin or other VKA therapy.
Surgery and invasive procedures: Apixaban should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of unacceptable or clinically significant bleeding. Apixaban should be discontinued at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding or where the bleeding would be non-critical in location and easily controlled. If surgery or invasive procedures cannot be delayed, exercise appropriate caution taking into consideration an increased risk of bleeding. This risk of bleeding should be weighed against the urgency of intervention. In non-valvular atrial fibrillation patients, bridging anticoagulation during the 24 to 48 hours after stopping apixaban and prior to the intervention is not generally required.
Apixaban should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established.
Apixaban can be initiated or continued in NVAF patients who may require cardioversion.
For patients not previously treated with anticoagulants, at least 5 doses of apixaban 5 mg twice daily [2.5 mg twice daily in patients who qualify for a dose reduction (see Recommended dosage: Prevention of stroke and systemic embolism: NVAF as previously mentioned)] should be given before cardioversion to ensure adequate anticoagulation.
If cardioversion is required before 5 doses of apixaban can be administered, a 10 mg loading dose should be given, followed by 5 mg twice daily. The dosing regimen should be reduced to a 5 mg loading dose followed by 2.5 mg twice daily if the patient meets the criteria for dose reduction (see Recommended dosage: Prevention of stroke and systemic embolism: NVAF as previously mentioned). The administration of the loading dose should be given at least 2 hours before cardioversion.
Confirmation should be sought prior to cardioversion that the patient has taken apixaban as prescribed. Decisions on initiation and duration of treatment should take established guideline recommendations for anticoagulant treatment in patients undergoing cardioversion into account.
Mode of Administration: For patients who are unable to swallow whole tablets, 5 mg and 2.5 mg apixaban tablets may be crushed and suspended in water, 5% dextrose in water (D5W), or apple juice, or mixed with applesauce and promptly administered orally. Alternatively, apixaban tablets may be crushed and suspended in 60 mL of water or D5W and promptly delivered through a nasogastric tube.

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, 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.

Hypersensitivity to the active substance or to any of the excipients.
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. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities.
Concomitant treatment with any other anticoagulant agent, e.g., unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, rivaroxaban, dabigatran, etc.) except under specific circumstances of switching anticoagulant therapy or when UFH is given at doses necessary to maintain an open central venous or arterial catheter.

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.
Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia (spinal/epidural anesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents for 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 traumatic or repeated epidural or spinal puncture. If 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 is 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.
Hip fracture surgery: Apixaban has not been studied in clinical trials in patients undergoing hip fracture surgery to evaluate efficacy and safety in these patients. Therefore, apixaban is not recommended in these patients.
Patients with Prosthetic Heart Valves: The safety and efficacy of apixaban have not been studied in patients with prosthetic heart valves. Therefore, use of apixaban is not recommended in these patients.
Acute PE in Hemodynamically Unstable Patients or Patients who require Thrombolysis or Pulmonary Embolectomy: Initiation of apixaban is not recommended as an alternative to unfractionated heparin for the initial treatment of patients with PE who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.
Patients with antiphospholipid syndrome: Direct-acting oral anticoagulants (DOACs), including apixaban, are not recommended for use in patients with triple-positive antiphospholipid syndrome (APS). For patients with APS (especially those who are triple positive [positive for lupus anticoagulant, anticardiolipin, and anti-beta 2-glycoprotein I antibodies]), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.
Effect on ability to drive and to use machines: Apixaban has no or negligible influence on the ability to drive and use machines.
Use in Children: The efficacy and safety of apixaban in children below age 18 have not been established. No data are available.

Pregnancy: There are limited data from the use of apixaban in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. Apixaban is not recommended during pregnancy.
Breastfeeding: It is unknown whether apixaban or its metabolites are excreted in human milk.
Available data in animals have shown excretion of apixaban in milk. In rat milk, a high milk to maternal plasma ratio (Cmax about 8, AUC about 30) was found, possibly due to active transport into the milk. A risk to newborns and infants cannot be excluded.
A decision must be made to either discontinue breast-feeding or to discontinue/abstain from apixaban therapy.
Fertility: Studies in animals dosed directly with apixaban have shown no effect on fertility.
However, in the female offspring of pregnant rats treated with apixaban, there were decreases in mating and fertility.

The following clinically significant adverse reactions are discussed in greater detail in other sections of the prescribing information: Increased risk of thrombotic events after premature discontinuation; Bleeding; Spinal/Epidural anesthesia or puncture.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Reduction of risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation: The safety of apixaban was evaluated in the ARISTOTLE and AVERROES studies, including 11,284 patients exposed to apixaban 5 mg twice daily and 602 patients exposed to apixaban 2.5 mg twice daily. The duration of apixaban exposure was >12 months for 9375 patients and >24 months for 3369 patients in the two studies. In ARISTOTLE, the mean duration of exposure was 89 weeks (>15,000 patient-years). In AVERROES, the mean duration of exposure was approximately 59 weeks (>3000 patient-years).
The most common reason for treatment discontinuation in both studies was for bleeding-related adverse reactions; in ARISTOTLE this occurred in 1.7% and 2.5% of patients treated with apixaban and warfarin, respectively, and in AVERROES, in 1.5% and 1.3% on apixaban and aspirin, respectively.
Bleeding in patients with nonvalvular atrial fibrillation in ARISTOTLE and AVERROES: Tables 1 and 2 show the number of patients experiencing major bleeding during the treatment period and the bleeding rate (percentage of subjects with at least one bleeding event per 100 patient-years) in ARISTOTLE and AVERROES. (See Table 1.)

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In ARISTOTLE, the results for major bleeding were generally consistent across most major subgroups including age, weight, CHADS2 score (a scale from 0 to 6 used to estimate risk of stroke, with higher scores predicting greater risk), prior warfarin use, geographic region, and aspirin use at randomization (Figure 3). Subjects treated with apixaban with diabetes bled more (3% per year) than did subjects without diabetes (1.9% per year). (See Figure 3.)

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Note: The figure as previously shown presents effects in various subgroups, all of which are baseline characteristics and all of which were prespecified, if not the groupings. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted. (See Table 2.)

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Other adverse reactions: Hypersensitivity reactions (including drug hypersensitivity, such as skin rash, and anaphylactic reactions, such as allergic edema) and syncope were reported in <1% of patients receiving apixaban.
Prophylaxis of deep vein thrombosis following hip or knee replacement surgery: The safety of apixaban has been evaluated in 1 Phase II and 3 Phase III studies including 5924 patients exposed to apixaban 2.5 mg twice daily undergoing major orthopedic surgery of the lower limbs (elective hip replacement or elective knee replacement) treated for up to 38 days.
In total, 11% of the patients treated with apixaban 2.5 mg twice daily experienced adverse reactions.
Bleeding results during the treatment period in the Phase III studies are shown in Table 3.
Bleeding was assessed in each study beginning with the first dose of double-blind study drug. (See Table 3.)

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Adverse reactions occurring in >1% of patients undergoing hip or knee replacement surgery in the 1 Phase II study and the 3 Phase III studies are listed in Table 4. (See Table 4.)

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Less common adverse reactions in apixaban-treated patients undergoing hip or knee replacement surgery occurring at a frequency of >0.1% to <1%: Blood and lymphatic system disorders: thrombocytopenia (including platelet count decreases).
Vascular disorders: hypotension (including procedural hypotension).
Respiratory, thoracic, and mediastinal disorders: epistaxis.
Gastrointestinal disorders: gastrointestinal hemorrhage (including hematemesis and melena), hematochezia.
Hepatobiliary disorders: liver function test abnormal, blood alkaline phosphatase increased, blood bilirubin increased.
Renal and urinary disorders: hematuria (including respective laboratory parameters).
Injury, poisoning, and procedural complications: wound secretion, incision-site hemorrhage (including incision-site hematoma), operative hemorrhage.
Less common adverse reactions in apixaban-treated patients undergoing hip or knee replacement surgery occurring at a frequency of <0.1%: Gingival bleeding, hemoptysis, hypersensitivity, muscle hemorrhage, ocular hemorrhage (including conjunctival hemorrhage), rectal hemorrhage.
Treatment of DVT and PE and reduction in the risk of recurrence of DVT or PE: The safety of apixaban has been evaluated in the AMPLIFY and AMPLIFY-EXT studies including 2676 patients exposed to apixaban 10 mg twice daily, 3359 patients exposed to apixaban 5 mg twice daily, and 840 patients exposed to apixaban 2.5 mg twice daily. Common adverse reactions (≥1%) were gingival bleeding, epistaxis, contusion, hematuria, rectal hemorrhage, hematoma, menorrhagia, and hemoptysis.
AMPLIFY Study: The mean duration of exposure to apixaban was 154 days and to enoxaparin/warfarin was 152 days in the AMPLIFY study. Adverse reactions related to bleeding occurred in 417 (15.6%) apixaban-treated patients compared to 661 (24.6%) enoxaparin/warfarin-treated patients. The discontinuation rate due to bleeding events was 0.7% in the apixaban-treated patients compared to 1.7% in enoxaparin/warfarin-treated patients in the AMPLIFY study.
In the AMPLIFY study, apixaban was statistically superior to enoxaparin/warfarin in the primary safety endpoint of major bleeding (relative risk 0.31, 95% CI [0.17, 0.55], P-value <0.0001).
Bleeding results from the AMPLIFY study are summarized in Table 5. (See Table 5.)

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Adverse reactions occurring in ≥1% of patients in the AMPLIFY study are listed in Table 6. (See Table 6.)

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AMPLIFY-EXT Study: The mean duration of exposure to apixaban was approximately 330 days and to placebo was 312 days in the AMPLIFY-EXT study. Adverse reactions related to bleeding occurred in 219 (13.3%) apixaban-treated patients compared to 72 (8.7%) placebo-treated patients. The discontinuation rate due to bleeding events was approximately 1% in the apixaban-treated patients compared to 0.4% in those patients in the placebo group in the AMPLIFY-EXT study.
Bleeding results from the AMPLIFY-EXT study are summarized in Table 7. (See Table 7.)

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Adverse reactions occurring in ≥1% of patients in the AMPLIFY-EXT study are listed in Table 8. (See Table 8.)

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Other adverse reactions: Less common adverse reactions in apixaban-treated patients in the AMPLIFY or AMPLIFY-EXT studies occurring at a frequency of ≥0.1% to <1%: Blood and lymphatic system disorders: hemorrhagic anemia.
Gastrointestinal disorders: hematochezia, hemorrhoidal, hemorrhage, gastrointestinal hemorrhage, hematemesis, melena, anal hemorrhage.
Injury, poisoning, and procedural complications: wound hemorrhage, postprocedural hemorrhage, traumatic hematoma, periorbital hematoma.
Musculoskeletal and connective tissue disorders: muscle hemorrhage.
Reproductive system and breast disorders: vaginal hemorrhage, metrorrhagia, menometrorrhagia, genital hemorrhage.
Vascular disorders: hemorrhage.
Skin and subcutaneous tissue disorders: ecchymosis, skin hemorrhage, petechiae.
Eye disorders: conjunctival hemorrhage, retinal hemorrhage, eye hemorrhage.
Investigations: blood urine present, occult blood positive, occult blood, red blood cells urine positive.
General disorders and administration-site conditions: injection-site hematoma, vessel puncture-site hematoma.

Apixaban is a substrate of both CYP3A4 and P-gp. Inhibitors of CYP3A4 and P-gp increase exposure to apixaban and increase the risk of bleeding. Inducers of CYP3A4 and P-gp decrease exposure to apixaban and increase the risk of stroke and other thromboembolic events.
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 drugs that are combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir). For patients receiving apixaban at a dose of 2.5 mg twice daily, avoid co-administration with combined P-gp and strong 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 concomitant use of 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: Co-administration of antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic NSAID use increases the risk of bleeding.
APPRAISE-2, a placebo-controlled clinical trial of apixaban in high-risk, post-acute coronary syndrome patients treated with aspirin or the combination of aspirin and clopidogrel, was terminated early due to a higher rate of bleeding with apixaban compared to placebo. The rate of ISTH major bleeding was 2.8% per year with apixaban versus 0.6% per year with placebo in patients receiving single antiplatelet therapy and was 5.9% per year with apixaban versus 2.5% per year with placebo in those receiving dual antiplatelet therapy.
In ARISTOTLE, concomitant use of aspirin increased the bleeding risk on apixaban from 1.8% per year to 3.4% per year and concomitant use of aspirin and warfarin increased the bleeding risk from 2.7% per year to 4.6% per year. In this clinical trial, there was limited (2.3%) use of dual antiplatelet therapy with apixaban.
Naproxen (500 mg), an inhibitor of P-gp, led to 1.5-fold and 1.6-fold increase in mean apixaban AUC and Cmax, in healthy subjects, respectively. Corresponding increases in clotting tests were observed for apixaban. No changes were observed in the effect of naproxen on arachidonic acid-induced platelet aggregation and no clinically relevant prolongation of bleeding time was observed after concomitant administration of apixaban and naproxen.
Despite these findings, apixaban should be used with caution when co-administered with NSAIDs (including ASA) because these medicinal products typically increase the bleeding risk.

Store below 30°C.

Anticoagulants, Antiplatelets & Fibrinolytics (Thrombolytics)

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

D