Apixastal-2.5/Apixastal-5

Apixaban-2.5: Peach colored, round shaped, biconvex, film-coated tablet plain on both sides.
Each film-coated tablet contains: Apixaban 2.5 mg.
Apixaban-5: Peach colored, oval shaped, biconvex, film-coated tablet plain on both sides.
Each film-coated tablet contains: Apixaban 5 mg.

Pharmacotherapeutic group: Antithrombotic agents, direct factor Xa inhibitor.
Pharmacology: Pharmacodynamics: Mechanism of action: 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.
Pharmacodynamic effects: 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.
Apixaban also demonstrates anti-FXa activity as evident by reduction in Factor Xa enzyme activity in multiple commercial anti-FXa kits, however results differ across kits. Data from clinical studies are only available for the Rotachrom Heparin chromogenic assay. Anti-FXa activity exhibits a close direct linear relationship with Apixaban plasma concentration, reaching maximum values at the time of Apixaban peak plasma concentrations. The relationship between Apixaban plasma concentration and anti-FXa activity is approximately linear over a wide dose range of Apixaban.
The dose- and concentration-related changes observed following Apixaban administration are more pronounced, and less variable, with anti-FXa activity compared with clotting tests.
Table 1 as follows shows the predicted steady state exposure and anti-Factor Xa activity for each indication. In patients taking Apixaban for the prevention of VTE following hip or knee replacement surgery, the results demonstrate a less than 1.6-fold fluctuation in peak-to-trough levels. In non-valvular atrial fibrillation patients taking Apixaban for the prevention of stroke and systemic embolism, the results demonstrate a less than 1.7-fold fluctuation in peak-to-trough levels. In patients taking Apixaban for the treatment of DVT and PE or prevention of recurrent DVT and PE, the results demonstrate a less than 2.2-fold fluctuation in peak-to-trough levels. (See Table 1.)

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Although treatment with Apixaban does not require routine monitoring of exposure, a calibrated quantitative anti-Factor Xa assay may be useful in exceptional situations where knowledge of Apixaban exposure may help to inform clinical decisions, e.g., overdose and emergency surgery.
Pharmacokinetics: Absorption: The absolute bioavailability of Apixaban is approximately 50% for doses up to 10 mg. Apixaban is rapidly absorbed with maximum concentrations (C_max) appearing 3 to 4 hours after tablet intake. Intake with food does not affect Apixaban AUC or C_max 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 comparable to exposure 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 C_max and AUC were 21% and 16% lower, respectively, when compared to administration of 2 intact 5 mg tablets. Following administration of a crushed 5 mg Apixaban tablet suspended in 60 mL of D5W and delivered via a nasogastric tube, exposure was similar to exposure seen in other clinical trials involving healthy subjects receiving a single oral 5 mg Apixaban tablet dose.
Distribution: Plasma protein binding in humans is approximately 87%. The volume of distribution (Vss) is approximately 21 liters.
Metabolism and Elimination: 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. Renal excretion of Apixaban accounts for approximately 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 about 3.3 L/h and a half-life of approximately 12 hours. O-demethylation and hydroxylation at the 3-oxopiperidinyl moiety are the major sites of biotransformation. Apixaban is metabolized mainly via CYP3A4/5 with minor contributions from CYP1A2, 2C8, 2C9, 2C19, and 2J2. Unchanged Apixaban is the major drug-related component in human plasma with no active circulating metabolites present. Apixaban is a substrate of transport proteins, P-gp and breast cancer resistance protein (BCRP).
Renal Impairment: There was no impact of impaired renal function on peak concentration of Apixaban. There was an increase in Apixaban exposure correlated to decrease in renal function, as assessed via measured creatinine clearance. In individuals with mild (creatinine clearance 51-80 mL/min), moderate (creatinine clearance 30-50 mL/min) and severe (creatinine clearance 15-29 mL/min) renal impairment, Apixaban plasma concentrations (AUC) were increased 16, 29, and 44% respectively, compared to individuals with normal creatinine clearance. Renal impairment had no evident effect on the relationship between Apixaban plasma concentration and anti-FXa activity. No dose adjustment is necessary in patients with mild, moderate or severe renal impairment except as described in Dosage & Administration.
In subjects with end-stage renal disease (ESRD), the AUC of Apixaban was increased by 36% when a single dose of Apixaban 5 mg was administered immediately after hemodialysis, compared to that seen in subjects with normal renal function. Hemodialysis, started two hours after administration of a single dose of Apixaban 5 mg, decreased Apixaban AUC by 14% in these ESRD subjects, corresponding to an Apixaban dialysis clearance of 18 mL/min.
Hepatic Impairment: Apixaban has not been studied in patients with severe hepatic impairment or active hepatobiliary disease. Apixaban is not recommended in patients with severe hepatic impairment (see Precautions).
Elderly: Elderly patients (above 65 years) exhibited higher plasma concentrations than younger patients, with mean AUC values being approximately 32% higher. No dose adjustment is required, except as described in Recommended Dosage: Prevention of stroke and systemic embolism in patients with AF: NVAF under Dosage & Administration.
Gender: Exposure to Apixaban was approximately 18% higher in females than in males. No dose adjustment is required.
Ethnic Origin and Race: The results across phase 1 studies showed no discernible difference in Apixaban pharmacokinetics between White/Caucasian, Asian and Black/African American subjects. Findings from a population pharmacokinetic analysis in patients who received Apixaban following elective hip or knee replacement surgery were generally consistent with the phase 1 results. No dose adjustment is required.
Body Weight: Compared to Apixaban exposure in subjects with body weight of 65 to 85 kg, body weight >120 kg was associated with approximately 30% lower exposure and body weight <50 kg was associated with approximately 30% higher exposure. No dose adjustment is required, except as described in Recommended Dosage: Prevention of stroke and systemic embolism in patients with AF: NVAF under Dosage & Administration.
Pharmacokinetic/Pharmacodynamic Relationship: The pharmacokinetic/pharmacodynamic (PK/PD) relationship between Apixaban plasma concentration and several PD endpoints (anti-FXa activity, INR, PT, aPTT) has been evaluated after administration of a wide range of doses (0.5-50 mg). The relationship between Apixaban plasma concentration and anti-FXa activity was best described by a linear model. The PK/PD relationship observed in patients who received Apixaban in Phase 2 or Phase 3 clinical trials was consistent with that established in healthy subjects.

Prevention of VTE in Surgical Patients: 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 Patients with AF: Nonvalvular atrial fibrillation: Apixaban is indicated to reduce the risk of stroke, systemic embolism, and death in patients with nonvalvular 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 in surgical patients: 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 in patients with AF: 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 in surgical patients: 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 (see Pharmacology: Pharmacokinetics under Actions). 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 (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Prevention of stroke and systemic embolism in patients with AF: 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 in patients with AF: 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 (see Pharmacology: Pharmacokinetics under Actions).
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 (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Apixaban is not recommended in patients with severe hepatic impairment (see Precautions and Pharmacology: Pharmacokinetics under Actions).
Body Weight: Prevention of VTE in surgical patients: Elective hip or knee replacement surgery: No dose adjustment required.
Prevention of stroke and systemic embolism in patients with AF: NVAF: See Recommended Dosage: Prevention of stroke and systemic embolism in patients with AF: 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 in surgical patients: Elective hip or knee replacement surgery: No dose adjustment required (see Pharmacology: Pharmacokinetics under Actions).
Prevention of stroke and systemic embolism in patients with AF: NVAF: See Recommended Dosage: Prevention of stroke and systemic embolism in patients with AF: 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 nonvalvular 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 previously)] 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 previously). 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.
Administration Options: For patients who are unable to swallow whole tablets, 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 (see Pharmacology: Pharmacokinetics under Actions). Alternatively, Apixaban tablets may be crushed and suspended in 60 mL of water or D5W and promptly delivered through a nasogastric tube. Crushed Apixaban tablets are stable in water, D5W, apple juice, and applesauce for up to 4 hours.

There is no antidote to Apixaban. Overdose of Apixaban may result in a higher 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 a day for 7 days or 50 mg once a day for 3 days) had no clinically relevant adverse effects.
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, and had no impact on C_max. Mean half-life of Apixaban decreased from 13.4 hours when Apixaban was administered alone to 5.3 hours and 4.9 hours, respectively, when activated charcoal was administered 2 and 6 hours after Apixaban. Thus, administration of activated charcoal may be useful in the management of Apixaban overdose or accidental ingestion.
Hemodialysis is unlikely to be an effective means of managing Apixaban overdose.

Hypersensitivity to the active substance or to any of the excipients.
Clinically significant active bleeding.

Hemorrhage Risk: As with other anticoagulants, patients taking Apixaban are to be carefully observed for signs of bleeding. Apixaban is recommended to be used with caution in conditions with increased risk of hemorrhage, such as: congenital or acquired bleeding disorders; active ulcerative gastrointestinal disease; bacterial endocarditis; thrombocytopenia; platelet disorders; history of hemorrhagic stroke; severe uncontrolled hypertension; and recent brain, spinal, or ophthalmological surgery. Apixaban is not recommended in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk. Apixaban administration should be discontinued if severe hemorrhage occurs (see Overdosage).
In the event of hemorrhagic complications, treatment must be discontinued and the source of bleeding investigated. The initiation of appropriate treatment, e.g., surgical hemostasis or the transfusion of fresh frozen plasma, should be considered. If life-threatening bleeding cannot be controlled by the previously mentioned measures, administration of prothrombin complex concentrates (PCCs) or recombinant factor VIIa may be considered. Reversal of Apixaban pharmacodynamic effects, as demonstrated by changes in the thrombin generation assay, has been demonstrated after administration of 4-factor PCCs in healthy subjects. However, there is no clinical experience with the use of 4-factor PCC products to reverse bleeding in individuals who have received Apixaban. Currently, there is no experience with the use of recombinant factor VIIa in individuals receiving Apixaban.
Temporary Discontinuation of Apixaban: Discontinuing anticoagulants, including Apixaban, for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of thrombosis. Avoid lapses in therapy, and if anticoagulation with Apixaban must be temporarily discontinued for any reason, restart therapy as soon as possible.
Renal Impairment: Prevention of VTE in surgical patients: Elective hip or knee replacement surgery: 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 (see Renal Impairment under Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Prevention of stroke and systemic embolism in patients with AF: NVAF: There are no data in patients undergoing dialysis, therefore, Apixaban is not recommended in these patients (see Pharmacology: Pharmacokinetics under Actions). Treatment of VTE: 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 (see Pharmacology: Pharmacokinetics under Actions).
Hepatic Impairment: Apixaban is not recommended in patients with severe hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
Apixaban may be used with caution in patients with mild or moderate hepatic impairment (Child Pugh A or B) (see Hepatic Impairment under Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Interaction with Strong Inhibitors of Both Cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp): Apixaban can be administered with caution in patients receiving concomitant systemic treatment with strong inhibitors of both Cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp), such as azole-antimycotics (e.g., ketoconazole, itraconazole, voriconazole and posaconazole), HIV protease inhibitors (e.g., ritonavir). These medicinal products may increase Apixaban exposure by 2-fold (see Interactions).
Interaction with Strong Inducers of Both CYP3A4 and P-gp: Prevention of VTE: Elective hip or knee replacement surgery: The concomitant use of Apixaban with strong CYP3A4 and P-gp inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital or St. John's Wort) may lead to a ~50% reduction in Apixaban exposure. Use caution when co-administering Apixaban with strong inducers of both CYP3A4 and P-gp (see Interactions).
Prevention of stroke and systemic embolism: NVAF: The concomitant use of Apixaban with strong CYP3A4 and P-gp inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital or St. John's Wort) may lead to a ~50% reduction in apixaban exposure. Use caution when co-administering Apixaban with strong inducers of both CYP3A4 and P-gp (see Interactions).
Treatment of VTE: The concomitant use of Apixaban with strong CYP3A4 and P-gp inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital or St. John's Wort) may lead to a ~50% reduction in apixaban exposure. For the treatment of DVT or PE, Apixaban is not recommended in patients receiving concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp (see Interactions). For prevention of recurrent DVT and PE, use caution when co-administering Apixaban with strong inducers of both CYP3A4 and P-gp (see Interactions).
Interaction with Other Medicinal Products Affecting Hemostasis: The concomitant use of Apixaban with antiplatelet agents increases the risk of bleeding. Care is to be taken if patients are treated concomitantly with non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid (ASA). Other platelet aggregation inhibitors or other antithrombotic agents are not recommended concomitantly with Apixaban following surgery (see Interactions).
Spinal/Epidural Anesthesia or Puncture: Prevention of VTE in surgical patients: Elective hip or knee replacement surgery: 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 post-operative use of indwelling epidural catheters or the concomitant use of medicinal products affecting hemostasis. Indwelling epidural or intrathecal catheters must be removed at least 5 hours prior to the first dose of Apixaban . The risk may also be increased by traumatic or repeated epidural or spinal puncture. Patients are to be frequently monitored for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, 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: Prevention of VTE in surgical patients: Elective hip or knee replacement 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: Safety and efficacy of Apixaban have not been studied in patients with prosthetic heart valves, with or without atrial fibrillation. Therefore, the use of Apixaban is not recommended in this setting.
Acute PE in Hemodynamically Unstable Patients or Patients Who Require Thrombolysis or Pulmonary Embolectomy: Treatment of VTE: 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), Apixaban including, are not recommended for patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome (APS). In particular for patients who are triple positive (for lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies), treatment with DOACs could be associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy. The efficacy and safety of Apixaban in patients with APS have not been established.
Effects on Ability to Drive and 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 yet been established. No data are available.

Fertility: Studies in animals dosed directly with Apixaban have shown no effect on fertility.
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.
Lactation: It is unknown whether Apixaban or its metabolites are excreted in human milk. Available data in animals have shown excretion of Apixaban in milk. A risk to newborns and infants cannot be excluded.
A decision must be made to either discontinue breastfeeding or to discontinue/abstain from Apixaban therapy.

Clinical Experience: Prevention of VTE in surgical patients: Elective hip or knee replacement surgery: The safety of Apixaban has been evaluated in one phase II and three phase III studies including 5,924 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. As with other anticoagulants, bleeding may occur during Apixaban therapy in the presence of associated risk factors such as organic lesions liable to bleed. Common adverse reactions were anemia, hemorrhage, contusion, and nausea. The overall incidences of adverse reactions of bleeding, anemia and abnormalities of transaminases (e.g., alanine aminotransferase levels) were numerically lower in patients on Apixaban compared to enoxaparin in the phase II and phase III studies in elective hip and knee replacement surgery. The adverse reactions should be interpreted within the surgical setting.
As with any anticoagulant, the use of Apixaban may be associated with an increased risk of occult or overt bleeding from any tissue or organ, which may result in posthemorrhagic anemia. The signs, symptoms, and severity will vary according to the location and degree or extent of the bleeding. Adverse reactions in the one phase II study and the three phase III studies are listed in Table 2 by system organ classification (MedDRA) and by frequency. (See Table 2.)

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Prevention of stroke and systemic embolism in patients with AF: NVAF: The safety of Apixaban has been evaluated in the ARISTOTLE and AVERROES studies, including 11284 patients exposed to Apixaban 5 mg twice daily and 602 patients to 2.5 mg twice daily. The Apixaban exposures were ≥12 months for 9375 patients and ≥24 months for 3369 patients in the two studies. In ARISTOTLE, the mean duration of exposure was 89.2 weeks on Apixaban and 87.5 weeks on warfarin; total patient years for exposure was 15534 on Apixaban and 15184 on warfarin. In AVERROES, the mean duration of exposure was approximately 59 weeks in both treatment groups; total patient years for exposure was 3193 on Apixaban and 3150 on ASA.
The overall discontinuation rate due to adverse reactions was 1.8% for Apixaban and 2.6% for warfarin in the ARISTOTLE study, and was 1.5% for Apixaban and 1.3% for ASA in the AVERROES study. The overall incidence of adverse reactions related to bleeding was numerically lower in patients on Apixaban compared to warfarin in the ARISTOTLE study (24.3% vs 31.0%) and was similar in patients on Apixaban compared to ASA in the AVERROES study (9.6% vs 8.5%).
Adverse reactions in the ARISTOTLE and AVERROES studies are listed in Table 3 by system organ classification (MedDRA) and by frequency. The frequency assignments in Table 3 are primarily based on the frequencies observed in the ARISTOTLE study. The adverse reactions observed in the AVERROES study were consistent with those observed in the ARISTOTLE study. (See Table 3.)

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Treatment of VTE: 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. The mean duration of exposure to Apixaban was 154 days and to enoxaparin/warfarin was 152 days in the AMPLIFY study. The mean duration of exposure to Apixaban was approximately 330 days and to placebo was 312 days in the AMPLIFY-EXT study.
In the AMPLIFY study, adverse reactions related to bleeding occurred in 417 (15.6%) of Apixaban treated patients compared to 661 (24.6%) of 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-EXT study, adverse reactions related to bleeding occurred in 219 (13.3%) of Apixaban treated patients compared to 72 (8.7%) of 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.
Common adverse reactions (≥1%) were gingival bleeding, epistaxis, contusion, hematuria, hematoma, and menorrhagia.
Adverse reactions in the AMPLIFY and AMPLIFY-EXT studies are listed in Table 4 by system organ classification (MedDRA) and by frequency. (See Table 4.)


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Effect of Other Drugs on Apixaban: Inhibitors of CYP3A4 and P-gp: Co-administration of Apixaban with ketoconazole (400 mg once a day), a strong inhibitor of both CYP3A4 and P-gp, led to a 2-fold increase in mean Apixaban AUC and a 1.6-fold increase in mean Apixaban C_max. No dose adjustment for Apixaban is required with concomitant ketoconazole therapy, however Apixaban should be used with caution in patients receiving concomitant systemic treatment with azole-antimycotics such as ketoconazole or other strong inhibitors of both CYP3A4 and P-gp (see Precautions).
Active substances that are not considered strong inhibitors of both CYP3A4 and P-gp (e.g., diltiazem, naproxen, clarithromycin, amiodarone, verapamil, quinidine) are expected to increase Apixaban plasma concentration to a lesser extent. No dose adjustment for Apixaban is required when co-administered with agents that are not strong inhibitors of both CYP3A4 and P-gp. For example, diltiazem (360 mg once a day), considered a moderate CYP3A4 and a weak P-gp inhibitor, led to a 1.4-fold increase in mean Apixaban AUC and a 1.3-fold increase in C_max. Naproxen (500 mg, single dose), an inhibitor of P-gp but not an inhibitor of CYP3A4, led to a 1.5-fold and 1.6-fold increase in mean Apixaban AUC and C_max, respectively. Clarithromycin (500 mg, twice a day), an inhibitor of P-gp and a strong inhibitor of CYP3A4, led to a 1.6-fold and 1.4-fold increase in mean Apixaban AUC and C_max, respectively.
Inducers of CYP3A4 and P-gp: Co-administration of Apixaban with rifampin, a strong inducer of both CYP3A4 and P-gp, led to an approximate 54% and 42% decrease in mean Apixaban AUC and C_max, respectively. The concomitant use of Apixaban with other strong CYP3A4 and P-gp inducers (e.g., phenytoin, carbamazepine, phenobarbital or St. John's Wort) may also lead to reduced Apixaban plasma concentrations. No dose adjustment for Apixaban is required during concomitant therapy with such agents for the prevention of VTE following elective hip or knee replacement surgery or for the prevention of stroke or systemic embolism in nonvalvular atrial fibrillation patients, however, strong inducers of both CYP3A4 and P-gp should be co-administered with caution (see Precautions).
For the treatment of DVT and PE, concomitant therapy with strong inducers of both CYP3A4 and P-gp is not recommended (see Precautions). For the prevention of recurrent DVT and PE, strong inducers of both CYP3A4 and P-gp should be co-administered with caution (see Precautions).
Anticoagulants, platelet aggregation inhibitors and NSAIDs: After combined administration of enoxaparin (40 mg single dose) with Apixaban (5 mg single dose), an additive effect on anti-FXa activity was observed. Pharmacokinetic or pharmacodynamic interactions were not evident in healthy subjects when Apixaban was co-administered with ASA 325 mg once a day.
Apixaban co-administered with clopidogrel (75 mg once daily), with the combination of clopidogrel 75 mg and ASA 162 mg once daily, or with prasugrel (60 mg followed by 10 mg once daily) in phase 1 studies did not show a relevant increase in bleeding time or further inhibition of platelet aggregation compared to administration of the antiplatelet agents without Apixaban. Increases in clotting tests (PT, INR, and aPTT) were consistent with the effects of Apixaban alone.
Naproxen (500 mg), an inhibitor of P-gp, led to a 1.5-fold and 1.6-fold increase in mean Apixaban AUC and C_max, 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. NVAF patients with ACS and/or undergoing PCI can be treated with Apixaban in combination with antiplatelet agents (see Precautions).
Despite these findings, Apixaban should be used with caution when co-administered with NSAIDs, ASA or P2Y12 inhibitors because these medicinal products typically increase the bleeding risk.
Other agents associated with serious bleeding are not recommended concomitantly with Apixaban, such as: unfractionated heparins and heparin derivatives (including low molecular weight heparins (LMWH)), FXa inhibiting oligosaccharides (e.g., fondaparinux), direct thrombin II inhibitors (e.g., desirudin), thrombolytic agents, GPIIb/IIIa receptor antagonists, dipyridamole, dextran, sulfinpyrazone, vitamin K antagonists, and other oral anticoagulants. It should be noted that unfractionated heparin can be administered at doses necessary to maintain a patent central venous or arterial catheter (see Precautions).
Other concomitant therapies: No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when Apixaban was co-administered with atenolol or famotidine. Co-administration of Apixaban 10 mg with atenolol 100 mg did not have a clinically relevant effect on the pharmacokinetics of Apixaban. Following administration of the two drugs together, mean Apixaban AUC and C_max were 15% and 18% lower than when administered alone. The administration of Apixaban 10 mg with famotidine 40 mg had no effect on Apixaban AUC or C_max.
Laboratory parameters: Clotting tests (e.g., PT, INR, and aPTT) are affected as expected by the mechanism of action of Apixaban (see Pharmacology: Pharmacodynamics under Actions). Changes observed in these clotting tests at the expected therapeutic dose are small and subject to a high degree of variability (see Pharmacology: Pharmacodynamics under Actions).
Pediatric population: Interaction studies have only been performed in adults.
Effect of Apixaban on Other Drugs: In vitro Apixaban studies showed no inhibitory effect on the activity of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6 or CYP3A4 (IC50 >45 μM) and weak inhibitory effect on the activity of CYP2C19 (IC50 >20 μM) at concentrations that are significantly greater than peak plasma concentrations observed in patients. Apixaban did not induce CYP1A2, CYP2B6, CYP3A4/5 at a concentration up to 20 μM. 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. In studies conducted in healthy subjects, as described as follows, Apixaban did not meaningfully alter the pharmacokinetics of digoxin, naproxen, or atenolol.
Digoxin: Co-administration of Apixaban (20 mg once a day) and digoxin (0.25 mg once a day), a P-gp substrate, did not affect digoxin AUC or C_max. Therefore, Apixaban does not inhibit P-gp mediated substrate transport.
Naproxen: Co-administration of single doses of Apixaban (10 mg) and naproxen (500 mg), a commonly used NSAID, did not have any effect on the naproxen AUC or C_max.
Atenolol: Co-administration of a single dose of Apixaban (10 mg) and atenolol (100 mg), a common beta-blocker, did not alter the pharmacokinetics of atenolol.

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Anticoagulants, Antiplatelets & Fibrinolytics (Thrombolytics)

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

Rx