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Pharmacodynamic Effects: The pharmacodynarnic 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 phannacodynamic effects of apixaban.
Apixaban also demonstrates anti-FXa activity as evident by reduction in Factor Xa enzyme activity in 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 concentration and anti-FXa activity is linear over a wide dose range of apixaban, and precision of the Rotachrom assay is well within acceptable limits for use in a clinical laboratory. The dose- and concentration related changes observed following apixaban administration are more pronounced, and less variable, with anti-FXa activity compared with clotting tests.
Predicted steady-state peak and trough anti-FXa activity with apixaban 2.5 mg BID dosing are 1.3 IU/mL (5th/95th percentile 0.67-2.4 IU/mL) and 0.84 IU/mL (5th/95th percentile 0.37-1.8 IU/mL), respectively, demonstrating less than a 1.6-fold fluctuation in peak-to-trough anti-FXa activity over the dosing interval.
Table 1 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, the results demonstrate a less than 1.7-fold fluctuation in peak-to-trough levels.
Click on icon to see table/diagram/imageAlthough 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.
Clinical Efficacy and Safety: Prevention of VTE: elective hip or knee replacement surgery: The apixaban clinical program was designed to demonstrate the efficacy and safety of apixaban for the prevention of VTE in a broad range of adult patients undergoing elective hip or knee replacement. A total of 8464 patients were randomized in two pivotal, double-blind, multinational studies, comparing apixaban 2.5 mg given orally twice daily or enoxaparin 40 mg once daily. Included in this total were 1262 patients of age 75 or older, 1004 patients with low body weight (≤60 kg), 1495 patients with BMI ≥33 kg/m2 and 437 patients with severe or moderate renal impairment. The ADVANCE-3 study included 5407 patients undergoing elective hip replacement, and the ADVANCE-2 study included 3057 patients undergoing elective knee replacement. Subjects received either apixaban 2.5 mg given orally twice daily (po bid) or enoxaparin 40 mg administered subcutaneously once daily (sc od). The first dose of apixaban was given 12 to 24 hours post-surgery, whereas enoxaparin was started 9 to 15 hours prior to surgery. Both apixaban and enoxaparin were given for 32-38 days in the ADVANCE-3 study and for 10-14 days in the ADVANCE-2 study.
Apixaban demonstrated a statistically superior reduction in the primary endpoint, a composite of all VTE/all cause death, and in the Major VTE endpoint, a composite of proximal DVT, non-fatal PE, and VTE-related death, compared to enoxaparin in both elective hip or knee replacement surgery (see Table 2).
Click on icon to see table/diagram/imageThe safety endpoints of major bleeding, the composite of major and clinically relevant non-major (CRNM) bleeding, and all bleeding showed similar rates for patients treated with apixaban 2.5 mg compared with enoxaparin 40 mg (see Table 2). All the bleeding criteria included surgical site bleeding.
In both phase III studies, bleeding was assessed beginning with the first dose of double-blind study drug, which was either enoxaparin or injectable placebo, given 9 to 15 hours before surgery. Bleeding during the treatment period includes events that occurred before the first dose of apixaban, which was given 12 to 24 hours after surgery. Bleeding during the post-surgery treatment period only included events occurring after the first dose of study drug after surgery.
Over half the occurrences of major bleeding in the apixaban group occurred prior to the first dose of apixaban. Table 3 shows the bleeding results from the treatment period and the post-surgery treatment period. (See Table 3.)
Click on icon to see table/diagram/imagePrevention of stroke in patients with non-valvular atrial fibrillation (NVAF): A total of 23,799 patients were randomised in the clinical program (ARISTOTLE: apixaban versus warfarin, AVERROES: apixaban versus ASA) including 11,927 randomised to apixaban. The program was designed to demonstrate the efficacy and safety of apixaban for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and one or more additional risk factors, such as: prior stroke or transient ischaemic attack (TIA); age ≥75 years; hypertension; diabetes mellitus; symptomatic heart failure (NYHA Class ≥ II).
ARISTOTLE STUDY: In the ARISTOTLE study a total of 18,201 patients were randomized to double-blind treatment with apixaban 5 mg twice daily (or 2.5 mg twice daily in selected patients [4.7%], see Dosage & Administration) or warfarin (target INR range 2.0-3.0), patients were exposed to study drug for a mean of 20 months.
The mean age was 69.1 years, the mean CHADS2 score was 2.1 and 18.9% of patients had prior stroke or TIA.
In the study, apixaban achieved statistically significant superiority in the primary endpoint of prevention of stroke (haemorrhagic or ischaemic) and systemic embolism (see Table 4) compared with warfarin.
Click on icon to see table/diagram/imageFor patients randomized to warfarin, the median percentage of time in therapeutic range (TTR) (INR 2-3) was 66%.
Apixaban showed a reduction of stroke and systemic embolism compared to warfarin across the different levels of center TTR; within the highest quartile of TTR according to center, the hazard ratio for apixaban vs warfarin was 0.73 (95% CI, 0.38, 1.40).
Key secondary endpoints of major bleeding and all cause death were tested in a pre-specified hierarchical testing strategy to control the overall type 1 error in the trial. Statistically significant superiority was also achieved in the key secondary endpoints of both major bleeding and all-cause death (see Table 5). With improving monitoring of INR the observed benefits of apixaban compared to warfarin regarding all cause death diminish.
Click on icon to see table/diagram/imageThe overall discontinuation rate due to adverse reactions was 1.8% for apixaban and 2.6% for warfarin in the ARISTOTLE study.
The efficacy results for prespecified subgroups, including CHADS2 score, age, body weight, gender, status of renal function, prior stroke or TIA and diabetes were consistent with the primary efficacy results for the overall population studied in the trial.
The incidence of ISTH major gastrointestinal bleeds (including upper GI, lower GI, and rectal bleeding) was 0. 76%/year with apixaban and 0.86%/year with warfarin.
The major bleeding results for prespecified subgroups including CHADS2 score, age, body weight, gender, status of renal function, prior stroke or TIA and diabetes were consistent with the results for the overall population studied in the trial.
AVERROES STUDY: In the AVERROES study a total of 5,598 patients considered to be unsuitable for VKA by the investigators were randomized to treatment with apixaban 5 mg twice daily (or 2.5 mg twice daily in selected patients [6.4%], see Dosage & Administration) or ASA. ASA was given at a once daily dose of 81 mg (64%), 162 (26.9%), 243 (2.1%), or 324 mg (6.6%) at the discretion of the investigator. Patients were exposed to study drug for a mean of 14 months. The mean age was 69.9 years, the mean CHADS2 score was 2.0 and 13.6% of patients had prior stroke or TIA.
Common reasons for unsuitability for VKA therapy in the AVERROES study included unable/unlikely to obtain INRs at requested intervals (42.6%), patient refused treatment with VKA (37.4%), CHADS2 score =1 and physician did not recommend VKA (21.3%), patient could not be relied on to adhere to VKA medication instruction (15.0%), and difficulty/expected difficulty in contacting patient in case of urgent dose change (11.7%).
AVERROES was stopped early based on a recommendation by the independent Data Monitoring Committee due to clear evidence of reduction of stroke and systemic embolism with an acceptable safety profile.
The overall discontinuation rate due to adverse reactions was 1.5% for apixaban and 1.3% for ASA in the AVERROES study.
In the study, apixaban achieved statistically significant superiority in the primary endpoint of prevention of stroke (haemorrhagic, ischaemic or unspecified) or systemic embolism (see Table 6) compared to ASA.
Click on icon to see table/diagram/imageThere was no statistically significant difference in the incidence of major bleeding between apixaban and ASA (see Table 7).
Click on icon to see table/diagram/imagePaediatric Population: The European Medicines Agency has deferred the obligation to submit the results of studies with ELIQUIS in one or more subsets of the paediatric population in venous and arterial embolism and thrombosis (see Dosage & Administration).
Pharmacokinetics: 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 tablet 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.
Distribution: Plasma protein binding in humans is approximately 87%. The volume of distribution (Vss) is approximately 21 litres.
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 faeces. Renal excretion of apixaban accounts for approximately 27% of total clearance. Additional contributions from biliary and direct intestinal excretion were observed in clinical and non-clinical 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. There are no data available in patients with creatinine clearance <15 mL/min or in patients undergoing dialysis, therefore apixaban is not recommended in these patients (see Dosage & Administration and Precautions).
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).
In a study comparing subjects with mild and moderate hepatic impairment (classified as Child Pugh A and B, respectively) to healthy control subjects, the single-dose pharmacokinetics and pharmacodynamics of apixaban 5 mg were not altered in subjects with hepatic impairment. Changes in anti-Factor Xa activity and INR were comparable between subjects with mild to moderate hepatic impairment and healthy subjects. No dose adjustment is required in patients with mild or moderate hepatic impairment; however, given the limited number of subjects studied, caution is advised when using ELIQUIS in this population (see Dosage & Administration and 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 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 were 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 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 concentration and factor Xa activity was best described by a linear model. The PK/PD relationship observed in patients who received apixaban following elective hip or knee replacement surgery was consistent with that established in healthy subjects.
Toxicology: Preclinical Safety Data: Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenic potential, fertility and embryofoetal development (see Use in Pregnancy & Lactation). In the offspring of pregnant rats treated with apixaban, there were decreases in mating and fertility. These effects were minimal and observed only at exposures considered sufficiently in excess of the maximum human exposure, indicating little relevance to clinical use.
The major observed effects in the repeated-dose toxicity studies were those related to the pharmacodynamic action of apixaban on blood coagulation parameters. In the toxicity studies, little to no increase of bleeding tendency was found. However, since this may be due to a lower sensitivity of the non-clinical species compared to humans, this result should be interpreted with caution when extrapolating to humans.
