Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Bristol-Myers Squibb/Pfizer EEIG, Plaza 254, Blanchardstown Corporate Park 2, Dublin 15, D15 T867, Ireland
Pharmacotherapeutic group: Antithrombotic agents, direct factor Xa inhibitors
ATC code: B01AF02
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.
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). In adults, 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-Factor Xa activity (AXA) as evident by reduction in Factor Xa enzyme activity in multiple commercial AXA kits, however results differ across kits. Results from apixaban paediatric studies indicate that the linear relationship between apixaban concentration and AXA is consistent with the previously documented relationship in adults. This lends support to the documented mechanism of action of apixaban as a selective inhibitor of FXa. The AXA results presented below was obtained using the STA Liquid Anti-Xa Apixaban assay.
Across weight tiers 9 to ≥35 kg in Study CV185155, the geometric mean (%CV) AXA min and AXA max ranged between 27.1 (22.2) ng/mL and 71.9 (17.3) ng/mL, corresponding to geometric mean (%CV) Cminss and Cmaxss of 30.3 (22) ng/mL and 80.8 (16.8) ng/mL. The exposures achieved at these AXA ranges using the pediatric dosing regimen were comparable to those seen in adults who received an apixaban dose of 2.5 mg twice daily.
Across weight tiers 6 to ≥35 kg in Study CV185362, the geometric mean (%CV) AXA min and AXA max ranged between 67.1 (30.2) ng/mL and 213 (41.7) ng/mL, corresponding to geometric mean (%CV) Cminss and Cmaxss of 71.3 (61.3) ng/mL and 230 (39.5) ng/mL. The exposures achieved at these AXA ranges using the pediatric dosing regimen were comparable to those seen in adults who received an apixaban dose of 5 mg twice daily.
Across weight tiers 6 to ≥35 kg in Study CV185325, the geometric mean (%CV) AXA min and AXA max ranged between 47.1 (57.2) ng/mL and 146 (40.2) ng/mL, corresponding to geometric mean (%CV) Cminss and Cmaxss of 50 (54.5) ng/mL and 144 (36.9) ng/mL. The exposures achieved at these AXA ranges using the pediatric dosing regimen were comparable to those seen in adults who received an apixaban dose of 5 mg twice daily.
The predicted steady state exposure and anti-Factor Xa activity for the paediatric studies suggests that the steady state peak-to-trough fluctuation in apixaban concentrations and AXA levels were approximately 3-fold (min, max: 2.65-3.22) in the overall population.
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.
Study CV185325 was a randomised, active controlled, open label, multi-centre study of apixaban for the treatment of VTE in paediatric patients. This descriptive efficacy and safety study included 217 paediatric patients; requiring anticoagulation treatment for VTE and prevention of recurrent VTE; 137 patients in age group 1 (12 to <18 years), 44 patients in age group 2 (2 to < 12 years), 32 patients in age group 3 (28 days to <2 years) and 4 patients in age group 4 (birth to <28 days). The index VTE was confirmed by imaging, and independently adjudicated. Prior to randomization, patients were treated with SOC anticoagulation for up to 14 days (mean (SD) duration of treatment with SOC anticoagulation prior to start of study medication was 4.8 (2.5) days, and 92.3% of patients was started ≤7 days). Patients were randomised according to a 2:1 ratio to an age-appropriate formulation of apixaban (doses adjusted for weight equivalent to a loading dose of 10 mg BID for 7 days followed by 5 mg BID in adults) or SOC. For patients 2 to <18 years, SOC was comprised of low molecular weight heparins (LMWH), unfractionated heparins (UFH) or vitamin K antagonists (VKA). For patients 28 days to <2 years of age, SOC will be limited to heparins (UFH or LMWH). The main treatment phase lasted 42 to 84 days for patients aged <2 years, and 84 days in patients aged >2 years. Patients aged 28 days to <18 years who were randomized to receive apixaban had the option to continue apixaban treatment for 6 to 12 additional weeks in the Extension Phase.
The primary efficacy endpoint was the composite of all image-confirmed and adjudicated symptomatic and asymptomatic recurrent VTE and VTE-related death. No patient in either treatment group had a VTE-related death. A total of 4 (2.8%) patients in the apixaban group and 2 (2.8%) patients in the SOC group had at least 1 adjudicated symptomatic or asymptomatic recurrent VTE event.
The median extent of exposure in 143 treated patients in the apixaban arm was 84.0 days. Exposure exceeded 84 days in 67 (46.9%) of patients. The primary safety endpoint of composite of Major and CRNM bleeding was seen in 2 (1.4%) patients on apixaban vs 1 (1.4%) patient on SOC, with a RR of 0.99 (95% CI 0.1;10.8). In all cases this concerned a CRNM bleeding. Minor bleeding was reported in 51 (35.7%) patients in the apixaban group and 21 (29.6%) patients in the SOC group, with a RR of 1.19 (95% CI 0.8; 1.8).
Major bleeding was defined as bleeding that satisfies one or more of the following criteria: a (i) fatal bleeding; (ii) clinically overt bleeding associated with a decrease in Hgb of at least 20 g/L (2 g/dL) in a 24-hour period; (iii) bleeding that is retroperitoneal, pulmonary, intracranial, or otherwise involves the central nervous system; and (iv) bleeding that requires surgical intervention in an operating suite (including interventional radiology).
CRNM bleeding was defined as bleeding that satisfies one or both of the following: (i) overt bleeding for which a blood product is administered, and which is not directly attributable to the subject’s underlying medical condition and (ii) bleeding that requires medical or surgical intervention to restore hemostasis, other than in an operating suite.
Minor bleeding was defined as any overt or macroscopic evidence of bleeding that does not fulfill the above criteria for either major bleeding or clinically relevant, non-major bleeding. Menstrual bleeding, was classified as a minor bleeding event rather than clinically relevant non-major.
In 53 patients who entered the extension phase and were treated with apixaban, no event of symptomatic and asymptomatic recurrent VTE or VTE related mortality was reported. No patients in the Extension Phase experienced an adjudicated Major or a CRNM bleeding event. Eight (8/53; 15.1%) patients in the Extension Phase experienced Minor bleeding events.
There were 3 deaths in the apixaban group and 1 death in the SOC group, all of which were assessed as not treatment-related by the investigator. None of these deaths were due to a VTE or bleeding event per the adjudication performed by the independent event adjudication committee.
The safety database for apixaban in paediatric patients is based on Study CV185325 for treatment of VTE and prevention of recurrent VTE, supplemented with the PREVAPIX-ALL study and the SAXOPHONE study in VTE primary prophylaxis, and single-dose study CV185118. It includes 970 paediatric patients, 568 of whom received apixaban.
There is no authorised paediatric indication for the primary prophylaxis of VTE.
In the PREVAPIX-ALL study, a total of 512 patients age ≥1 to <18 with newly diagnosed ALL or LL, undergoing induction chemotherapy including asparaginase via an indwelling central venous access device, were randomised 1:1 to open-label thromboprophylaxis with apixaban or standard of care (with no systemic anticoagulation). Apixaban was administered according to a fixed-dose, body weight-tiered regimen designed to produce exposures comparable to those seen in adults who received 2.5 mg twice daily (see Table 3). Apixaban was provided as a 2.5 mg tablet, 0.5 mg tablet, or 0.4 mg/mL oral solution. The median duration of exposure in the apixaban arm was 25 days.
Table 3. Apixaban dosing in the PREVAPIX-ALL study:
| Weight Range | Dose schedule |
|---|---|
| 6 to <10.5 kg | 0.5 mg twice daily |
| 10.5 to <18 kg | 1 mg twice daily |
| 18 to <25 kg | 1.5 mg twice daily |
| 25 to <35 kg | 2 mg twice daily |
| ≥35 kg | 2.5 mg twice daily |
The primary efficacy endpoint was a composite of adjudicated symptomatic and asymptomatic non- fatal deep vein thrombosis, pulmonary embolism, cerebral venous sinus thrombosis, and venous thromboembolism-related death. The incidence of the primary efficacy endpoint was 31 (12.1%) in the apixaban arm versus 45 (17.6%) in the standard of care arm. The relative risk reduction did not achieve significance.
Safety endpoints were adjudicated according to ISTH criteria. The primary safety endpoint, major bleeding, occurred in 0.8% of patients in each treatment arm. CRNM bleeding occurred in 11 patients (4.3%) in the apixaban arm and 3 patients (1.2%) in the standard of care arm. The most common CRNM bleeding event contributing to the treatment difference was mild to moderate intensity epistaxis. Minor bleeding events occurred in 37 patients in the apixaban arm (14.5%) and 20 patients (7.8%) in the standard of care arm.
SAXOPHONE was a randomised 2:1 open-label, multi-center comparative study of patients 28 days to <18 years of age with congenital or acquired heart disease who require anticoagulation. Patients received either apixaban or standard of care thromboprophylaxis with a vitamin K antagonist or low molecular weight heparin. Apixaban was administered according to a fixed-dose, body weight-tiered regimen designed to produce exposures comparable to those seen in adults who received a dose of 5 mg twice daily (see Table 4). Apixaban was provided as a 5 mg tablet, 0.5 mg tablet, or 0.4 mg/mL oral solution. The mean duration of exposure in the apixaban arm was 331 days.
Table 4. Apixaban dosing in the SAXOPHONE study:
| Weight Range | Dose schedule |
|---|---|
| 6 to <9 kg | 1 mg twice daily |
| 9 to <12 kg | 1.5 mg twice daily |
| 12 to <18 kg | 2 mg twice daily |
| 18 to <25 kg | 3 mg twice daily |
| 25 to <35 kg | 4 mg twice daily |
| ≥35 kg | 5 mg twice daily |
The primary safety endpoint, a composite of adjudicated ISTH defined major and CRNM bleeding, occurred in 1 (0.8%) of 126 patients in the apixaban arm and 3 (4.8%) of 62 patients in the standard of care arm. The secondary safety endpoints of adjudicated major, CRNM, and all bleeding events were similar in incidence across the two treatment arms. The secondary safety endpoint of drug discontinuation due to adverse event, intolerability, or bleeding was reported in 7 (5.6%) subjects in the apixaban arm and 1 (1.6%) subject in the standard of care arm. No patients in either treatment arm experienced a thromboembolic event. There were no deaths in either treatment arm.
This study was prospectively designed for descriptive efficacy and safety because of the expected low incidence of TE and bleeding events in this population. Due to the observed low incidence of TE in this study a definitive risk benefit assessment could not be established.
The European Medicines Agency has deferred the obligation to submit the results of studies for the treatment of venous thromboembolism with Eliquis in one or more subsets of the paediatric population (see section 4.2 for information on paediatric use).
Apixaban is rapidly absorbed, reaching maximum concentration (Cmax) in paediatric patients approximately 2 hours after single-dose administration.
In adults, 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.
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 whole 5 mg tablets.
Following oral administration of 10 mg of apixaban as 2 crushed 5 mg tablets with 30 g of apple puree, the Cmax and AUC were 21% and 16% lower, respectively, when compared to administration of 2 whole 5 mg tablets. The reduction in exposure is not considered clinically relevant.
Following administration of a crushed 5 mg apixaban tablet suspended in 60 mL of G5W and delivered via a nasogastric tube, exposure was similar to exposure seen in other clinical studies involving healthy subjects receiving a single oral 5 mg apixaban tablet dose.
Given the predictable, dose-proportional pharmacokinetic profile of apixaban, the bioavailability results from the conducted studies are applicable to lower apixaban doses.
In adults, plasma protein binding in humans is approximately 87%. The volume of distribution (Vss) is approximately 21 litres.
Apixaban has multiple routes of elimination. Of the administered apixaban dose in adults, approximately 25% was recovered as metabolites, with the majority recovered in faeces. In adults, renal excretion of apixaban accounted for approximately 27% of total clearance. Additional contributions from biliary and direct intestinal excretion were observed in clinical and nonclinical studies, respectively.
In adults, apixaban has a total clearance of about 3.3 L/h and a half-life of approximately 12 hours. In paediatrics patients, apixaban has a total apparent clearance of about 3.0 L/h.
O-demethylation and hydroxylation at the 3-oxopiperidinyl moiety are the major sites of biotransformation. Apixaban is metabolised mainly via CYP3A4/5 with minor contributions from CYP1A2, 2C8, 2C9, 2C19, and 2J2. Unchanged apixaban is the major active substance-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).
In paediatric patients ≥2 years of age, severe renal impairment is defined as an estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m² body surface area (BSA). In Study CV185325, in patients less than 2 years of age, the thresholds defining severe renal impairment by sex and post-natal age are summarized in Table 5 below; each corresponds to an eGFR <30 mL/min/1.73 m² BSA for patients ≥2 years of age.
Table 5. eGFR eligibility thresholds for study CV185325:
| Postnatal age (gender) | GFR reference range (mL/min/1.73 m²) | Eligibility threshold for eGFR* |
|---|---|---|
| 1 week (males and females) | 41 ± 15 | ≥8 |
| 2-8 weeks (males and females) | 66 ± 25 | ≥12 |
| >8 weeks to <2 years (males and females) | 96 ± 22 | ≥22 |
| 2-12 years (males and females) | 133 ± 27 | ≥30 |
| 13-17 years (males) | 140 ± 30 | ≥30 |
| 13-17 years (females) | 126 ± 22 | ≥30 |
* Eligibility threshold for CV185325 study participation, where estimated glomerular filtration rate (eGFR) was calculated per the updated bedside Schwartz equation (Schwartz, GJ et al., CJASN 2009). This per protocol threshold corresponded to the eGFR below which a prospective patient was considered to have “inadequate renal function” that precluded participation in Study CV185325. Each threshold was defined as an eGFR <30% of 1 standard deviation (SD) below the GFR reference range for age and gender. Threshold values for patients <2 years of age correspond to an eGFR <30 mL/min/1.73 m², the conventional definition of severe renal failure in patients >2 years of age.
Paediatric patients with glomerular filtration rates ≤55 mL/min/1.73 m² did not participate in Study CV185325, although those with mild to moderate levels of renal impairment (eGFR ≥30 to <60 mL/min/1.73 m² BSA) were eligible. Based on adult data and limited data in all apixaban-treated paediatric patients, no dose adjustment is necessary in paediatric patients with mild to moderate renal impairment. Apixaban is not recommended in paediatric patients with severe renal impairment (see sections 4.2 and 4.4).
In adults, 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-Factor Xa activity.
In adult 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 haemodialysis, compared to that seen in subjects with normal renal function. Haemodialysis, 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. Therefore, haemodialysis is unlikely to be an effective means of managing apixaban overdose.
Apixaban has not been studied in paediatric patients with hepatic impairment. In an adult study comparing 8 subjects with mild hepatic impairment, Child-Pugh A score 5 (n=6) and score 6 (n=2), and 8 subjects with moderate hepatic impairment, Child-Pugh B score 7 (n=6) and score 8 (n=2), to 16 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.
Gender differences in pharmacokinetic properties were not studied in paediatric patients.
In adults, exposure to apixaban was approximately 18% higher in females than in males.
Differences in pharmacokinetic properties relating to ethnic origin and race were not studied in paediatric patients.
Administration of apixaban to paediatric patients is based on a fixed-dose by weight-tier regimen.
In adults, when 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.
In adults, the pharmacokinetic/pharmacodynamic (PK/PD) relationship between apixaban plasma concentration and several PD endpoints (anti-Factor Xa activity [AXA], INR, PT, aPTT) has been evaluated after administration of a wide range of doses (0.5–50 mg). Similarly, results from apixaban paediatric PK/PD assessment indicate a linear relationship between apixaban concentration and AXA. This is consistent with the previously documented relationship in adults.
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, fertility and embryo-foetal development and juvenile toxicity.
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.
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.
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