Summary Basis of Decision for Eliquis

3.3.1 Pharmacodynamics

The clinical studies showed a direct linear relationship between the anti-FXa activity and the plasma apixaban concentration. The pharmacodynamic effects included the prolongation of blood clotting tests such as PT, International Normalized Ratio (INR) and aPTT, as well as inhibition of FXa activity and ex vivo thrombin generation.

Single IV doses of apixaban up to 5 mg were safe and well-tolerated in healthy subjects.

Apixaban at oral doses of 10 mg once a day (QD) and 50 mg QD for 3 days had no effect on QTc interval and were safe and well-tolerated in healthy subjects.

3.3.2 Pharmacokinetics

Absorption

Apixaban was rapidly absorbed with maximum plasma concentrations (C_max) appearing 3 to 4 hours after tablet intake. Intake with food did not affect apixaban exposure (AUC) or Cmax at the 10 mg dose. Apixaban demonstrated linear pharmacokinetics with doseproportional increases in exposure for oral doses up to 10 mg.

The absolute bioavailability of apixaban was approximately 50% for doses up to 10 mg.

Distribution

The volume of distribution at steady state was approximately 21 litres.

Average plasma protein binding in humans was approximately 87%.

Metabolism

Unchanged apixaban was the main drug-related circulating component in plasma representing 66-72% of the sample. No active circulating metabolites were present.

O-demethylation and hydroxylation at the 3-oxopiperidinyl moiety were the major sites of biotransformation. Apixaban was metabolized mainly by CYP3A4/3A5 enzymes. Minor contributions of CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP2J2 enzymes were reported.

Excretion

After IV administration, apixaban had a total clearance (CL) and renal clearance (RCL) of 3.3 L/h and 0.9 L/h, respectively.

Faecal and urinary excretion accounted for 46.7-56.0% and 24.5-28.8%, respectively, of the dose. In urine and faeces, apixaban was the main drug-related component (21.5-34.5% of the dose); all other metabolites accounted for ≤5.09% of the dose. Biliary excretion was only a minor elimination pathway (2.44% of the dose).

Special Populations

Hepatic Impairment

In a study comparing 16 subjects with mild and moderate hepatic impairment (classified as Child Pugh A and B, respectively) 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-FXa activity and INR were comparable between patients 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 patients studied, caution is advised when using Eliquis in this population. Patients with severe hepatic impairment were not studied. Therefore, apixaban is not recommended in patients with severe hepatic impairment.

Renal Impairment

Apixaban exposure gradually increased with increased degrees of renal impairment. Renal impairment did not affect the relationship between apixaban plasma concentration and anti-FXa activity or INR. No dose adjustment is necessary in patients with mild or moderate renal impairment. Limited clinical data in patients with severe renal impairment indicate that apixaban plasma concentrations are increased; therefore, apixaban is to be used with caution in these patients because of a potential higher risk of bleeding.

Drug Interactions

Co-administration of apixaban with ketoconazole (400 mg once a day), a strong inhibitor of CYP3A4 and P-gp, led to a 2-fold increase in mean apixaban AUC and a 1.6-fold increase in apixaban C_max. Therefore, the use of Eliquis is contraindicated in patients receiving concomitant systemic treatment with strong inhibitors of both CYP3A4 and Pgp.

Strong inducers of both CYP3A4 and P-gp should be co-administered with caution.

3.3.3 Clinical Efficacy

The efficacy and safety of Eliquis was evaluated in three pivotal double-blind multinational Phase III studies with 11,659 patients who had undergone major orthopaedic surgery (total hip replacement or total knee replacement). The three pivotal studies were part of the ADVANCE (Clinical Research trial to evaluate Apixaban Dosed orally Versus ANtiCoagulation with injectable Enoxaparin) 1, 2 and 3 clinical studies programme. The use of Eliquis 2.5 mg BID was compared to the gold standard for the prevention of venous thromboembolic events (VTE), enoxaparin. In two of the studies (ADVANCE-2 and ADVANCE-3), the non-North American regimen for enoxaparin was used, 40 mg once daily (OD). In Canada (and for knee replacement in the United States), the recommended regimen for enoxaparin for this indication is 30 mg BID, which results in a 50% higher daily exposure to enoxaparin. Only one of the Phase III studies (ADVANCE-1) used the latter dose of enoxaparin as the active control. A total of 3,195 patients were randomized in the ADVANCE-1 study.

All three studies had the same primary efficacy endpoint, the composite of all VTE and all-cause death. All VTE included symptomatic and asymptomatic distal or proximal deep vein thrombosis (DVT), and non-fatal pulmonary embolism (PE). In order to detect asymptomatic DVT, bilateral ascending venography at the end of the treatment period was mandatory.

In the two studies that used the non-North American regimen for enoxaparin (40 mg OD) as the active control, Eliquis showed superiority over enoxaparin, without increasing bleeding. In the ADVANCE-3 study, the rate of the primary endpoint was 1.39% for Eliquis and 3.86% for enoxaparin. In the ADVANCE-2 study, the total VTE and allcause death, was 15.06% for Eliquis and 24.37% for enoxaparin.

In the pivotal study with the Canadian enoxaparin regimen as a control (ADVANCE-1), Eliquis did not meet the pre-specified statistical criteria for non-inferiority. However, its use was associated with lower rates of clinically relevant bleeding. In the ADVANCE-1 study, the total VTE and all-cause death endpoint was 8.99% for Eliquis and 8.85% for enoxaparin. A plausible explanation for the failure of Eliquis in ADVANCE-1 with enoxaparin 30 mg BID as the active control, compared to its success in ADVANCE-2 and ADVANCE-3, is the obvious difference in enoxaparin daily dose. The dose of enoxaparin 30 mg BID represents a 50% higher daily dose compared to 40 mg OD. Whether this higher enoxaparin dose translates into higher efficacy is not very welldocumented, but seems reasonable when one looks at the results of other documented studies that suggest a greater effectiveness of enoxaprin 30 mg BID compared to 40 mg OD. In these studies, the 30 mg BID regimen prevented more thrombo-embolic events than 40 mg OD, but also caused more bleeding complications.

Another aspect of the three pivotal studies that needs to be considered concerns the differences in timing of the first dose of anticoagulant in relationship with the actual surgery. In the ADVANCE-2 and ADVANCE-3 studies, enoxaparin was started as its label indicates, that is 9-15 hours before surgery, while Eliquis was started 12-24 hours post-surgery. One might expect from these differences that enoxaparin would come outmore effective because of a longer duration of DVT protection, but with more perioperative bleeding events. Yet Eliquis turned out to be more effective, without raising the overall incidence of major and clinically relevant non-major (CRNM) bleeding. In the ADVANCE-1 study, both Eliquis and enoxaparin were started 12 to 24 hours postsurgery.

In conclusion, Eliquis 2.5 mg BID given 12-24 hours after surgery was more efficacious than enoxaparin 40 mg QD initiated 9-15 hours before surgery, and approached the efficacy of enoxaparin 30 mg BID initiated 12-24 hours after surgery, without worsening bleeding, and in comparison with enoxaparin 30 mg BID Eliquis appeared to lower major and CRNM bleeding.

3.3.4 Clinical Safety

The safety of Eliquis 2.5 mg BID was evaluated in the Phase II dose-finding study and the three Phase III studies (ADVANCE 1, 2, and 3). In total, 5,924 patients were exposed to Eliquis after undergoing major orthopaedic surgery of the lower limbs (elective hip replacement or elective knee replacement) and treated for up to 38 days.

The adverse event (AE) profile of Eliquis in the four VTE prevention studies was similar to that of enoxaparin 40 mg OD administered with a pre-surgery dose, and also similar to that of enoxaparin 30 mg BID administered post-surgery only. The frequencies of common AEs (reported for >1% of patients) in the Eliquis group and enoxaparin group were similar. The common adverse reactions (occurring at a rate of ≥1%) were nausea, anaemia, contusion, and haemorrhage.

The death rate in the four VTE pooled studies was low and consistent with similar recent studies of new anticoagulants.

As expected, deep vein thrombosis (DVT) and pulmonary embolism (PE) were the most common serious adverse events (SAEs). The incidence of DVT was numerically less in the Eliquis groups versus the enoxaparin groups, but the incidence of PE was numerically higher in two of the studies, in particular in the pivotal study using the Canadian enoxaparin regimen as the active control (ADVANCE-1 study). The apparent imbalance may be caused by the low numbers in the study population. However, it is also possible that the relatively higher incidence of PE in that study merely reflects the slightly lesser efficacy of Eliquis 2.5 mg BID versus enoxaparin 30 mg BID.

Major bleeding, the composite of major and CRNM bleeding, and all bleeding occurred with similar frequency in the two pivotal studies, ADVANCE-2 and ADVANCE-3, where patients were treated with Eliquis 2.5 mg BID or enoxaparin 40 mg OD. In the ADVANCE-1 study with enoxaparin 30 mg BID as the active comparator, the risks of major bleeding, CRNM bleeding, and all bleeding were lower in the patients treated with Eliquis 2.5 mg BID.

Clinical studies with Eliquis in a patient population receiving double antiplatelet therapy revealed a significantly elevated bleeding risk (5 cases were fatal) when Eliquis 5 mg BID was added, compared to the addition of placebo to the double antiplatelet therapy. A warning for this SAE appears in the Eliquis Product Monograph.

Adverse events (AEs) of special interest included myocardial infarction, stroke, thrombocytopaenia, elevated liver enzymes, and neurologic AEs. The event rates for all of these AEs were low and similar in the Eliquis and enoxaparin groups. Data on liver safety, based on the four clinical studies as well as from various other finished and ongoing studies, do not indicate that Eliquis has the potential for hepatotoxicity. Health Canada will follow up on the data emerging from the ongoing studies, and will follow post-marketing data on liver safety, as well as on neurologic disease in the completed and ongoing studies.

No clinically relevant flags were raised for bleeding events or other SAEs within the following population subgroups: age; gender; race; weight; body mass index; level of renal impairment; number of risk factors for VTE; or type of (unilateral of bilateral) orthopaedic surgery.