Regulatory Decision Summary for Xarelto

This Supplement to a New Drug Submission (SNDS) was filed to obtain market authorization for a new dosage form (granules for oral suspension, 1 milligram per millilitre (mg/mL) and a new pediatric indication. The sponsor proposed to use the currently approved film-coated tablet (15 mg, 20 mg) or the new granules for oral suspension for the treatment of venous thromboembolic events (VTE) and prevention of VTE recurrence in pediatric patients aged from neonates to less than 18 years following initiation of standard anticoagulation treatment.

The proposed indication of Xarelto for treatment of venous thromboembolic events (VTE) and prevention of VTE recurrence in children were based on the results of one Phase III, and five Phase I or II trials, as well as extrapolation from adult data. The new granules for oral suspension formulation were developed to facilitate convenient oral administration in young children and allow precise dosing.

The single pivotal trial, EINSTEIN Junior Phase III study, was a randomized, active-controlled, open-label multicenter clinical study in 500 pediatric patients (aged birth to less than18 years) with confirmed acute VTE. The patients received initial parenteral anticoagulation treatment for at least 5 days and were randomized 2:1 to either Xarelto or comparator group (heparins, vitamin K antagonist).

The primary efficacy outcome (symptomatic recurrent VTEs) occurred in 4 of 335 patients (1.2%) in the Xarelto group and in 5 of 165 patients (3.0%) in the comparator group, hazard ratio (HR) 0.40 (95% confidence interval [CI] 0.11% - 1.41%) at the end of the main treatment period. The secondary efficacy outcome (composite of symptomatic recurrent VTE and asymptomatic deterioration of the thrombus burden on repeat imaging) occurred in 5 of 335 children (1.5%; 95% CI 0.6%-3.4%) in the Xarelto group, and in 6 of 165 children (3.6%; 95% CI 1.6%-7.6%) in the comparator group. These findings were generally similar among age groups. During the extended treatment period, recurrent VTE occurred in three children; one of them had been randomized to Xarelto and two had been randomized to comparator.

At the end of the main treatment period, the primary safety outcome (composite of major bleeding and clinically relevant non-major bleeding [CRNMB]) was reported in 10 of 329 children (3.0%, 95% CI 1.6% - 5.5%) treated with Xarelto and in 3 of 162 children (1.9%, 95% CI 0.5%-5.3%) in the comparator group, with a hazard ratio of 1.58 (95% CI 0.51%-6.27%). No major bleeding events were observed in children treated with Xarelto. More treatment emergent CRNMB events occurred in the Xarelto group (10/329, 3.0%) than the comparator group (1/162, 0.6%). The occurrences of any confirmed treatment-emergent bleeding were higher in the Xarelto group (119/329, 36.2%) than that in the comparator group (45/162, 27.8%). The safety results were generally similar between Xarelto and comparator treatment in the various pediatric age groups. Overall, the safety profile in the 412 children treated with Xarelto was similar to that observed in the adult population and consistent across age subgroups. The increased risk of bleedings has been addressed as Warnings and Precautions in the Product Monograph.

The overall benefit of Xarelto was considered to outweigh the risk of bleeding. Given that currently no approved medication is on the market in Canada with an indication for the treatment of VTE and prevention of recurrent VTE in pediatric patients, the approval of Xarelto will provide a new treatment option for the unmet need. The approval of the new formulation and the new indication of Xarelto will provide the pediatric VTE patients the first oral anticoagulant without need for routine monitoring.

The submitted Risk Management Plan (RMP) was designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will put in place to minimize risks associated with the product. Upon review, the RMP was considered acceptable.

In conclusion, the data on safety, efficacy and quality have demonstrated that Xarelto has a favourable benefit/risk profile for the treatment of venous thromboembolic events (VTE) and prevention of VTE recurrence in children.

For further details about Xarelto, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.