Regulatory Decision Summary for Bridion

This Supplement to a New Drug Submission was filed by Merck Canada Inc. to obtain market authorization, pursuant to section C.08.004 of the Food and Drugs Regulations, for Bridion (sugammadex), to revise the indication to include patients aged birth to less than 2 years of age, which currently limits sugammadex use to patients 2 years of age and older. Upon review of the submitted data package, Health Canada authorized Bridion as filed.

To support the addition of pediatric patients aged birth to 2 years, this submission included the results of a Phase 4 clinical trial (Study 169). Part A of Study 169, used pharmacokinetic (PK) data to confirm the doses of Bridion that produce similar exposures in infants and children from birth to 2 years of age when compared to systemic exposure in adults after administration of 2 milligrams per kilogram (mg/kg) and 4 mg/kg. Both the clinical pharmacology data and results of a population PK analysis confirmed that 2 mg/kg and 4 mg/kg could also be used to reverse moderate or deep neuromuscular blockade, respectively in the proposed population (birth to less than 2 years of age).

Part B of Study 169 was a randomized, double-blind trial that compared the safety and efficacy of Bridion 2 mg/kg (n = 44) and neostigmine 2.5 micrograms per kilogram (mcg/kg) (n = 31) in the reversal of moderate neuromuscular blockade and Bridion 4 mg/kg (n = 63) in the reversal of deep neuromuscular blockade induced by neuromuscular blocking agents, vecuronium and rocuronium, used during surgery. Patients aged birth to less than 2 years were stratified into four age cohorts of birth to 27 days, 28 days to less than 3 months, 3 to less than 6 months, and 6 months to less than 2 years of age.

The primary efficacy endpoint, time to neuromuscular recovery, was significantly faster (p = 0.0002) for Bridion 2 mg/kg (median: 1.4 minutes) compared to neostigmine (median: 4.4 minutes) for the reversal of moderate blockade. Time to neuromuscular recovery with Bridion 4 mg/kg to reverse the deep blockade (median: 1.1 minutes) was similar to that of the moderate blockade. With respect to the secondary efficacy endpoint, time to extubation, approximately 79% (23/29) of patients in the Bridion 2 mg/kg group were extubated within 15 minutes from administration of the reversing agent compared with 71% (22/31) of those in the neostigmine arm. These differences were not statistically significant (p = 0.217).

Overall, the safety profile of Bridion in patients aged birth to less than 2 years of age is similar to that in older pediatric (from age 2 to less than 17 years of age) and adult patients. Vomiting and procedural pain were the most frequently reported adverse events. No new safety issues were discovered in this study. One case of bradycardia in the Bridion 2 mg/kg arm was considered serious and required intervention. These findings are in line with the current warnings in the Product Monograph for bradycardia. In light of the expanded indication/population (birth to less than 2 years of age), the Product Monograph was amended to include that cases have been observed across all age groups and that some required medical intervention. There were no cases of adverse events of special interest which included drug-induced liver injury, reported cases of Hy’s law, or adjudicated hypersensitivity/anaphylaxis.

An updated Risk Management Plan was reviewed and found to be acceptable by the Marketed Health Products Directorate.

Following review and requested revisions, the final labelling and Product Monograph were considered to be acceptable

Overall, the benefit–harm–uncertainty profile of Bridion (sugammadex) 2 mg/kg and 4 mg/kg for the reversal of moderate to deep neuromuscular blockade in pediatric patients aged birth to less than 2 years of age, was favourable. Therefore, a Notice of Compliance was recommended.

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