Regulatory Decision Summary for Xydalba

This Supplement to a New Drug Submission (SNDS) proposed the addition of the pediatric population (aged 3 months to less than 18 years) to the indication of Xydalba (dalbavancin for injection).

The New Drug Submission (NDS) for Xydalba was reviewed under the priority review policy and was granted a Notice of Compliance (NOC) by Health Canada in 2018 for the treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of gram-positive microorganisms: Staphylococcus aureus (S. aureus) (including methicillin-susceptible and methicillin-resistant strains), Streptococcus pyogenes (S. pyogenes), Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus anginosus (S. anginosus) group (including Streptococcus anginosus, Streptococcus intermedius, Streptococcus constellatus) and Enterococcus faecalis (vancomycin susceptible strains).

The request to include the pediatric population (aged 3 months to less than 18 years) in the existing Xydalba indication for the treatment of acute bacterial skin and skin structure infection (ABSSSI) relied on extrapolation of clinical efficacy and safety based on comparable plasma exposures in children to those in adults. The acceptance of extrapolation was based on assumptions that the disease, mechanism of action and thus Pharmacokinetics/Pharmacodynamics (PK/PD) were the same in pediatric patients as in adults, and therefore the doses selected achieved similar plasma exposures and probability of PK/PD target attainment (PTA) in children as in adults.

The available population PK (popPK) model showed that no clinically important differences in drug exposure between pediatric age groups (3 months to less than 18 years) and adults were expected following administration of the age-dependent, recommended, single dose of dalbavancin. In all pediatric age groups, the single-dose regimen resulted in PTA > 90% for minimum inhibitory concentrations (MICs) up to 0.125 mg/L (breakpoint for dalbavancin for all labeled pathogens). The target attainment for pediatric patients was similar to target attainment for adult patients. The simulations therefore supported the proposed pediatric dosing regimen tested as part of the pediatric clinical program.

The clinical efficacy and safety of Xydalba for the treatment of pediatric patients with ABSSSI was evaluated in one adequately designed and well-controlled pivotal Phase III open-label, multi-centre, randomized, comparator controlled trial (DUR001-306). Clinical and microbiological responses were generally similar across age cohorts and dosing groups, and similar to comparator treatments. The proportion of clinical responders was > 96% in both Xydalba treatment arms at 48 to 72 hours. The clinical cure rate was > 95% in both Xydalba arms at the Test of Cure (TOC) visit in the Modified Intent-to-Treat (mITT) population and was sustained at the follow-up visit. The favorable clinical response observed at 48-72 hours was similar regardless of baseline pathogen at the End of Treatment (EOT), TOC and follow-up visits. The microbiological response was favorable (eradication or presumed eradication) in most participants at all timepoints and was maintained through the follow-up visit. The response was comparable across all age cohorts and all baseline Gram-positive pathogens.

Xydalba single intravenous (IV) dose was generally safe and well tolerated in pediatric participants with ABSSSI across all age cohorts. No new risks were identified in comparison with known safety findings in adults. There was no indication that the safety profile in the pediatric population would be different from that established in adults. It should be noted that the pediatric safety database, although acceptable, is of limited size to detect adverse reactions that are uncommon or rare. The safety concerns associated with the use of dalbavancin in pediatric patients are considered adequately reported in the Product Monograph (PM).

The approved recommended dose is a single dose of 22.5 mg/kg (maximum 1,500 mg) in patients aged 3 months to less than 6 years and a single dose of 18 mg/kg (maximum 1,500 mg) in patients aged 6 years to less than 18 years. The Sponsor did not propose to include the alternative two-dose regimen for the pediatric population. The long half-life of dalbavancin and high PTA justify the proposed single-dose regimens for pediatric patients.

Xydalba is not recommended for use in pediatric patients with severe renal impairment as there was insufficient information to recommend dosage adjustment. The use of Xydalba in pediatric patients with hepatic impairment (mild, moderate or to severe) has not been evaluated, therefore caution should be used for these patients. The PM was updated to reflect this information.

A Risk Management Plan (RMP) was submitted for Xydalba and found to be acceptable. Post-marketing adverse events will continue to be monitored through standard pharmacovigilance activities.

Overall, Xydalba exhibited a favorable benefit-harm-uncertainty profile when used as directed for pediatric patients aged 3 months to less than 18 years with ABSSSI caused by susceptible microorganisms.

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