Summary Basis of Decision for Xydalba

Clinical Pharmacology

Dalbavancin, the medicinal ingredient in Xydalba, is a semi-synthetic bactericidal lipoglycopeptide antibiotic active against susceptible strains of Gram-positive bacteria. This antibiotic interferes with cell wall synthesis by binding to the D-alanyl-D-alanine terminus of the stem pentapeptide in nascent cell wall peptidoglycan, thereby preventing cross-linking (transpeptidation and transglycosylation) of disaccharide subunits. Such disruption of the cell wall leads to bacterial cell death. Dalbavancin is bactericidal in vitro against Staphylococcus aureus and Streptococcus pyogenes at concentrations similar to those sustained throughout treatment in humans according to the recommended dosage regimen.

Dalbavancin has a long terminal elimination half-life (t_1/2 = 346 hours) and mean plasma protein binding is approximately 93%. It is excreted in urine and feces.

Dalbavancin clearance was reduced and the area under the concentration-time curve (AUC) increased in patients with renal impairment. Hemodialysis did not appreciably remove dalbavancin after 3 hours. In patients with severe renal impairment (creatinine clearance less than 30 mL/min) and not receiving regular hemodialysis, the recommended dose should be reduced to either 1,000 mg dalbavancin administered as a single infusion or 750 mg dalbavancin followed one week later by 375 mg dalbavancin.

Dalbavancin pharmacokinetics in patients with mild hepatic impairment (Child-Pugh Class A) was similar to that observed in subjects with normal hepatic function. Therefore, no dose adjustment is recommended for patients with mild hepatic impairment. Mean values of area under the plasma concentration-time curve extrapolated through infinity (AUC_0-∞) were lower in patients with moderate and severe hepatic impairment (Child-Pugh Class B and C). There are insufficient data to recommend an appropriate dosing regimen in these patients. Accordingly, caution should be exercised when prescribing Xydalba to patients with moderate or severe hepatic impairment.

No clinical drug-drug interaction studies have been conducted with Xydalba. There is minimal potential for drug-drug interactions between dalbavancin and cytochrome P450 (CYP450) substrates, inhibitors or inducers.

In the thorough QT study conducted, there was no apparent significant QTc prolongation effect of dalbavancin under the conditions tested.

The clinical pharmacological data support the use of Xydalba for the recommended indication.

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

Clinical Efficacy

The efficacy of Xydalba was supported by data derived from three pivotal Phase III clinical studies in patients with acute bacterial skin and skin structure infections (Study DUR001-301, Study DUR001-302 and Study DUR001-303).

Two-dose regimen of Xydalba (1,000 mg followed one week later by 500 mg)

The two-dose regimen of Xydalba was evaluated in 1,312 adult patients with acute bacterial skin and skin structure infections in two Phase III, randomized, double-blind, double-dummy, non-inferiority clinical studies of similar design, Study DUR001-301 and Study DUR001-302. Patients were treated for two weeks with either a two-dose regimen of intravenous Xydalba (1,000 mg Day 1; 500 mg Day 8) or intravenous vancomycin (1,000 mg or 15 mg/kg every 12 hours, with the option to switch to oral linezolid after 3 days). The total treatment duration ranged from 10 to 14 days. Xydalba-treated patients with creatinine clearance of less than 30 mL/min received 750 mg followed one week later by 375 mg. Approximately 5% of patients also received a protocol-specified empiric course of treatment with intravenous aztreonam for coverage of Gram-negative pathogens. The specific infections in these trials included: cellulitis (approximately 50% of patients across treatment groups), major abscesses (approximately 30%), and wound infections (approximately 20%). The median lesion area at baseline was 341 cm². In addition to local signs and symptoms of infection, patients were also required to have at least one systemic sign of disease at baseline, defined as temperature 38°C or higher (approximately 85% of patients), white blood cell count greater than 12,000 cells/mm³ (approximately 40%), or 10% or more band forms on white blood cell differential (approximately 23%). The demographic and baseline characteristics were similar between the treatment and comparator arms in both trials.

In both studies, the primary endpoint was the clinical response rate where responders were defined as patients who had no increase from baseline in lesion area 48 to 72 hours after initiation of therapy, and had a temperature consistently at or below 37.6°C upon repeated measurement. The non-inferiority margin was -10%.

The primary endpoint analysis in both studies demonstrated that Xydalba was non-inferior to the regimen of vancomycin/linezolid. In Study DUR001-301, the clinical response rate was 240/288 (83.3%) in the Xydalba-treated group and 233/285 (81.8%) in the comparator group. The clinical response rates in Study DUR001-302 were 285/371 (76.8%) and 288/368 (78.3%) in the Xydalba-treated patients and the comparator-treated patients, respectively. Since the lower bound of the 95% confidence interval (CI) for the treatment difference was above -10% (-4.6% in Study DUR001-301 and -7.4% in Study DUR001-302), both studies met their primary objectives.

Single-dose regimen of Xydalba (1,500 mg)

The single-dose regimen of Xydalba (1,500 mg) was evaluated in a Phase IIIb, double-blind, non-inferiority clinical study (Study DUR001-303). The study included 698 adult patients with acute bacterial skin and skin structure infections who were treated with either a single 1,500 mg dose of Xydalba or a two-dose regimen of 1,000 mg followed one week later by 500 mg. Patients with creatinine clearance less than 30 mL/min had their dose adjusted. Approximately 5% of patients also received a protocol-specified empiric course of treatment with intravenous aztreonam for coverage of Gram-negative pathogens. The specific infections and other patient characteristics in this trial were similar to those in Study DUR001-301 and Study DUR001-302.

The primary endpoint was the clinical response rate where responders were defined as patients who had at least a 20% decrease from baseline in lesion area 48 to 72 hours after randomization without receiving any rescue antibacterial therapy. The results from this trial demonstrated that a single 1,500 mg dose of Xydalba was non-inferior to the two-dose regimen. The clinical response rate was 284/349 (81.4%) in the single-dose arm and 294/349 (84.2%) in the two-dose regimen arm, with a lower bound of the 95% CI of -8.5%.

Indication

The New Drug Submission for Xydalba was filed by the sponsor with the following indication:

• Xydalba (dalbavancin for injection) is a lipoglycopeptide indicated for treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSI) including treatment of bacteremia associated with these infections.

To ensure safe and effective use of the product, Health Canada approved the following indication:

• Xydalba (dalbavancin for injection) is indicated for treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSI), caused by susceptible isolates of the following Gram-positive microorganisms: Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant strains), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus anginosus group (including Streptococcus anginosus, Streptococcus intermedius, Streptococcus constellatus) and Enterococcus faecalis (vancomycin susceptible strains).

The following caveat statements have also been included in the approved indication:

• Xydalba is not active against Gram-negative bacteria; therefore, combination therapy may be clinically indicated if the ABSSSI is polymicrobial and includes a suspected or documented Gram-negative pathogen.
  
  
• Xydalba has been studied in the treatment of cellulitis/erysipelas, major cutaneous abscesses, or wound infections. Other types of complicated skin infections (including diabetic foot ulcer, necrotizing fasciitis, or decubitus ulcer) have not been studied.
  
  
• To reduce the development of drug-resistant bacteria and maintain the effectiveness of Xydalba and other antibacterial drugs, Xydalba should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

For more information, refer to the Xydalba Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety profile of Xydalba was evaluated in eight completed Phase II/III clinical studies comprising 2,473 patients treated with Xydalba. Of these, 1,778 patients were treated with Xydalba in seven Phase II/III trials comparing Xydalba to comparator antibacterial drugs, whereas 695 patients received Xydalba in one Phase III trial that compared the safety profile of the 1,500 mg single-dose regimen to the safety profile of the two-dose regimen (Study DUR001-303, described in the Clinical Efficacy section).

The most common adverse reactions in patients treated with any regimen of Xydalba included nausea (4.7%), headache (3.8%), diarrhea (3.4%), vomiting (2.4%), constipation (2.3%), pruritus (1.8%), and rash (1.7%). The median duration of adverse reactions was 3.0 days in patients treated with Xydalba. Serious adverse reactions occurred in 121/2,473 (4.9%) of patients treated with any regimen of Xydalba. Xydalba was discontinued due to an adverse reaction in 64/2,473 (2.6%) patients treated with any regimen of Xydalba.

A similar distribution of adverse events was seen in Study DUR001-303 in the single-dose and two-dose Xydalba treatment groups, although some events that were observed at a >1% rate in the overall Phase II/III database were reported at a rate <1%, including rash and pruritus.

Some special safety concerns for Xydalba included (but were not limited to):

• Infusion-related reactions: There is a known association between glycopeptides and infusion-related reactions. An occurrence of "red man syndrome" following administration of a 1,500 mg dose of Xydalba was reported in one subject in the thorough QT trial.
• Clostridium difficile-associated disease: In the Phase II/III safety database, Clostridium difficile-associated disease was reported in patients treated with Xydalba.
• Hepatic effects: In the Phase II/III safety database, more Xydalba-treated subjects than comparator-treated subjects with normal baseline transaminase levels had post-baseline alanine aminotransferase (ALT) elevation greater than three times the upper limit of normal. Overall, abnormalities in liver tests (ALT, aspartate aminotransferase, bilirubin) were reported with similar frequency in the Xydalba and comparator arms.
• Hypersensitivity reactions: Among patients treated with Xydalba, one patient experienced an anaphylactoid reaction whereas several patients experienced rash and pruritus.

Overall, the safety and tolerability profile of the Xydalba two-dose regimen (1,000 mg Day 1; 500 mg Day 8) was comparable to that seen for patients treated with the comparator agents. Furthermore, the safety and tolerability of the single-dose (1,500 mg) Xydalba regimen was similar to that of the two-dose Xydalba regimen. Appropriate warnings and precautions are in place in the approved Xydalba Product Monograph to address the identified safety concerns.

For more information, refer to the Xydalba Product Monograph, approved by Health Canada and available through the Drug Product Database.