Regulatory Decision Summary for Zerbaxa

Health Canada considers that the benefits of Zerbaxa (ceftolozane and tazobactam) outweigh the potential risks for the treatment of Complicated Intra-abdominal infections (cIAI) and Complicated Urinary Tract infections (cUTI), including pyelonephritis infections, when caused by Zerbaxa-susceptible strains of the designated microorganisms in patients 18 years of age or older as indicated below:

• Complicated Intra-abdominal Infections
  • Zerbaxa is indicated for the treatment of complicated intra-abdominal infections (cIAI) caused by the following Gram-negative and Gram-positive microorganisms: Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Bacteroides fragilis, Streptococcus anginosus, Streptococcus constellatus, and Streptococcus salivarius.
  In the treatment of cIAI, Zerbaxa should be used in combination with metronidazole in order to provide adequate anaerobic coverage.
• Complicated Urinary Tract Infections, including Pyelonephritis
  • Zerbaxa is indicated for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis caused by the following Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa.

Benefits

Phase III studies in cUTI and cIAI patient populations demonstrated that Zerbaxa, administered alone in patients with cUTI and in combination with metronidazole in patients with cIAI, is effective and shows comparable cure rates relative to comparator agents (levofloxacin in cUTI, and meropenem in cIAI). In both populations, the studies met their primary efficacy endpoint, exhibiting non-inferiority to the comparator based on a 10% margin. The primary efficacy endpoint for cIAI was the clinical response at the test-of-cure visit in the microbiological intent-to-treat (MITT) population, which included all patients who had at least one baseline intra-abdominal pathogen. Outcomes were 83% for Zerbaxa plus metronidazole versus 87% for the comparator. The primary efficacy endpoint for cUTI was defined as complete resolution or marked improvement of the clinical symptoms and microbiological eradication (all uropathogens found at baseline at ≥10⁵ were reduced to <10⁴ colony-forming units/mL) at the TOC visit 7 (± 2) days after the last dose of study drug. Outcomes were 83% for Zerbaxa versus 80% for the comparator. A detailed analysis of efficacy results in patient subgroups generally confirmed the overall results, but differences favoring meropenem in some subgroups in the cIAI study population were observed (elderly patients, renally impaired patients, patients with the colon as the anatomic site of origin).

Examination of per-pathogen response rates confirmed that Zerbaxa was effective against the major causative gram-negative pathogens of cUTI (when used as monotherapy) and cIAI (when used in combination with metronidazole for effective anaerobic coverage).

The primary efficacy outcomes provide evidence of Zerbaxas therapeutic benefit in patients with cUTI and cIAI. Zerbaxa has activity against common Gram-negative pathogens, including some ESBL-producing Enterobacteriaceae, and against P. aeruginosa. Ceftolozane exhibits only weak activity against staphylococci, and like other cephalosporins, ceftolozane has very limited activity against enterococci.

Risks

Zerbaxa was generally well tolerated. Most adverse events (AEs) seen were mild or moderate in severity. The majority of events reported in the Phase III studies are well-described adverse drug reactions associated with β-lactam antibiotic therapy. There were few discontinuations from treatment due to AEs, and the rates were comparable between Zerbaxa and comparator arms. No cases of anaphylaxis or other severe hypersensitivity or allergic reactions were reported in patients treated with Zerbaxa. Cases of Clostridium difficile-associated diarrhea were reported; the incidence of these events was low, similar to the comparators, and consistent with the event rate of other antibiotics in this class. No clinically relevant effect of Zerbaxa treatment on hematology or chemistry laboratory tests, or vital signs was observed. A thorough QT study was negative with no findings to indicate an effect of Zerbaxa on cardiac repolarization. In addition, no clinically relevant drug-drug interaction is expected with Zerbaxa.

In the cIAI studies (Phase II and III), death occurred in 2.5% (14/564) of patients receiving Zerbaxa and in 1.5% (8/536) of patients receiving meropenem. The causes of death in Zerbaxa-treated patients included cardiac causes, multi-organ failure, sudden death, septic shock, pseudomonal lung infection, acute renal failure, and ischemic stroke. None of the deaths were considered directly related to study drug. Lack of efficacy of the study drug was a plausible contributing factor in some patients. Among patients who died, certain baseline characteristics were more common in the Zerbaxa arm compared to meropenem, for example, age ≥ 65 years, involvement of the colon, renal impairment, need for laparotomy, and an Acute Physiology and Chronic Health Evaluation II (APACHE II) score greater than or equal to ten. There was one death in the Zerbaxa arm of the cUTI studies, which was considered unrelated to study drug.

Zerbaxa is substantially excreted by the kidney and the risk of adverse reactions to Zerbaxa may be greater in patients with impaired renal function. There is also the potential for reduced efficacy of Zerbaxa in patients with decreased renal function. Elderly patients are more likely to have decreased renal function; care should be taken in dose selection in this age group and renal function should be monitored. Dosage adjustment for elderly patients should be based on renal function. Renal target organ toxicity was not noted, but is a possibility based on the renal excretion of Zerbaxa.

Common AEs associated with Zerbaxa involve mainly the digestive system and included abdominal pain, nausea, vomiting, diarrhea and constipation. Skin rash was reported. Central nervous system AEs included headache, dizziness, anxiety and insomnia. Local AEs at the site of injection included phlebitis and inflammation. These common AEs were generally mild and resolved spontaneously after discontinuation of therapy. Elevations were seen in one or more of the hepatic enzymes and anemia was reported. There were two cases of positive Coombs test, but no hemolytic anemia noted.

Uncertainties

Overall, Zerbaxa plus metronidazole versus meropenem appear equally efficacious in the treatment of cIAI but in patients with the colon as the primary anatomic site of infection, the clinical cure rate for the Zerbaxa subgroup was inferior to the comparator subgroup in both the MITT and the ME populations.

Experience in subjects with severe renal failure is limited.

Extended spectrum beta-lactam isolates of a specific genotype were seen in patients who were deemed to be either successes or failures. Results of susceptibility testing will be most helpful in selecting appropriate antibacterial therapy.

Zerbaxa is a parenteral product that is intended for short-term use. No long term safety studies were conducted. As with other antibacterials, it is anticipated that prolonged use of Zerbaxa might result in overgrowth of non-susceptible organisms.

Overall Benefit versus Risk

Zerbaxa, 1.5 g every 8 hours administered as a 1-hour intravenous infusion, is an effective treatment in patients with cUTI and in patients with cIAI (in combination with metronidazole 500 mg every 8 hours administered as intravenous infusion) in patients with susceptible pathogens. Treatment with Zerbaxa was not associated with any notable unexpected safety signals or concerns. The efficacy and safety data support a favorable benefit-harm-uncertainty assessment for the use of Zerbaxa in the treatment of adult patients with cUTI (when used as monotherapy) and cIAI (when used together with metronidazole).

For more information on Health Canadas decision, please view the Summary Basis of Decision.