Summary Basis of Decision for Zerbaxa

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Zerbaxa is located below.

Recent Activity for Zerbaxa

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Post-Authorization Activity Table (PAAT) for Zerbaxa

Updated:

2023-03-30

The following table describes post-authorization activity for Zerbaxa, a product which contains the medicinal ingredients ceftolozane (as ceftolozane sulfate) and tazobactam (as tazobactam sodium). For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.

For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.

Drug Identification Number (DIN):

  • DIN 02446901 - 1.5 g/vial, 1 g ceftolozane and 0.5 g tazobactam, powder for solution, intravenous administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
Summary Safety Review Not applicable Posted 2023-01-23 Summary Safety Review posted for cephalosporins (Assessing the potential risk of seizures).
New safety and effectiveness review Not applicable Started between 2021-10-01 and 2021-10-31 Health Canada started a safety and effectiveness review for cephalosporins related to seizures.
Drug Recall Not applicable Posted 2020-12-16 Drug Recall posted on the Recalls and safety alerts website for the general public, healthcare professionals, and hospitals.
SNDS # 238477 2020-06-03 Issued NOC 2020-10-09 Submission filed as a Level I – Supplement to update the PM. The changes were in response to Advisement Letters issued by Health Canada dated 2020-02-05 and 2020-04-24, requesting revisions related to beta-lactam antibiotics and the risk of severe skin side effects (severe cutaneous adverse reactions [SCAR]). The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions section of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
SNDS # 224729 2019-02-15 Issued NOC 2019-08-30 Submission filed as a Level I – Supplement for a new indication with an increased dosage. The submission was reviewed under the Priority Review of Drug Submissions Policy. The indication authorized was: the treatment of nosocomial pneumonia (hospital-acquired pneumonia [HAP] and ventilator-associated pneumonia [VAP]), caused by susceptible Gram-negative microorganisms, at a dose of 3 g. The submission was reviewed and considered acceptable, and an NOC was issued. A Regulatory Decision Summary was published.
Summary Safety Review Not applicable Posted 2018-09-10 Summary Safety Review posted for beta-lactam antibiotics (Assessing the potential risk of severe skin side effects).
NC # 205115 2017-04-26 Issued No Objection Letter
2017-07-27		 Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM to reflect revisions in the company core data sheet.
As a result of the NC, modifications were made to the Serious Warnings and Precautions Box, Contraindications, Warnings and Precautions, Adverse Reactions, Drug Interactions, Dosage and Administration, Overdosage sections of the PM. Corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
NC # 195705 2016-06-03 Issued No Objection Letter
2016-08-16		 Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the Product Monograph (PM) to reflect revisions in the company core data sheet. Revisions were made to the Adverse Reactions, Microbiology, and Toxicology sections of the PM. Corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
Drug product (DIN 02446901) market notification Not applicable Date of first sale:
2016-01-12		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 178006 2014-09-15 Issued NOC 2015-09-30 Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Zerbaxa

Date SBD issued: 2015-11-30

The following information relates to the new drug submission for Zerbaxa.

Ceftolozane and tazobactam
Zerbaxa 1.5 g /vial, ceftolozane (1 g as ceftolozane sulfate) and tazobactam (0.5 g as tazobactam sodium), powder for solution, intravenous

Drug Identification Number (DIN):

  • 02446901

Merck Canada Inc.

New Drug Submission Control Number: 178006

 

On September 30, 2015, Health Canada issued a Notice of Compliance to Merck Canada Inc. for the drug product, Zerbaxa.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology, toxicology, and microbiology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit/risk profile of Zerbaxa is favourable for the treatment of patients 18 years of age or older with the following infections when caused by Zerbaxa susceptible strains of the designated microorganisms:

  • 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.
1 What was approved?

Zerbaxa, an antibacterial consisting of a cephalosporin and a beta-lactamase inhibitor, was authorized for the following infections when caused by Zerbaxa susceptible strains of the designated microorganisms:

  • 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.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Zerbaxa and other antibacterial drugs, Zerbaxa 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.

In the Phase III clinical studies, a higher incidence of adverse reactions was observed in patients aged 65 years and older. In the cIAI study, cure rates were lower in elderly patients. This finding in the elderly population was not observed in the cUTI study.

The safety and effectiveness in pediatric patients (<18 years of age) have not been established.

Zerbaxa is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container, as well as patients with known serious hypersensitivity to penicillins, cephalosporins, or other beta-lactams. Zerbaxa was approved for use under the conditions stated in the Zerbaxa Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Zerbaxa [1.5 g /vial, ceftolozane (1 g as ceftolozane sulfate) and tazobactam (0.5 g as tazobactam sodium)] is presented as a powder for solution. In addition to the medicinal ingredients, the powder also contains citric acid, L-arginine, and sodium chloride.

For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Zerbaxa Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Zerbaxa approved?

Health Canada considers that the benefit/risk profile of Zerbaxa is favourable for the following infections when caused by Zerbaxa susceptible strains of the designated microorganisms:

  • 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.

The serious nature of cUTI and cIAI, and the increasing prevalence of antimicrobial resistant-pathogens seen in these infections, attest to the need for new antimicrobial agents with activity against difficult-to-treat pathogens, especially extended spectrum beta lactamase (ESBL) producing strains of Escherichia coli and Klebsiella pneumoniae, and drug-resistant Pseudomonas aeruginosa.

Ceftolozane, an active ingredient in Zerbaxa, is a new cephalosporin antibiotic developed for the treatment of infections primarily due to Gram-negative bacteria. Ceftolozane exerts bactericidal activity by inhibiting essential penicillin-binding proteins (PBPs), resulting in the inhibition of cell-wall synthesis and subsequent cell death. Ceftolozane has enhanced activity against Pseudomonas aeruginosa in non-clinical assays. Tazobactam is an irreversible inhibitor of beta lactamases, broadening the spectrum of activity to include some ESBL-producing Escherichia coli, Klebsiella pneumoniae, and other Enterobacteriaceae. The addition of tazobactam has no significant impact on the antipseudomonal activity of ceftolozane, since Pseudomonas aeruginosa rarely produces ESBL-producing bacteria.

The Phase III clinical studies for the cUTI and the cIAI indications confirmed that Zerbaxa administered alone in patients with cUTI and together with metronidazole in patients with cIAI, was effective and showed comparable cure rates relative to the comparator agents (levofloxacin for cUTI and meropenem for cIAI). For both indications, the studies met their primary efficacy endpoint, exhibiting non-inferiority to the comparator based on a 10% margin. A detailed analysis of efficacy results in patient subgroups generally confirmed the results overall, but differences favouring meropenem in some subgroups in the cIAI study populations 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 pathogens of cUTI and cIAI (when used in combination with metronidazole for effective anaerobic coverage). For patients with cUTI with a levofloxacin-resistant and/or ESBL-positive baseline uropathogen, Zerbaxa was superior to levofloxacin in terms of cure rates. In cIAI, Zerbaxa plus metronidazole generally demonstrated similar clinical cure rates to meropenem, typically considered the therapy of choice for empiric coverage of ESBL-producing pathogens and Pseudomonas aeruginosa. Clinical cure rates in the microbiologically evaluable (ME) population in ESBL-producing Escherichia coli and Pseudomonas aeruginosa infections were 100% in the Zerbaxa plus metronidazole treatment arm compared with 90% and 93%, respectively, in the meropenem treatment arm.

Ceftolozane exhibits weak in vitro activity against staphylococci, and like other cephalosporins, ceftolozane has very limited in vitro activity against enterococci.

Zerbaxa was generally well-tolerated. Most adverse events (AEs) were mild or moderate in severity. The majority of AEs reported in the Phase III studies are well-described adverse drug reactions associated with beta-lactam antibiotic therapy. There were few discontinuations from treatment due to AEs, and the rates were comparable between Zerbaxa and the comparator arms. No cases of anaphylaxis or other severe hypersensitivity or allergic reactions were reported in patients treated with Zerbaxa. However, serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials; this safety concern is included in a Serious Warnings and Precautions box in the Zerbaza Product Monograph. 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 on vital signs was observed. A thorough QT study was negative. No clinically relevant drug-drug interaction is expected with Zerbaxa.

Zerbaxa is 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. Dosage adjustment for elderly patients should be based on renal function. Renal target organ toxicity was not reported, but is a possibility based on the renal excretion of Zerbaxa and potential accumulation of ceftolozane in renal tissue, based on findings in animal studies.

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

Health Canada reviewed the Look-alike Sound-alike Report submitted by the sponsor and accepted the proprietary name for the drug product.

In conclusion, Zerbaxa 1.5 g every 8 hours administered to patients with susceptible pathogens as a 1-hour intravenous (IV) infusion was an effective treatment in patients with cUTI and in patients with cIAI (in combination with metronidazole 500 mg IV every 8 hours). Treatment with Zerbaxa was not associated with any notable unexpected safety signals or concerns. The totality of the efficacy and safety data supports a favorable benefit-harm-uncertainty assessment for the use of Zerbaxa in the treatment of adult subjects with cUTI and cIAI (when used in conjunction with metronidazole). The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Zerbaxa Product Monograph to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections. (Chemistry and Manufacturing) Basis for Decision sections.

3 What steps led to the approval of Zerbaxa?

Submission Milestones: Zerbaxa

Submission Milestone Date
Pre-submission meeting: 2014-06-18
Submission filed: 2014-09-15
Screening  
Screening Deficiency Notice issued: 2014-11-07
Response filed: 2014-11-18
Screening Acceptance Letter issued: 2014-12-04
Review  
Quality Evaluation complete: 2015-09-30
Clinical Evaluation complete: 2015-09-30
Labelling Review complete: 2015-09-30
Notice of Compliance issued by Director General: 2015-09-30

The Canadian regulatory decision on the clinical review of Zerbaxa was based on a critical assessment of the Canadian data package; and for the non-clinical review, was based on the United States Food and Drug Administration (FDA) review, with the European Medicines Agency (EMA) review as added reference. The foreign reviews completed by the EMA and the FDA were used as an added reference for the clinical review.

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

4 What follow-up measures will the company take?

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

5 What post-authorization activity has taken place for Zerbaxa?

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decision was negative or positive. The PAAT will continue to be updated during the product's lifecycle.

The PAAT for Zerbaxa is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

6 What other information is available about drugs?

Up to date information on drug products can be found at the following links:

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision

Clinical Pharmacology

Zerbaxa contains two active ingredients, ceftolozane as ceftolozane sulfate and tazobactam as tazobactam sodium.

The bactericidal action of ceftolozane results from inhibition of cell wall biosynthesis, and is mediated through binding to penicillin-binding proteins (PBPs). Ceftolozane is an inhibitor of PBPs of Pseudomonas aeruginosa and Escherichia coli.

Tazobactam has little clinically relevant in vitro activity against bacteria due to its reduced affinity to penicillin-binding proteins. It is an irreversible inhibitor of some beta lactamases and can bind covalently to some chromosomal and plasmid-mediated bacterial beta-lactamases.

Nine Phase I studies evaluated the use of ceftolozane alone or ceftolozane in combination with tazobactam in a total of 305 subjects. The evaluation included pharmacokinetic (PK) studies in healthy adults and adults with renal impairment, a drug-drug interaction study, and a thorough QT study. Study results supported the selection of the dose regimen of ceftolozane/tazobactam 1.5 g every 8 hours as a 1-hour IV infusion for Phase II and Phase III studies in patients with normal renal function or mild renal impairment. Dose adjustment is required for patients with moderate or severe renal impairment and for patients with end-stage renal disease who are on hemodialysis. No dose adjustment is necessary for patients with hepatic impairment. Zerbaxa is unlikely to cause clinically relevant drug-drug interactions related to cytochrome P450 enzymes and transporters at therapeutic concentrations.

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

Clinical Efficacy

The efficacy and safety data of Zerbaxa in patients with complicated intra-abdominal infections (cIAI) and patients with complicated urinary tract infections (cUTI), including pyelonephritits were each derived from two large, identical, multicentre, randomized, double-blind, active-controlled Phase III studies per indication, subsequently pooled to form 1 submission dataset for each indication. The combined dataset for cIAI (Trial 1) was based on a total of 806 patients, and the combined dataset for cUTI (Trial 2) was based on a total of 800 patients. The studies were designed to test non-inferiority against concurrent active control arms; meropenem for the cIAI indication and levofloxacin for the cUTI indication.

In Trial 1, patients with cIAI received Zerbaxa 1.5 g and metronidazole 500 mg every 8 hours, or the comparator drug meropenem 1 g every 8 hours. Both groups received their treatment as a 1-hour intravenous (IV) infusion. Although Zerbaxa has in vitro activity against some anaerobes, metronidazole was added for treatment of all patients with cIAI to ensure full anaerobic coverage. Metronidazole is approved and widely used adjunctively (especially with cephalosporins) in the treatment of mixed aerobic and anaerobic infections. Patients were administered treatment for 4 to 8 days.

The primary efficacy endpoint for Trial 1 was the clinical response at the test-of-cure (TOC) visit in the microbiological intent-to-treat (MITT) population, which included all patients who had at least one baseline intra-abdominal pathogen. The key secondary efficacy endpoint was clinical response at the TOC visit in the microbiologically evaluable (ME) population, which included all protocol-adherent MITT patients. Zerbaxa plus metronidazole was shown to be non-inferior (using a non-inferiority margin of 10%) to meropenem based on the difference in clinical cure rates in the MITT and ME populations at the TOC visit, respectively, at a 1-sided 0.025 significance level. Zerbaxa and metronidazole demonstrated clinical cure rates of 83.0% (323/389) while the comparator drug had clinical cure rates of 87.3% (364/417) for the MITT population. The treatment difference was -4.2. For the ME population, Zerbaxa and metronidazole demonstrated clinical cure rates of 94.2% (259/275) while the comparator drug had clinical cure rates of 94.7% (304/321). The treatment difference was -1.0.

Based on the data provided, the following pathogens were shown to be sensitive to Zerbaxa at baseline culture and were deemed eradicated following treatment with Zerbaxa: Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumonia, Proteus mirabilis, Pseudomonas aeruginosa, Bacteroides fragilis, Streptococcus anginosus, Streptococcus constellatus and Streptococcus salivarius. Zerbaxa was not consistently effective against all extended spectrum beta lactamase (ESBL) producing strains. There was no documented emergence of decreased susceptibility or resistance in either treatment arm. Bacteremia was relatively uncommon, occurring in only 2.6% of patients. Clinical response at TOC for patients with baseline bacteremia was 6/8 (75%) for the Zerbaxa treatment arm and 12/12 (100%) for Meropenem.

In Trial 2, patients with cUTI received Zerbaxa (1.5 g every 8 hours) or the comparator drug levofloxacin (750 mg once daily). Both groups received their treatment as a 1-hour IV infusion. Patients were administered treatment for 7 days. The primary efficacy endpoint 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. The primary efficacy analysis population was the microbiologically modified intent-to-treat (mMITT) population, which included all patients who received study medication and had at least 1 baseline uropathogen. The key secondary efficacy endpoint was the composite microbiological and clinical cure response at the TOC visit in the ME population, which included protocol-adherent mMITT patients with a urine culture at the TOC visit.

Zerbaxa showed a statistically superior outcome against levofloxacin for the primary efficacy outcome (composite microbiological and clinical cure rates) with the mMITT population achieving 76.9% (306/398) versus (vs.) 68.4% (275/402) for the comparator levofloxacin. The treatment difference was 8.5. When levofloxacin-resistant pathogens were excluded from the analysis, the outcome was similar between the two treatment arms of the study for the primary efficacy outcome, with Zerbaxa achieving composite microbiological and clinical cure rates of 82.6% (246/298) vs. 79.7% (231/290) for levofloxacin. Clinical outcomes were similar for the two treatment arms of the study at the end of treatment (EOT) visit, the TOC, and at the late follow-up (LFU) visit.

Zerbaxa showed very limited activity against Gram-positive bacteria; levofloxacin demonstrated a broader Gram-positive coverage than Zerbaxa. Both Zerbaxa and levofloxacin failed against some ESBL-producing pathogens. This lack of activity was seen more frequently with levofloxacin. Adequate numbers of pathogens were studied to support labelling for sensitive strains of Escherichia coli, Klebsiella pneumonia, Proteus mirabilis, andPseudomonas aeruginosa. In the mMITT population, composite cure rates in patients with concurrent bacteremia were 23/29 (79.3%) for Zerbaxa and 19/33 (57.6%) for levofloxacin.

Overall, the primary efficacy outcomes provided evidence of Zerbaxa's therapeutic benefit in patients with cUTI and cIAI caused by the susceptible strains of the designated microorganisms stated in the authorized indications.

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

Indications

During the original filing of this New Drug Submission (NDS), the sponsor proposed the following indications:

Zerbaxa (ceftolozane/tazobactam) is indicated for the treatment of patients ≥18 years of age with the following infections caused by designated susceptible microorganisms, including beta-lactamase-producing strains.

  • Complicated Intra-abdominal Infections
    • in combination with metronidazole for the treatment of complicated intra-abdominal infections, including intra-abdominal abscess and peritonitis, caused by the following Gram-negative and Gram-positive microorganisms: Enterobacter cloacae, Escherichia coli (including CTX-M-14/15 extended spectrum beta-lactamase (ESBL)-producing strains), Klebsiella oxytoca, Klebsiella pneumoniae (including CTX-M-15 ESBL-producing strains), Proteus mirabilis, Pseudomonas aeruginosa, Bacteroides fragilis, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides vulgatus, Streptococcus anginosus, Streptococcus constellatus, and Streptococcus salivarius.
       
  • Complicated Urinary Tract Infections, including Pyelonephritis
    • for the treatment of complicated urinary tract infections, including pyelonephritis, with or without concurrent bacteremia, caused by the following Gram-negative microorganisms: Escherichia coli (including levofloxacin resistant and/or CTX-M-14/15 ESBL-producing strains), Klebsiella pneumoniae (including levofloxacin resistant and/or CTX-M-15-ESBL producing strains), Proteus mirabilis, and Pseudomonas aeruginosa.

Following the review of the NDS, Health Canada revised the indications to include only the specific pathogens supported by the data. The text that specified various anatomic sites of infection within the intra-abdominal infection indication was also removed as this was considered implicit within the indication.

Health Canada recommended the following indications:

Zerbaxa (ceftolozane and tazobactam) is indicated for the treatment of patients 18 years of age or older with the following infections when caused by Zerbaxa susceptible strains of the designated microorganisms:

  • 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.

Clinical Safety

The clinical safety of Zerbaxa was evaluated in Phase III comparator-controlled clinical studies of complicated intra-abdominal infections (cIAI) and complicated urinary tract infections (cUTI), which included a total of 1,015 patients treated with Zerbaxa and 1,032 patients treated with comparator (levofloxacin or meropenem) for up to 14 days. For more information about the Phase III studies, see the Clinical Efficacy section.

In general, the adverse events (AEs) seen with Zerbaxa were infrequent, balanced between the Zerbaxa and comparator groups and widely distributed across multiple body systems. The most common adverse drug reactions (≥5% for either indication) in patients treated with Zerbaxa were nausea, diarrhea, pyrexia and headache. The majority of adverse drug reactions were reported as mild to moderate in severity. Treatment discontinuation due to AEs occurred in 2.0% (20/1,015) of patients treated with Zerbaxa and 1.9% (20/1,032) of patients who received the comparator drugs. Renal impairment led to discontinuation of treatment in 5/1,015 (0.5%) of patients who received Zerbaxa and none in the comparator arms. All 5 patients who discontinued study therapy because of renal events had at least mild renal impairment at baseline. As no dosing recommendation was available for patients with a creatinine clearance (CrCL) of <30 mL/min, patients with a CrCL <30 mL/min while on therapy were required to discontinue treatment. The acute renal failure events generally represented non-clinically significant categorical shifts in renal function based on CrCL occurring in patients with at least mild renal impairment at baseline.

The overall incidence of mild, moderate, and severe AEs was similar for patients treated with Zerbaxa and the comparator drugs. In the cIAI studies (Phase II and III), death occurred in 2.5% (14/564) of patients treated with Zerbaxa and in 1.5% (8/536) of patients treated with meropenem. The causes of death varied and included worsening and/or complications of infection, surgery and underlying conditions. Among patients who died, certain baseline characteristics were more common in the Zerbaxa arm compared to meropenem, for example (e.g.) age ≥65 years, involvement of colon, renal impairment, need for laparotomy, and higher Acute Physiology and Chronic Health Evaluation (APACHE) score.

Specific serious adverse reactions that are associated with the cephalosporin class of antibiotics, include hypersensitivity, pseudomembranous colitis, hemolytic disorders, thrombophlebitis, and acute renal failure. These adverse reactions were uncommon in the integrated Phase III studies, particularly in the Zerbaxa treatment arm. None of the patients treated with Zerbaxa in the integrated Phase III studies experienced an anaphylactic reaction. The incidence of pseudomembranous colitis was 0.4% and 0.3% in the Zerbaxa and comparator arms, respectively. No hemolytic disorders were reported in the integrated Phase III studies. This is consistent with the low rate of Coombs' test conversions noted in the Phase III studies. The incidence of thrombophlebitis was low and comparable between treatment arms in the integrated Phase III studies; 0.8% and 1.1% of patients in the Zerbaxa and comparator arms, respectively. The incidence of infusion-related events was also low (<1% of patients).

The review of hematology and clinical chemistry parameters showed no clinically meaningful effect of Zerbaxa therapy on any laboratory parameters other than transaminases. Transaminase elevations are a known consequence of beta-lactam therapy. In both the cUTI and cIAI indications, the incidence of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevations was low and comparable between treatment arms.

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials. This safety concern is included in a Serious Warnings and Precautions box in the Zerbaza Product Monograph.

Overall, the safety data supports the approval of Zerbaxa for the recommended indication. Appropriate warnings and precautions are in place in the approved Zerbaxa Product Monograph to address the identified safety concerns.

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

7.2 Non-Clinical Basis for Decision

Zerbaxa has two active ingredients, ceftolozane and tazobactam. The submission presented a comprehensive scope of pharmacotoxicological and microbiological studies characterizing ceftolozane and a summary of published information supplemented with targeted studies for characterizing tazobactam. Any limitations of data were considered manageable and adequately addressed via revisions to proposed label information.

The non-clinical safety-related assessment showed that the safety margins were 0.49-fold (based on Area under the Curve) for ceftolozane and 0.26-fold (based on Human Equivalent Dose) for tazobactam, regarding reproductive and developmental toxicity findings. Based on maximum plasma concentrations (Cmax), the ceftolozane safety margins were greater than 10-fold. Other findings relevant to clinical use and management were ceftolozane accumulation in renal tissue with a 76-hour half-life and ceftolozane hypersensitivity under sensitized conditions. Combined ceftolozane and tazobactam (2:1 ratio) administration did not result in new safety-related effects, unexpected toxicities or altered incidence/severity of findings for the individual compounds. These findings are considered adequately addressed via revisions to the Zerbaxa Product Monograph.

The investigations found no clinically relevant concerns from the pharmacology studies.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Zerbaxa Product Monograph. In view of the intended use of Zerbaxa, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.

Microbiology

Key findings from the microbiology studies identified limitations on the spectrum of activity for ceftolozane and tazobactam and the potential for resistance development. Interpretive data approved by the United States Food and Drug Administration (FDA) and Clinical and Laboratory Standards Institute (CLSI), along with test methodologies and standards are presented in the Zerbaxa Product Monograph.

The drug submission presented the addition of tazobactam, a beta-lactamase inhibitor, to ceftolozane in a fixed dose combination, thereby providing some augmentation to the spectrum of activity. Limitations in the tazobactam pharmacokinetic/pharmacodynamic (PK/PD) dose optimization program are considered adequately mitigated for the unadjusted dose via limited claims regarding the contribution of tazobactam to the spectrum of activity, limits on clinical predictability of tazobactam effectiveness against beta-lactamases and ESBL producing strains, and lower-than-proposed interpretive criteria.

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

7.3 Quality Basis for Decision

The Chemistry and Manufacturing information submitted for Zerbaxa has demonstrated that the drug substances (ceftolozane sulfate and tazobactam sodium) and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf-life of 30 months is considered acceptable when the drug product is stored under refrigeration at 2 to 8°C and protected from exposure to light.

Proposed limits of drug-related impurities are considered adequately qualified; that is within International Council for Harmonisation (ICH) limits and/or qualified from toxicological studies.

All sites involved in production are compliant with Good Manufacturing Practices.

All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The excipients used in the drug product formulation are not of animal or human origin.

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