Products

Date: 2017-10-02

Type of information: Acceptation for review of a sNDA

Product name: Avycaz®/Zavicefta®

Compound: ceftazidime-avibactam

Therapeutic area: Infectious diseases

Action mechanism:

• antibiotic/cephalosporine/beta-lactamase inhibitor. Avycaz® consists of a cephalosporin (ceftazidime), an established treatment for serious bacterial infections, and a next generation non-beta lactam beta-lactamase inhibitor (avibactam).  The addition of avibactam protects ceftazidime from being broken down by beta-lactamases that are produced by resistant bacteria.
• Avycaz® has demonstrated in vitro activity against Enterobacteriaceae in the presence of some beta-lactamases and ESBLs of the following groups: TEM, SHV, CTX-M, Klebsiella pneumoniae carbapenemase (KPCs), AmpC and certain oxacillinases (OXA). Avycaz® also demonstrated in vitro activity against Pseudomonas aeruginosa in the presence of some AmpC beta-lactamases, and certain strains lacking outer membrane porin (OprD). Avycaz® is not active against bacteria that produce metallo-beta lactamases (MBLs) and may not have activity against Gram-negative bacteria that overexpress efflux pumps or have porin mutations.
• Ceftazidime and avibactam is being jointly developed with AstraZeneca . Allergan holds the rights to commercialize ceftazidime and avibactam in North America , while AstraZeneca holds the rights to commercialize the combination in the rest of the world.

Company: AstraZeneca (UK) - Forest Laboratories (USA - NJ), an Actavis' subsidiary (Ireland), now Allergan (Ireland)

Disease:

• complicated intra-abdominal infections (cIAI), in combination with metronidazole
• complicated urinary tract infections (cUTI), including kidney infections (pyelonephritis)
• hospital-acquired pneumonia (HAP), including ventilator-associated pneumonia (VAP)

 

Latest news:

• • On October 2, 2017, Allergan  announced the FDA  has accepted a supplemental New Drug Application (sNDA) for  Avycaz® (ceftazidime and avibactam) for priority review. The sNDA filing seeks to expand the current indications for  Avycaz® to include hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/VABP) in adult patients based on positive results from a Phase 3 clinical trial evaluating Avycaz® for the treatment of patients with HABP/VABP. The FDA granted priority review status to the application based on the previous Qualified Infectious Disease Product (QIDP) designation for  Avycaz® and is expected to take action on the filing in the first quarter of 2018. Pending the sNDA approval, this will be the third indication for Avycaz®. Avycaz®  was first approved in Feburary 2015 in the U.S. for the treatment of adult patients with complicated intra-abdominal infections (cIAI), in combination with metronidazole, and complicated urinary tract infections (cUTI), including pyelonephritis, caused by designated susceptible bacteria, including certain Enterobacteriaceae and Pseudomonas aeruginosa. This application seeks to add a new indication in the label based on favorable results from a pivotal Phase 3 study evaluating the efficacy and safety of Avycaz® for the treatment of adult patients with HABP/VABP. The multicenter, randomized double-blind REPROVE study demonstrated the non-inferiority of Avycaz® to meropenem with regard to the FDA primary endpoint, 28-day all-cause mortality in the ITT (intent-to-treat) population, and Avycaz® was also non-inferior to meropenem with respect to the key secondary endpoint, clinical cure at the test of cure (TOC) visit in the ITT population. In a subset of patients infected with Gram-negative pathogens producing certain ESBL group and AmpC beta-lactamases, the clinical and microbiological cure rates were similar to the overall results. In the study, the overall safety profile observed for Avycaz® was consistent with the current product labeling.
• • On January 30, 2017,  Allergan announced the FDA has approved the company's supplemental New Drug Application (sNDA) to update the label for Avycaz®( ceftazidime and avibactam) with clinical data from two Phase 3 trials supporting the indication to treat patients with complicated urinary tract infections (cUTI), including pyelonephritis, caused by designated susceptible Gram-negative microorganisms. In Trial 1, known as RECAPTURE,  Avycaz® was non-inferior to doripenem with regard to both primary endpoints. In Trial 2, known as REPRISE, Avycaz® demonstrated a higher combined clinical and microbiological cure rate vs. best available therapy (BAT), including meropenem, imipenem, doripenem, and colistin. Additionally, both trials included a subset of patients with infections caused by pathogens producing certain ESBL groups and AmpC beta-lactamases in which the clinical and microbiological cure rates were similar to the overall results. RECAPTURE results: In this pivotal multicenter, double-blind, Phase 3 study of 1,020 adults hospitalized with cUTI, Avycaz® was non-inferior to doripenem with regard to both primary endpoints (patient-reported symptomatic response at Day 5 and combined patient-reported symptomatic response and microbiological cure at the Test of Cure [TOC] visit) in the microbiologically modified intent-to-treat (mMITT) population. The symptomatic response rate at Day 5 in the Avycaz® treated patients was 70.2% (276/393) compared to 66.2% (276/417) in doripenem treated patients, a treatment difference of 4.0% (95% confidence interval [CI]: -2.4, 10.4). The combined symptomatic and microbiological response rate at TOC in the Avycaz® treated patients was 71.2% (280/393) compared to 64.5% (269/417) in doripenem treated patients, a treatment difference of 6.7% (95% CI: 0.3 to 13.1). Avycaz® was effective in treating a subset of 75 cUTI patients infected with CAZ-NS pathogens. Additionally, in a subset of patients (n= 86 in the Avycaz® group) with infections caused by pathogens producing certain ESBL groups (e.g. TEM-1, SHV-12, CTX-M15 and OXA-48) and AmpC, the microbiological and clinical cure rates were similar to the overall trial results. REPRISE results: In the multicenter, open-label, Phase 3 study of 305 patients with cUTI caused by ceftazidime non-susceptible Gram-negative pathogens, the combined clinical and microbiological cure rate at Days 21 to 25 in the mMITT population was higher in Avycaz®-treated patients than in patients on BAT. The combined cure rates were 70.1% (101/144) for patients treated with Avycaz® and 54% (74/137) for BAT-treated patients, a treatment difference of 16.1% (CI 95%; 4.8 to 27.1). Avycaz® was effective in treating a subset of cUTI patients with pathogens containing certain ESBL groups (including select KPCs and OXA-48) and AmpC beta-lactamases. Clinical and microbiological cure rates in this subset were similar to the overall trial results.
• • On 28 April 2016, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for Zavicefta®, intended for the treatment of complicated intra-abdominal and urinary tract infections, hospital-acquired pneumonia and infections due to aerobic Gram-negative organisms where treatment options are limited. The applicant for this medicinal product is AstraZeneca. The most common side effects are Coomb’s direct test positive, nausea and diarrhoea. The full indication is: “Zavicefta is indicated for the treatment of the following infections in adults :
• • Complicated intra-abdominal Infection (cIAI)
• • Complicated urinary tract infection (cUTI), including pyelonephritis
• • Hospital-acquired pneumonia (HAP), including ventilator-associated pneumonia (VAP)
• Zavicefta® is also indicated for the treatment of infections due to aerobic Gram-negative organisms in adult patients with limited treatment options.
• • On February 24, 2016, Allergan announced the FDA has accepted for filing the company's supplemental New Drug Application (sNDA) for Avycaz® (ceftazidime and avibactam). This filing will add important new clinical data to the current label from two Phase 3 trials evaluating the safety and efficacy of Avycaz®, in combination with metronidazole, for the treatment of complicated intra-abdominal infections (cIAI), including patients with infections due to ceftazidime-nonsusceptible (CAZ-NS) pathogens. The FDA granted priority review status to this application based on the previous Qualified Infectious Disease Product (QIDP) designation for Avycaz®. Allergan expects the Agency to take action on the filing in the second quarter of 2016.
• • On April 23, 2015, Actavis announced that Avycaz® (ceftazidime-avibactam) is now available for ordering by hospitals across the United States. Avycaz®  is indicated for the treatment of adult patients with complicated intra-abdominal infections (cIAI) (in combination with metronidazole) and complicated urinary tract infections (cUTI) including pyelonephritis caused by designated susceptible bacteria, including certain Enterobacteriaceae and Pseudomonas aeruginosa. As only limited clinical safety and efficacy data for Avycaz® are currently available, Avycaz® should be reserved for use in patients who have limited or no alternative treatment options.
• Avycaz® received a priority review and FDA approval was supported in part by the FDA's previous findings of efficacy and safety of ceftazidime for the treatment of cIAI and cUTI. In addition, the contribution of avibactam to Avycaz® was primarily established via in vitro data and animal models of infection. Avycaz® was studied in two Phase II, randomized, blinded, active controlled, multicenter trials, one each in cIAI and cUTI, including pyelonephritis. These studies were not designed with any formal hypotheses for inferential testing against the active comparators. Avycaz® for injection is supplied in single-use, clear glass vials for reconstitution. It is available to hospitals for purchase in cartons of ten (10) 2.5 g vials.
• • On February 25, 2015, the FDA approved Avycaz® (ceftazidime-avibactam) to treat adults with complicated intra-abdominal infections (cIAI), in combination with metronidazole, and complicated urinary tract infections (cUTI), including kidney infections (pyelonephritis), who have limited or no alternative treatment options. Avycaz® is the fifth approved antibacterial drug product designated as a Qualified Infectious Disease Product (QIDP).
• The most common side effects include vomiting, nausea, constipation and anxiety. Health care professionals should inform patients of these risks and also advise that decreased efficacy, seizures and other neurologic events were seen in patients with poor kidney function (renal impairment). Serious skin reactions and anaphylaxis may occur in patients with penicillin allergies.

Patents:

Submission of marketing authorization application USA :

Submission of marketing authorization application UE:

Withdrawal of marketing authorization application USA:

Withdrawal of marketing authorization application UE:

US authorization: 2015-02-25/2017-01-30

UE authorization: 2016-06-28

Favourable opinion UE: 2016-04-28

Favourable opinion USA:

Orphan status USA:

Orphan status UE:

Pediatric exclusivit _USA:

Pediatric exclusivity UE:

OTC status:

Other news:

Is general: Yes